摘要:

Monoterpenoids 0. H. Grayson University Chemical Laboratory Trinity College Dublin 2 Ireland Reviewing the literature published between January 1985 and December 1986 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 377) 1 Introduction 2 2,6-Dimethyloctanes 3 Irregular Monoterpenoids 4 Menthanes 5 Cineol Derivatives 6 Camphanes and Isocamphanes 7 Pinanes 8 Fenchanes 9 Thujanes 10 Caranes 11 Ionone Derivatives 12 Iridanes 13 Cannabinoids 14 References 1 Introduction This survey covers developments in monoterpenoid chemistry arising after completion of the previous Review,' and includes work published or abstracted up to issue 26 of Volume 106 (1987) of Chemical Abstracts. Trends include the use of monoterpenoids as chiral auxiliaries in synthetic organic chemistry and microbial transformations of common structures to give more highly functionalized substances which are of enhanced economic value.A further development to come must be a solution to the problems of cloning and expression of the gene systems for important flavour and fragrance materials in for example prokaryotic organisms. Reviews have been published on the pharmacology and toxicology of essential oils,2 on odoriferous monoterpenoids on the monoterpene amaroids of members of the R~biaceae,~ on volatile terpenes from yeast^,^ on the microbial trans-formation of monoterpenoids to give intermediates for the fragrance ind~stry,~,~ and on the formation and transform- ations of monoterpenoids by plant cell cultures.8-10 There has also been a substantial review on the biosynthesis of cyclic monoterpenoids.l1 Procedures for the synthesis and purification of several isoprenoid diphosphates have been outlined,12 and the inter- conversion and cyclization of acyclic allylic diphosphates during the biosynthesis of cyclic monoterpenoids in higher plants has been further investigated.13 In an interesting paper there is a discussion of the biosynthesis of mevalonic acid from lysine (principally) rather than from acetate in Halobacterium ~utirubrum.'~ A Japanese review on evolutionary aspects of the mevalonic acid pathway has appeared.l5 All four of the stereospecifically monodeuteriated mevalonolactones (1) have been synthesized.l6 Callus or suspension cultures of Rosa damascena can oxidatively metabolize exogenous monoterpenes at a rapid rate.17 Volatile terpenoids may have effects relating to communi- cation between plants,'* and the role of terpenoids in plant defence has been reviewed.lg The secretion of volatile terpenoids by coniferous trees as a function of temperature has been discussed with respect to fire hazards in plantations,20 and the rate of emission of isoprene from Quercus serrata has been found to exhibit a strong diurnal variation which can be correlated with light intensity.2' The first quantitative rate constants for the reaction of gas-phase hydroxyl radicals with a series of monoterpenoids have been determined,22 and their tropospheric lifetimes with HO' radical NO; and 0 have been estimated.Many interesting papers on essential oil chemistry have appeared in two conference Pr~ceedings.~~.~~ A selection of recent investigations on essential oils includes papers on monoterpene hydrocarbons from the roots of Coleus forsk- ~hlii,~~ monoterpenoids from the roots of Litsea cubeba (Lour.) the essential oil from the leaves of Eupatorium stoechadosum,27 and on the oils from Homalomena occulta Lour.,28 from Siphonostegia chinensis Benth.,29 and from a number of Middle Eastern populations of Artemisia herba- alba.,O There have also been papers on the (different) essential oils from blossoms and bracts of Tilia cordata Mill.,,' from the pericarp of Zanthoxylum zantho~yloides,~~ from the leaves of lodgepole pines (Pinus contorta) grown in dry versus those grown in wet areas,, from various parts of Scots pines (Pinus sylvestris) of differing ages,34 from the needles and shoots of Scots pines grown in various parts of Siberia,35 and from the leaves of Pinus strob~s.,~ The leaf monoterpenes of the long-lived redwood Sequoia sempervirens are of similar composition whatever the position of the leaf upon the tree.37 The compositions of the essential oils from ripe cones of wild and cultivated hops have been e~amined.,~ The wild variety is rich in monoterpenes whereas the cultivated form produces a greater proportion of sesqui- terpenes.The volatile constituents of Teucriumpolium have been identified and q~antified,,~ as have the monoterpene hydro- carbons from Cymbopogon martir~ii.~~ Seasonal variations in the oil of Cymbopogon parkeri which is rich in geraniol and nerol have been st~died.~' The monoterpenoids of some Rhododendron species have been examined,42 and reviews on the essential oils of Rosmarinus oj'icinali~~~ and of rose jasmine lavender and pelargonium plants44 have been pub- lished.The seasonal dynamics of the monoterpenes of Citrus limon have been determined.45 An article46 discusses the genetic basis for the isopinocamphane (rather than the p-menthane) chemotype of Mentha citrata hybrids. The monoterpenoids of grapes and grape products continue to attract interest. Various cultivars of Muscat grapes can be grouped on the basis of their monoterpene composition~,~~ and phases in the development of free and glycosidically bound monoterpenoids can be di~tinguished.~~ In some white grape varieties the free terpenes are associated mainly with the skin.4g High concentrations of glucosides occur in Muscat grapes during growth the free terpenes not becoming prevalent 419 17-2 NATURAL PRODUCT REPORTS i988 Ph 0 2 AcO A SPh (4) (6) C02Me4 $C02Me (7) (10) e (13) R = 0 0fl f (11) (14) (15) R = H,OH R = H.OAc HOzC DOH (19) R =H (20)R =(j-~-Glc until after the fruit reaches commercial maturity.50 These terpenol glucosides are important aroma factors in wine- making,51 and the effects of grape maturity and of juice treatments on them have been There have been reviews on the volatile terpenoids of wine and grape-juice aroma^,^^-^^ on the role of monoterpenoids and their glucosides in wine flavo~rs,~~,~~ on the general subject of terpenes in grapes and wines,58 and on their analysis.59 A capillary gas chromatography method for the determination of terpenes in wine has been described,6" as has a method for the rapid analysis of free and potentially volatile monoterpenoids in grapes.61 Several routes to useful functionalized isoprenes have been described.The reaction of isoprene with dioxygen in the presence of tetraphenylporphinatomanganese(11) yields di-methylallyl alcohol (2),62and dimethylallyl acetate can now be easily converted into the mono-epoxide (3).63 The highly oxygenated isoprene derivative (4) has been ~ynthesized,~~ and there are two good methods for obtaining the isoprenoid chiron (5).65 Other compounds whose uses have been investigated include the sulphide (6)66 and the allylic borane (7) which can be employed to isoprenylate carbonyl function^.^^ The cyclo- pentenes (8) and (9) have both been synthesized from iso- prene.68 There have been reviews on the synthesis of optically active cyclopentanoids from lim~nene,~~ on the synthesis of tetra- methylated monoterpenoids 70 on syntheses of geraniol citro- nellol and menthol for perfumery purposes,71 on the synthesis of monoterpenoid ketones,72 on the Kondakov acylation of monoterpenes 73 and on synthetically useful solvolyses of terpenoid allylic halides.74 Prins reactions with various mono- terpene hydrocarbons have been described. 75 as have experi- c +OR (21) R =H (23)R =Et mental details for the reduction of a number of @-unsaturated aldehydes and ketones (for example of carvone to dihydro- carvone) by using sodium hydrogen tell~ride.~~ Physicochemical measurements of a number of monoter- penoids and essential oils have been made77 and there have been reviews on physicochemical methods for the analysis of essential on the use of similarity indices for comparing spectral data in the gas-chromatographic-mass-spectrometric analysis of mon~terpenoids,~~ on headspace analysis of volatile components from fragrant sources,a0 and on the high-resolu- tion gas-chromatographic-Fourier- transform infrared-spectro- metric analysis of volatile terpenoids.81 Conditions for the separation of monoterpene hydrocarbons by gas chroma- tography have been optimized,82 and there has been a paper on the theory and practice of the steam-distillation of essential 0iis.83 The unusual hydrocarbon (10) has been isolated from Matricaria chamomilla .84 2 2,6aDimethyloctanes The new dioxabicycloheptane (1 1) has been isolateda5 from the volatiles of Granny Smith apples.A precursor of (1 1) may be 2-methylhept-2-en-6-one (1 2) which is an oxidation product of farnesene. The oxygenated tetrahydropyrans (13)-( 15) have been found in oils from Tanacetum boreale and Ajania fasti- giata.86The alcohol (14) is predominant in both cases.The novel unsaturated lactone scobinolide (16) has been obtained from cultures of the fungus Psathyrella s~obinacea.~' Arternisia santolinifolia has yielded88 the new linal-8-oic acid (1 7) and the basidiomycete fungus Gloeophyllum odorata CBS 444.61 pro-duce~~~ the methyl ester (18). 4-Hydroxygeraniol (19) and its NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON 421 POH 0Q HOT O H (28) R = H (30) (29) R =Ac Po CCHO$HO (33) R =OCHO (34) R =OC(O)BU' (35) R =OC(O)Bu' (36)R =OCH*Ph (37) R =OH glucoside (20) have been obtained from the rhizomes of Rhodiola rose^.'^ The diols (21) and (22) occur in wines and the derived ether (23) has now been isolated and characterized. Myrcene (24) together with limonene is a major component in hexane extracts of dried Clausena anisata (Willd.) Oli~.'~ The myrcene content of hop oil increases rapidly during the growth of inflorescence^.^^ cis-p-Ocimene (25) and dihydrotagetone (26) make up 40 YOand 18 YO,respectively of the oil of Tagetes rnin~ta,'~and dihydrotagetone comprises more than 80 YOof the essential oi! of Costa Rican Tagetes microglossa Benth.s5 Citronellol (27) is partly responsible for the rosy fragrance of flowers of Paeonia albz~7ora,~~ and it is also present at high concentrations in the grappa from Muscat grapes.97 The essential oil of Chinese Cinnamornurn porrectum is 95 YO linalool (2QSs and the same alcohol has been found in an oil from Satureja visianii Silic'' and in an ether extract of the flowers of Gardenia tahitensis.'OO The derived acetate (29) has been isolated from oils of Asarurn canadense,'"' Thymus praecox subsp.arcticus,lo2 and Salviu d~minicu,'~~ the last of these yielding the optically pure (-)-form. The new diols (30) and (31) have been shown to be original to the must and to the wine from Morio-Muscat grapes,1o4 but two groups have ~ho~n~~~-'~~ that the fungus Botrytis cinerea can produce them from linalool (28). The (E)-isomer (30) is the major product of this biotransformation. A strain of Pseudornonas fluorescens has been isolated which utilizes linalool (28) as its sole source of carbon and of energy.lo7 This ability can be encoded on to a transmissible plasmid and then transferred into other strains to give organisms that are useful in treatment of waste waters.6,7-Epoxy-6,7-dihydrolinalool(32) and several derived oxy- genated compounds have been isolated from the fruit of Carica papaya.'08 Some of the major contributors to the volatile flavour components of flowers and berries of elder have been identified as pyranoid and furanoid linalool oxides. log Geranyl formate (33) has been found in the oil from palmarosa grass (Cymbopogon martini-motia). Geranyl iso- valerate (34) comprises 30 O/O of the essential oil from Matricaria matricarioides,"' and the same ester together with myrcene (24) has been found in the aerial parts of Russian specimens of Matricaria discoidea DC.Il2 Geranyl pivalate (35)is oxidized at C-8 or C-9 by a Corynebacterium species as is the benzyl ether (36).lI3Several immobilized microbial and mammalian lipases catalyse the esterification of geraniol (37) to its isobutyrate or laurate esters in heptane as the s01vent.l~~ Geraniol (37) is a major terpenoid contributor to the aroma of Dagestani champagnes.'l5 When wine is deacidified by using calcium carbonate the change in pH leads to increased concentrations of geraniol(37) nerol(38) and citronellol(27) all of which are essential to the specific aroma of Morio-Muscat and Gewued- durztramiper grape varieties. The effect is due to enhanced enzymic hydrolysis of the corresponding glucosides. 116 Immobilized (pelletized) Ceratocystis moniliforrnis produces nerol (38) geraniol (37) and citronellol (27) in low yields.'17 The sequence geraniol (37) -+ citronellol (27) -+citronella1 (39) has been established to occur in Cymbopogon winterianus by labelling experiments.118 Geraniol (37) is converted into geranial (40) with loss of its I(pro-lS)-proton in the leaf blades of the lemongrass Cyrnbopogonflexuos~s.~~~ Nerol (38) similarly yields neral (41) with loss of its l(pro-1R)-proton. A cyclase which effects the conversion geranyl diphosphate -+ NATURAL PRODUCT REPORTS 1988 (yHO 0!? (43)R =H (44) (86) R =Ac p0 0 $OH (45)R =Me (47) (46) R =OEt 0$ (54) fSiMe3 (59) R=O (-)-bornyl diphosphate has been identified in a soluble enzyme preparation from Tanaceturn vulgare. 120 The presence of P-cyclocitral (42) in lake water has been correlated with high densities of freshwater phytoplankton of the genus Microcystis.12' There have been reviews on the industrial synthesis of dehydrolinalool (43) (E/Z)-citral (40/4 l) linalool (28) and geraniol (37),12 and on the synthesis of tagetone (44) and dihydrotagetone (26).123 A careful study has been made of acid- catalysed rearrangements solvolyses and cyclizations of linalool geraniol nerol and their derivatives and this work has been published in a paper124 which contains much of bio- organic and biosynthetic interest.Myrcene (24) yields the addition products (45) or (46)when it is irradiated in the presence of pentane-2,4-dione or ethyl 3- oxobutanoate re~pective1y.l~~ The reaction of myrcene with trichloroacetic acid followed by hydrolysis gives a-terpineol (47) as the major product in all solvent systems that have been POH (55) (64) X = S examined.'26 Myrcenol (48) is a minor product in these reactions but it can be obtained efficiently by treating',' the allylic amine (49) with for example {Pd(~3-C3H5)(Ph,P[CH2]4-PPh,)}' ClO,.The sultone (50) can be converted into the dienol(5 1).128 Dehydrohalogenation of the allylic chloride (52) using NaOH Pd(PPh,), and Bu,NCl leads to the tetraene (53).129 A mixture of (E)-and (3-ocimenones (54) gives filifolone (59 together with isopiperitenone (56) when it is treated with aluminium chloride. Heating (54) in the presence of hydroquinone leads to the Diels-Alder dimer (57).130 Syntheses of both (-)-karahana ether (58) and (-)-karahana lactone (59) have been described.131 The natural ether (58) has consequently been shown to be almost racemic.131 Racemic karahana ether (58) has also been synthesized starting from the epoxygeranic acid derivative (60).132 Neither karahana ether (58) nor hop ether (61) is a major flavour constituent of beers.133 Syntheses of pyrocin (62) rosefuran (63),135and rosethiophene (64)136have been reported.Rosethiophene has NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON HO I OAc (67) (68) pRfR (70) R =OAC (71) R =OAC (72) R=OAC (75) R =SMe (76) R =SMe (77) R =SMe Me,+ 4 S (73) R=OAC (78) R =SMe (74) (79) (80) tNCOHMe y2Me (83) koH been converted into the alcohol (65) which is a potential precursor of homogeraniol.136 Stereochemically pure perillenal (66) has been prepared,13' and arnebinol (67) has been ~ynthesizedl~~ via cyclization of the geranyl derivative (68). The reaction of the sulphonium perchlorate (69) with isopentenyl acetate in the presence of a base gives the prenylated derivatives (70)-(73) in a combined yield of 24%. The salt (74) undergoes a related intramolecular prenylation reaction to give (75)-(78) in similar amount.139 Members of the same research group have been able to prenylate the dinitro- phenyl ether (79) with 3-methylbut-1-en-3-01 in the presence of HX to give the C, ethers (8O).l4O An unusual and interesting reaction has been reported141* 142 [structure (86) is with (4311 in which the N,N-digeranylethanolamine(8 1) is converted into the alkyne (82) with NaNO and aqueous AcOH.The nitroso- compounds (83) and (84) are minor products of the reaction. Citronellol (27) similarly gives the alkyne (85) (in 95 YOyield!) and the hydroxyl group can be dispensed with (if desired) without affecting the outcome of the tran~formation.~~~ Asymmetric syntheses of enantiomerically pure (+)-(S)-and (-)-(R)-linalool have been de~cribed,'~~ as has a new route to the racemate of this The effects of alloy phase changes on the selectivity of hydrogenation of dehydrolinalool (43) to linalool (28) over Pd-Ru catalysts have been investi- gated.146 Dehydrolinalyl acetate (86) undergoes electrochemical oxidation to the ketone (87) via formation of the 6,7-epoxide NATURAL PRODUCT REPORTS 1988 (87) R =Ac (90) (89) R =H OH 5 coHroH CHO (91) (92) (93) RR b, Q-30%" QHO 'OH A // (-) -(94) R=H (95a) R=Me (96a) R=Me (97) (296) R =Ac (95b) R=H (96b) R=H $-OH roH (98) (99) 0' (88).The hydroxy-ketone (89) derived from (87) yields karahanaenone (90) when it is heated to 200 OC.14' In an important paper,148 Noyori describes the formation of optically active citronellols (27) by the asymmetric hydro- genation of geraniol (37) or of nerol (38) using chiral BINAP-rhodium(1) catalysts. A large-scale preparation of (-)-($)-citronello1 [the enantiomer of (27)] of 96 % enantio-meric excess (e.e.) has been 0ut1ined.l~~ (+)-(R)-Citronellol (27) yields the hydroxy-aldehyde (9 1) when it is oxidized with selenium dioxide and this compound is reduced by Saccharornyces cerevisiae to the (3R,7S)-form of the saturated diol(92).(-)-(9-Citronellol similarly affords the (3S,7S)-isomer of (92). Both diols are obtained in enantio- merically and diastereomerically pure form and are useful chiral intermediate^.'^^ The P-D-glucopyranosides of (-)-(s>-citronellol (93) and of (-)-(R)-linalool have been synthesized from these alcohols by using acetobromoglucose in the presence of silver silicate. 151The 0-P-D-glucosides of citronellol geraniol and nerol have been prepared15 in good yields and their spectroscopic characteristics have been recorded. The Schiff base that forms from citral (40/41) and (+)-ephedrine can be catalytically reduced to give after acid hydrolysis optically active citronellal (39).153 The selectivity of the catalytic reduction of citral(40/41) to citronellal (39) (using cyanoethylenediaminocobalt in water-methanol mixtures) de- pends critically on the ratio of the components of the solvent system and reaches 99 YOwhen this is 2 :1 It has been shown that Ru/TiO catalysts are more reactive and selective towards hydrogenation of the C=O rather than the C=C bond in citronellal than are Ru/SiO or Ru/C Citronella1 (39) forms a 1 1 complex with trimethyl-aluminium which cyclizes cleanly to isopulegol (94) when a solution in 1,2-dichloroethane is warmed. Mixtures of products are formed if other solvents are used while use of other trialkylaluminium reagents (for example Et,Al or Bu3Al) gives mainly citronellol (27).15'j It is clearly advantageous to make a careful search for optimum conditions when examining reactions of this type.The 3-methylcitronellal (95a) cyclizes to give methylisopulegol (96a) of 90% e.e. when it is allowed to react with the chiral BINAP-zinc complex (97).157,158 Inter-estingly the nor-derivative (95b) cyclizes to the analogous racernic alcohol (96b) under the same condition^.'^^ Linalool (28) is oxidized by either the MoV1 or the Wv' oxodiperoxohexamethylphosphoamido-complexesto give the 6,7-epoxide (32) but geraniol (37) yields the 2,3-epoxide (98) with these reagents. 159 The catalytic epoxidation of geraniol (37) to the 2,3-epoxide (98) using polymer-supported molyb- ,denum(vr) and vanadium(v) complexes has been exarninedl'j' and a comparison has been made of the catalytic activities of Ti(OPr')? Ti(O)(acac), and Ti(O)(tpp) [tpp = tetraphenyl-porphyrinato] towards the epoxidation of geraniol with t- butyl hydroperoxide.161 The porphyrin-based system gives exclusively the 2,3-epoxide (98) while the other catalysts lead to mixtures which contain ca. 20% of the 6,7-epoxide (99) in 425 NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON qHH OH roR (102) R = tetrahydropyran -2-yi (103) (115) R =CH=CH2 03SCF3 LOH 'CHO (105) (106) R = OAC (107) R'= R2=OH (108) R = COzMe (109) R'=R2= CO2H (114) (112) (113) [structure (115) is with (10211 PCH0POHPOH (116) 0 0 0 (120) x =o (121) X =CHC02Et addition to (98).161 The neryl epoxide (100) has been converted into the ester (101) which is a component of a pheromone of the scale insect Quadraspidiotus perniciosus Comstock.162 Geranyl tetrahydropyran-2-yl ether (102) is hydroboronated to give after oxidation and hydrolysis an 85 :15 mixture of the triols (103) and (104); these have been utilized in a synthesis of A part of an antibi~tic.'~~ photochemical step has been employed in a new synthesis of (2E,6E)- 10-hydroxygeraniol (105).164 Reduction of the acetoxy-aldehyde (106) with bakers' yeast followed by further processing of the product yields the (7S)-diol (107) which is secreted by male Danaid butterflies. The aldehydo-ester (108) similarly gives the (7S)-dioic acid (109) this being a pheromone of the azuki bean weevil (Callosobruchus chinensis).165 Compressed monolayers of geraniol (37) or of nerol (38) if held over 50% sulphuric acid are relatively inert to chemical change. However expanded monolayers of nerol (38) undergo almost complete cyclization to a-terpineol (47) under this condition presumably via conformers of high energy and low probability. Geraniol (37) yields mainly acyclic products when similarly treated.166 The mononeryl ether of (+)-(R)-1 ,l'-bis-2- naphthol cyclizes to (+)-limonene (1 lo) of 77 % e.e. when it reacts with the aluminium species (1 1 l).167 Geraniol (37) affords a mixture of digeranyl ether (1 12) and the two other ether derivatives (1 13) and (1 14) when it is allowed to reactI6* with isopentenyl acetate in CH3N0 and CF,CO,H.If geranyl vinyl ether (1 15) is heated it yields the Claisen rearrangement product (1 16) which has been converted into a number of analogues of bakuchi01.'~~ Cyclopropanation of geraniol (37) using BuiAI and CHJ, leads to the 6,7-derivative (1 17).170 This result contrasts with the outcome of Simmons-Smith cyclopropanation of geraniol when the 2,3-analogue (1 18) is produced. The latter compound has been used as starting material for the synthesis of a series of juvenile hormone analogues.171 Other juvenile hormone analogues that have been made from geraniol include com- pounds (1 19F(122).172 Geranyl acetate (70) gives a high yield of the dimeric tetraene NATURAL PRODUCT REPORTS 1988 L L/ f PCN (126) R = CL (130) (131) (132) R =OH (127) R = 0 @ (133) R = Ph3P+X-(128) R =O@ (129) R = CH*CH=CHOPh P'""rcHo 0- (135) (123) when treated with zinc in the presence of (PPh,),Pd.173 A study has been made of the influences of leaving groups and the ligands of n-allylpalladium derivatives of geranyl and neryl systems with reference to their substitution reactions with ~arbani0ns.l~~ Some cationic y3-geranyl complexes (124) and y3-neryl complexes (125) of palladium have been synthesized in > 90% isomeric purity and their amination reactions have been A method has been described for the conversion using tris(tetrabuty1ammonium) hydrogen diphosphate of geranyl chloride (126) into geranyl diphosphate (127).176 Geranyl halides or better geranyl phosphate (128) yield the ether (129) when they react with phenoxyallyl-lithium.177 The sulphuric- acid-mediated cyclization of geranonitrile (1 30) to the cyclo- citral derivative (13 I) has been described.17s (137) A process for the synthesis of homogeraniol (132) from geraniol (37) has been fully detailed.179 The homogeranyl phosphonium salt (133) has been utilized in a synthesis of palisadin A.lSo The ether (1 34) undergoes ene-like chlorination with HOCl to give (135) and this is converted into (E/Z)-citral (40/41) when it is treated with (Ph,P),Pd.lsl The sweetener Aspartame reacts with both geranial(40) and neral(41) to give Schiff bases which have been demonstrated to be of low toxicity.lR2 The selective hydrogenation using ruthenium triarylphosphine catalysts of citral (40/41) to give the ap-unsaturated aldehyde (1 36) has been studied.ls3 The 2,3-epoxy-2,3-dihydrocitral (137) condenses with ethyl cyanoacetate to yield the expected product (138) and the related acetal (139) can be converted into the acetonide (140) if it is treated with FeCl in acetone.lE4 427 NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON 0 / ,COzH (141) (142) (143) CO2 Me Me02 C MeOzC C02Me YCHOk/ x (+) -(153) R =H (155)R = SiR'3 (156) R =Me 0 ?SiR; COzMe 0 '+-(157) ( Et Ol2 C$ C02 Me COzMe 3 Irregular Monoterpenoids The flowers of Achillea fragrantissima (Forssk.) Sch.Bip. contain santolina alcohol (141) and artemisia ketone (142).la5 A study has been made of the production of chrysanthemic acid (143) by tissue cultures of Chrysanthemum cinerariaefolium.lE6 The lactone (144) has been made and has been used as a common intermediate for syntheses of (R)-santolinatriene (145) (9-lavandulol (146) (1 S,3R)-chysanthemol (147) and (+)-(1S,2R)-rothrockene (148)lS7 (which has an antipodal relationship to natural rothrockene). A synthesis of lavandulol which employs organo-iron chemistry has been described,lsa as has another route to (+)-lineatin (149).lE9 The resolved dihydrofuran (1 50) yields enantiomerically pure caronic aldehydes (1 5 1) when it is irradiated at 185 nm.lgO The racemic forms of the cis- and the trans-isomer of (151) have again been synthesi~ed,'~' as have the isomeric dimethyl caronates (1 52).lg2 Racemic cis-chrysanthemic acid (1 53) has EtO C02 Me )(\COzMe been stereoselectively prepared via the alicyclic Claisen re- arrangement of (1 54) to the ester (1 55),lg3 and a similar strategy has been employed to obtain (+)-(153).lg4 Stereo- and enantio- selective syntheses of both optical isomers of methyl cis- chrysanthemate (1 56) have been described,lg5 and full details of the microbial route to the (lR,3S)-chrysanthemic acid (153) which begins with the dione (157) have been p~b1ished.l~~ A synthesis of the deuterium-labelled trans-ester (158) is now available.lg7 A review of syntheses of chrysanthemic esters via cyclo- propanation reactions (catalysed by asymmetric copper species) has appeared.lga The reaction of 2,5-dimethylhexa-2,4-diene (159) with ethyl diazoacetate to give the ethyl esters (160) is catalysed by Ar,N+ SbCl; (Ar = 2,4-dibrom0phenyl).'~~ 1,3- Dipolar cycloaddition of dimethyldiazomethane to (2)-and to (E)-6methylsorbates yields chrysanthemic esters,200 and Michael addition-cyclization of the potassium salt of 2-nitro-propane with the ester (161) gives (162) which is a precursor NATURAL PRODUCT REPORTS 1988 (168) E = Me allyl,SMe etc.(169 1 B 9. (173) R =OH (174 1 (191) R=H Qo of methyl chrysanthemate.201Similar methodology has been employed to obtain the cyano-ester (163) from (164).'02 The chloro-ester (165) has been prepared,203and reductive carbonyl-ation of the dibromide (166) [using Ni(CO) and imidazole] yields the lactone (167).'04 Methyl chrysanthemate (156) can be alkylated adjacent to the ester group to give products (168) when LiNPri is used as the base.205The chrysanthemyl acetate (169) gives a mixture of the trienes (170) and (171) when it reacts with allyltri-methylsilane in the presence of TiC1,.'06 4 Menthanes Limonene (110) is the major component of oils from Xanthium ca~anillesii~~~ and from the flowers of Croton zambesicus.208 Several dimers of a-phellandrene (172) have been isolated from the oleorosin of Canarium luzonic~m.~~~ The dienol (173) has been isolated as a natural product for the first time from olibanum and terpinen-4-01 (174) has been found in Curcuma wenyujin.211This alcohol (174) is the most active component of the essential oil of Artemisia vulgaris which is a repellent against the yellow-fever mosquito (Aedes aegypti).212 I R (-) -(182) R = H (183) R =O-P-D-GIC Menthol (175) occurs as its P-glucoside in the leaves of Dalmatian Salvia oficinali~,'~~ and the leaves of Pelargonium tomentosum contain an oil which is 27 % menthone (176) and 61 % isomenthone (177).214A high yield of essential oil ( =-1 ml per 100 grams of fresh weight) is obtainable from Bystropogon plumosus and it is especially rich in p-menthenones and p-menthadienones.215 A review on the monoterpenoid con-stituents of Mentha rotundifolia which is rich in (+)-piperitenone oxide (178) has appeared.Piperitone (1 79) is the major volatile component of Artemisia judaica grown in the Egyptian Both piperitone oxide (180) and piperi-tenone oxide (178) are important in the oil from Calamintha nepeta subsp. glandulosa their relative concentrations de-pending on the maturity of the plant.'18 A decrease in the concentration of (+)-piperitenone oxide (178) followed by the appearance of the (-)-form and then by the formation of (+)-1,2-epoxyneomenthylacetate (1Sl) has been traced during the growth of plants of Mentha rotundifolia (L.) Huds.'19 The essential oil of Ziziphora taurica subsp. taurica is rich in pulegone (182),"O and the new glycosylated hydroxypulegone schizonepetoside C (183) has been isolated from Schizonepeta tenuifolia.221 NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON 4299R 0 (185) R O s/ i0 (189) R =H (186) R =H (190) R = OH (187) R = 02CPh (193) R =OMe [structure (191) is with (173)] (192) (197) R = H (198) R = OH HO OOH -0 % YO The leaf oil of Evodia hortensis contains 64% menthofuran (184).222 The orthoester (185) has been obtained from the oil of Mentha piperita and its structure had been confirmed by its synthesis from (-)-isopulegol (94).223 The new paeonilactones A (186) B (187) and C (188) have been found in the roots of Paeonia albtflora var. tri~hocarpa.~~~ The essential oil of Thymus marschallianus consists mainly of p-cymene (1 89) thymol(l90) and p-mentha- 1 ,4-diene (1 9 1),225 CHO POH (194) (199) CHO I whilst the oils from Ethiopian Thymus schimperi,226 Egyptian Anabasis ~etifera,~~~ and Thymus pastoralis from the Kabar- dino-Balkarsk A.S.S.R.228 consist principally of thymol (190) and carvacrol (192).The carvacrol (192) and p-cymene (189) that are present in oils from Satureja montana may play differing roles in the inhibition of Gram-positive bacteria by this The methyl ether (193) has been found in Eupatorium cannabin~m,~~~other new naturally occurring thymol and derivatives which have been reported include (194) from Pulicuria undulata231 and the aldehyde (195) from the aerial parts of Calea pi10sa.~~~ More highly oxygenated compounds include eupatriol(196) from Eupatorium t~shiroi,~~~ the epoxide (197) from Inula ~rithmoides,~~~ its 10-hydroxy-derivative (198) from Callilepis Iaureola [which also produces (I 99)],235 com- pounds (200)-(203) from Schizogyne gl~berrima,~~~ and (204) from the roots of Piptothrix ~reolare.~~~ The compound (205) has been isolated from the heartwood of Callitris macleayana and may be either a diterpenoid or a Diels-Alder dimer of the dienone (206).238 NATURAL PRODUCT REPORTS 1988 (207) R =p-OH (208) (209) R = ~1-OH (214) (218) (219) p -epoxide I I The application of menthyl derivatives as chiral auxiliaries in organic synthesis continues unabated.A review on the use of 8- phenylmenthol (207) in this context has been as has a paper on the preparation and applications of this compound and its 2-epi-ent-epimer (208).240 A method for separating 8-phenylmenthol (207) from its diastereoisomer (209) which is effective on a large scale has been described.241 The glyoxylate (210) has been used in an ene-reaction in a synthesis of (-)-xyl~mollin,~~~ and the same researchers have studied applications of the corresponding p-fluoro-derivative (21 l).243 Addition of LiAlR to (-)-menthy1 phenylglyoxylate (212) yields menthyl (R)-mandelates (21 3).244 The lithium enolate (214) undergoes Michael addition to methyl but-2-enoate to give the threo-compound (215) as the major diastereoi~omer.~~~ The dienolate (21 6) which can be derived from di-( -)-menthy1 succinate reacts with bromo- chloromethane to form the dimenthyl trans-cyclopropane- 1,2- dicarboxylic acid (2 17) stereoselectively.246 When the mixture of epoxy-ethers (218) is treated with SnCI, the a-epoxide undergoes cyclization reactions and the p-isomer (219) of 60% e.e. can be recovered from the reaction The cycloaddition of the N-sulphinylcarbamate (213) R = alkyl OLi (216) R =(-)-menthy1 (217) R = (-) -menthy1 I (226) R =Me,Et or Pri (220) of 8-phenylmenthol to for example (2E,4E)-hexa-2,4- diene in a reaction that is catalysed by SnCl, gives the 3,6- dihydro- 1,2-thiazine 1-oxide (221) with good stereoselectivity at each of the three newly formed chiral The enantio- selectivity of the reaction of the diastereoisomeric dimenthyl tartrates towards salts of a-amino-alcohols has been studied and based on this chemistry a method has been developed for flash-partition-chromatographic separation of for example the enantiomers of n~rephedrine.~,~ The chiral borinic ester (222) can be obtained from (+)-menthol [the enantiomer of (1791 and 9-borabicyclo[3.3.I]- nonane (9-BBN). The reaction of (222) with potassium hydride gives the hydrido-derivative (223) which reduces acetophenone to afford a 90 YOyield of (9-1-phenylethanol of 12 YOe.e.250 The reaction of the N-menthylketenimine (224) with dimethyl- sulphonium methylide followed by acidic hydrolysis gives optically active methyl ketones. 251 When (-)-menthy1 phenyl- acetate (225) reacts with alkyl methanesulphonates (alkyl is Me Et or Pr') at a platinum cathode electrolytic asymmetric alkylation takes place to give the products (226) in optical yields of 1-22 The spectroscopic characteristics of the P-epimers of chloro- NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON 43 1 bPCI2 i\ 'Ph (227) R= nil (228) R=S 8 Q (231) (232a) R' =H,R2=OH (234) (235) (232b)R' =OH,R~=H (233) R'R*=O I I SnR, QNHAc n1 PSnR39 (236) (237) (238) R = Me or Ph (239) R=Me or Ph EtOzC P RoVoH A (245)R = Ac or Bn (+I (-)-menthyl(pheny1)phosphine (227) and of (-)-menthyl-(pheny1)thiophosphoryl chloride (228) have been recorded and analy~ed,~~, and both the (-)-and the (+)-form of dichloro- (menthy1)phosphine (229) have been synthesized and studied. 254 X-Ray and other spectroscopic studies have been made of (R,)-t-butyl(menthy1)thiophosphoryl (+)-p-Menth-1-ene (230) has been converted into the bromo-alcohol(231) and into the alcohols (232) and the ketone (233).256 The menthenes (230) and (234)-(236) all yield the 7-acetamido-derivative (237) when they undergo the Ritter reaction with MeCN and H2S0,.257The menthylstannanes (238) and (239) have been synthesized and their substitution reactions have been Several p-menthenols have been dehydrated over A120 to give mixtures of p-menthadienes and the relative amounts of these products have been correlated with their calculated heats -(246) (-1 -(247) of formation.259 If for example a-terpinene (240) is heated to 250 "C over A120, a mixture of all nine possiblep-menthadienes is formed.260 The reaction of a-terpinene (240) with ethyl diazoacetate to give (241) is catalysed by Ar,N+ SbC1; (Ar = 2,4-dibromophenyl).lg9 The photo-oxygenation of (R)-p-mentha-3,8-diene (242) has been applied261 in syntheses of (+)-(R)-menthofuran (184) and of (R)-evodone (243).Both (+)-(R)-menthofuran (184) and the (+)-trans-p-menthenolide (244) have been synthesized from (-)-isopulegol (94).262 (+)-(R)-Limonene (1 10) has been converted into the hyd- roxy-esters (245) which can be precursors of various steroidal ~ide-chains.~~~ The sesquiterpene hernandulcin (246) which has an intensely sweet taste has been synthesized from (+)-limonene (1 as has (-)-isohomolavandulol (247).265 (+)-Limonene (1 10) can be hydroxylated on a large scale (262) a-epoxide (264) (265) (263) p -epoxide using Diplodia gossypina to give the diol (248),266 and a further publication gives additional details of this transformation together with information on the use of Corynespora cassiicola to carry out the same reaction.267 Limonene (1 10) gives mainly the trans-dichloride (249) when it reacts with gaseous hydrogen chloride in CH2C1 at -3 0C.268 Optimized conditions for the conversion of limonene (1 10) into trans-carvyl chloride (250) using t-butyl hypochlorite as the reagent have been devised.269 Other minor products of this reaction include the chloro-compounds (25 1)-(254).Radical species do not appear to be involved in the reaction pathway. The autoxidation of (+)-limonene (1 10) at increased oxygen pressures in the presence of Co(OAc) * 4H,O and Ac,O leads to mixtures which are rich in carvone (255).270 When (+)-limonene (I 10) is exposed to an oxygen plasma discharge (-)-menthone (176) is formed.271 a-Terpinene similarly gives a carvomenthone (256) and p-mentha- 1,4-diene (19 1) yields the unsaturated alcohol (257).271 NATURAL PRODUCT REPORTS 1988 (260) X=Sn (261) X=Si Irradiation of (f)-limonene and Fe(CO) in benzene solution gives the complex (258) which is transformed into the a,n-allyl complex (259) after further photoly~is.~~~ The stannyl- and silyl-limonenes (260) and (261) have been ~ynthesized.~'~ The stereochemistries of the individual 8,9-epoxy-p-menth- 1-enes (262) and (263) which are derived from (+)-limonene (110) by metabolism in the human liver have been un-ambiguously determined.274 The 1,2-epoxy- 1,2-dihydrolimon- ene (264) is isomerized by activated carbon to a mixture which consists mainly of the menthenone (266) carvacrol (192) and p-cymene (1 89).275 Terpinolene oxide (267) has been converted into a series of acetals (268) which are potentially useful as aroma chemicals. 276 The Diels-Alder reaction of butadiene with (E)-but-2-enal yields (269) which has been sequentially converted into the o-menthenol (270) and the o-menthadiene (271).277 o-Mentha- 1,4-diene (272) gives a mixture that contains many of its isomers when it is heated over kieselguhr at 270 0C.278 NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON 433 0 0 I OOH OH &OH OH (276) (277) R' = Hg0Ac,R2=H (279) R' = HIR2= HgOAc (280) R'=R~=H d HOSrnC1 3--( OH 6 POR (281) R1= Me,R2= H (-) -(283) R=H (284) R =H ,*-;+' (287) (282) R' =H,R2=Me (285) R =CH2Ph Me02C 6.[structure (296) is with (9411 CI (294) R' =OH,R2=H (295) R'R2=0 Statistical methods have been applied in a study of optimization of processes for the catalytic reduction of a-terpineol (47).," When a-terpineol is ozonized and the product then acidified and steam-distilled the dienone (273) is obtained. This is rapidly oxidized in air to give the hydroperoxide (274).280 The absolute configurations of both diastereoisomers of uroterpenol (275) have been assigned281 (cf. ref. 274). Oxy- mercuration of the rn-menthenol (276) gives the derivatives (277) and the isomeric menthenol (278) yields (279) under the same conditions.Both (278) and (279) are reduced by sodium borohydride to give the rn-cineol (280).282 Terpinen-4-01(174) is a quality factor in gin; both (174) and a-pinene can be detected by U.V. analysis at 210 nm.283,284 Reduction of terpinen-4-01 (174) using H and Pd/C gives a mixture which contains 80 YOof the trans-p-menthanol (28 1) and 20 YOof the cis-isomer (282). When [Ir(cod)(Pcy,)(py)]+ PF,- is used as the catalyst hydrogen is delivered exclusively from the hydroxyl-bearing face of the molecule to yield solely the cis-p-menthanol (282).285 cis-Carveol (283) and its trans-epimer (284) react with benzyl alcohol in the presence of samarium trichloride to give a mixture of the epimeric benzyl ethers (285) and (286).These (286) R = CHzPh /OR QSASMe (297) (298) R = H (300) (299) R = C(S)SMe were found to be racemic suggesting the intermediacy of the symmetrical ion (287) in the reaction.2ss The allylic silane (288) derived from cis-carve01 (283) reacts with dimethyl benzylidenemalonate under PdO catalysis to give the cis bicyclic diester (289) as the major product. The analogous allylic silane derived from trans-carveol (284) similarly yields largely the trans-diester (290). Both (289) and (290) were obtained as racemates due to the intermediacy of the species (29 1).287 Oxymercuration4emercuration of ( -)-cis-carveol (283) yields (-)-pin01 (292) together with some of the tricyclic ether (293). 288 (-)-Isopulegol(94) reacts with hypochlorous acid to give the ene product (294).This can be oxidized to the corresponding ketone (295) which gives (+)-menthofuran (184) when it is treated with triethylamine or heated. ( -)-Isopulegyl acetate (296) is hydrolysed by Rhodotorula rnucilaginosa or by some Bacillus species to give (-)-isopulegol (94) of 97.6 YOoptical purity. The (+)-enantiomer of (296) is very little affected under these conditions and ( + )-neoisopulegyl acetate (297) is inert.290 Perillyl alcohol (298) has been converted into its xanthate ester (299) which undergoes thermal sigmatropic rearrangement to give (300). Irradiation of (300) yields a NATURAL PRODUCT REPORTS 1988 Q (301)n= 1 (303) P-OH (302)n =2 (304)CX-OH (308) 6..(311) R = OAc,CI,N3,etc. I (313) (314) (317) mixture of the menthadienyl thioether (301) and the related disulphide (302).291 The electronic structures of piquerol A (303) and piquerol B (304) have been the subject of theoretical calculations.292 A review on the synthesis and the sensory characteristics of the enantiomers of menthol has been and methods for the preparation of pure menthol and menthone isomers have been described.294 The 13C n.m.r. spectra of eight dihydroxy- and of seven trihydroxy-p-menthanes and of their acetates have been a~signed.”~ The conformations of the cis- and the trans-isomers of the 8-hydroxy-p-menthane (305) and the 8-hydroxy-o-menthane (306) have been studied by ‘H and 13C n.m.r.Racemic menthyl acetate (307) can be stereospecifically hydrolysed to give (-)-menthol (175) by using Bacillus subtilis; a reactor in which this process can be carried out has been described.297 (-)-Menthol (175) can be induced to react with MePhAsNEt to give a mixture of diastereoisomeric arsinites. These react with sulphur at 115 “C to give a mixture of diastereoisomeric 9OA b’ (307) .. I ‘#Me R -AS‘ ’Ph (309) (310) ! (312) Ar = Ph or p-MeOC6H4 +-NO N=O -AI Me 3 CI CL (316) thioarsinites (308) which may be separated and individually desulphurized to yield for example the diastereoisomerically pure arsinite (309). The latter reacts with Grignard reagents RMgX with retention of configuration to give the arsine (3 10).298 (-)-Menthol (175) can be converted into the (+)-neo- menthyl derivatives (31 1) by its reaction with ZnX and PPh and Et02CN=NC02Et.299 The hydroxylation of menthols (and of cineols) by rn-chloroperoxybenzoic acid has been investigated,300 and a synthesis of the menthoxy-P-lactams (3 12) has been The epimeric menthones (1 76) have been synthesized from 6-methylhept-5-en-2-0ne.~~~ Oxidation of menthone (1 76) with selenium dioxide yields the unsaturated ketone (313).303(+)-Isomenthone (1 77) has been converted into the derivative (3 14) which possesses antimicrobial properties.304 The nitroso-compound (3 15) reacts with hexamethyldialane at -80 “C to give the complex (316) which soon rearranges to (317). When this is hydrolysed the nitrone (318) is The crystal structure of (-)-menthonelactam (3 19) has been determined.306 It has been demonstrated that (+)-cis-isopulegone (320) NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON (320) Po (321) CIQo (323) (324) (325) (326) I P A OMe (331) +OM. (329) (330) (332) (333) p -Me ; P-H (334) a-Me ;a-H I I & A (335) R’ R2=O (339) (336) R’ =oH,R~=H (337) R’ =HI R2=OH &C02Et A (340) R1=a-Me.RZ=P-CH(SPhI2 (343) (341) R1= a-Me R2= a-CH(SPh12 (342) R1= p-Me R2=a-CH(SPh12 and not piperitenone (321) is the key intermediate in the conversion of (-)-isopiperitenone (322) into (+)-pulegone [the enantiomer of (182)] in Mentha ~iperita.~~~ The major insecti- cidal fraction of the oil from Lippia stoechadifolia is a piperitenone epoxide (1 78).308 (+)-Pulegone reacts with hypochlorous acid to give (323) which can be converted into (+)-menthofuran (184) by treating it with triethylamine or with AlC13.2s9 When the pulegone oxime (324) reacts with phenylmagnesium bromide in toluene the aziridine (325) is formed.309 The epoxypulegone (326) (or its epimer) reacts with BF3.Et20 to give a high yield of the cycloheptanedione (327).This reaction proceeds via the intermediate fluorohydrin (328) or its e~imer.~lO A review has been published on the industrial preparation of carvones using fungal The carvone epoxide (329) is a new natural product from Catasetum mac~latum.~~~ Im-mobilized cells of Rhodotorula mucilaginosa convert (+)-carvone (255) into (-)-neoisodihydrocarveol (330).313 (-)-Carvone [the enantiomer of (255)] has been used as the chiral starting material for a synthesis of the sesquiterpene (-)-upia1314 and the (+)-form (255) has been converted into the derivative (33l) which ultimately yields the cembranoid structure (332).315 The Diels-Alder reaction of (-)-carvone with for example isoprene in the presence of AlC1 yields a 9.5 1 mixture of the adducts (333) and (334) which should have applications in sesquiterpene (-)-Carvone reacts with seleno- phenol to give the Michael adduct (339 which can be reduced to the seleno-alcohol (336) and a small amount of the epimer (337).Oxidative fragmentation of (336) yields the carvenol (338).317Reduction of carvone (255) with sodium dithionite under phase-transfer conditions yields the dihydrocarvone (266) cleanly.318 Michael addition of (PhS),CLi to (-)-carvone followed by treatment of the product with s-butyl-lithium gives mainly the dithioacetal (339).This isomerizes when it is treated with a base to give a mixture of (340) and (341). Further treatment of (341) with a base leads to the isomer (342). The structures and conformations of (339)-(342) were deduced by n.m.r. Irradiation of carvone (255) in ethanolic solution using light from a XeCl excimer laser yields the well- known carvone-camphor which is then further transformed into the ester (343).320 NATURAL PRODUCT REPORTS. 1988 0 9.. P? 0. PR s? (344)R = CH2 (346) (345)R =O % Ob0 \ H%H \ Qo A (347) (348) (350) 0 t? 0 $ kc02Hkc02H (352) (353)a-H (354)p -H 4? (359) (360) (362)R =H (367)R =OH @ 9 &OH CHO (363)R1=Me,R2=OH (364) R’ =OH,R2 =Me The epoxy-diene (344) which can be obtained via olefin-ation of the corresponding ketone (345) reacts with CO and {(Pr’O),P}Pd to give the a-carbonate (346).The P-epoxide simi- larly gives the P-carb~nate.~~~ The stereoselective hydrogenation of thymol (190) in both the gaseous and the liquid phase has been studied; various catalysts were Thymol (1 90) yields many products including piperitenone (32 1) and umbellulone (347) when its solution in trifluorosulphonic acid is irradiated.323 Oxidation of thymol (190) with 0 and Co”(sa1en) gives the quinone (348) efficiently; carvacrol (1 92) behaves similarly.324 Previous work on the dimerization of (349) suggested that the indan (350) had been formed but this structure has now been revised to (351).325 A series of isomeric bromoacetylated alprenolylmenthanes have been prepared from the 1,8-diamine (352) and evaluated for adrenolytic Syntheses of mintlactone (353) and of isomintlactone (354) have been The acid (359 derived from limonene (1 lo) cyclizes with H,P04 to give mainly the lactone (356).The isomeric acid (357) yields the lactone (358) under the same conditions. The tetramethyl-limonene (359) gives the hydroxy-epoxide (360) when it is exposed to Gibberella cyanea but the epoxidation reaction is not completely stereospecific.329 Various chemical transformations of (359) have been described,330 and preparative methods for compounds (36 1)-(364) have been published.331 The epoxide (365) gives the ketone (366) and the NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON (370) 250 HOJkX R (373) (+I -(374) R =OAC (-) -(375) R = OAC (376) R =OH (379) R =OH (383) (377) R =OC(O)CH2CHMe2 (382) R = NHAc ( 378) R = p-hydroxycoumaroyloxy (384) R = OPh (432) R = Cl (496) R = OC(O)CF (385) R = I (386) R1 = I .R2=OMe (388) R= Br (387) R' = I ,R2=H (389) R1 = Br,R2= H (390) R = Br R2= Ph (391) R1 = H ~ R2= Ph (392) R' = O-alkyl,R2=Ph allylic alcohol (367) when it is treated with LiC104.332 The reaction of the alcohol (368) with N-lithioethylenediamine at 120 "C converts it into the aldehyde (369).333 5 Cineol Derivatives 1,8-Cineo1(370) is an important monoterpenoid in the essential oils from Artemisia r~tifolia,~~~ from the leaves of Eucalyptus pulver~lenta,~~~ and from Myrci- from Vitex agnus-c~stus,~~~ anthes p~ngens.~~~ The leaf oils of two cultivars of Callistemon viminalis have been examined.Both are rich in 1,8-cineol (370) but one contains much linalool and very little a-pinene or a-terpineol whereas the other contains only a small amount of linalool and substantial amounts of the latter two com-pound~.~~* A total synthesis of 1,8-cineol (370) has been described.339 Treatment of (370) with formic acid in the presence of A-4 or A-5 zeolite gives mainly a-terpineol (47) and P-terpineol (372) is formed when 1,4-cineol (371) is exposed to trichloroacetic acid and A-4 6 Camphanes and Isocamphanes Camphor (373) is a major constituent of the oils from Artemisia nil~girica,~~~ and Santolina chaemae- Achillea ~antolinoides,~~~ cyparissus subsp.~quarrosa.~~~ The last also contains bornyl acetate (374) and isobornyl acetate (375).343 (+)-Bornyl acetate (374) is also prevalent in the leaf oil of Boronia l~tipinna~~~ and in an oil from Guatemalan Juniperus ~omitana.~~~ Of seven species of Parthenium that were studied only the leaf oils from R (393) (394) R = C02Et .CN,C(O)R' ,etc. P. argentatum and P. confertum contained bornyl acetate.34s High levels of oils that contain borneol (376) and bornyl isovalerate (377) as major constituents have been found in the underground parts of Valeriana fedtschenkoi Coincy and V.jicariifolia Bo~ss.~~~ Bornyl p-coumarate (378) has been isolated from the roots of Eupatorium deltoide~m.~~~ Cultured cells of Nicotiana tabacum have been shown to hydrolyse the acetates of (R)-borneol and (R)-isoborneol enantioselectively.349 Brown has commented350 on a rationale for the exceptionally high rate of solvolysis of camphene hydrochloride (380) in the context of studies on the problem of non-classical carbonium ions. (+)-Camphene (381) undergoes a Ritter reaction with MeCN and HClO to give the isobornyl amide (382),351 as does isocamphanol (383),352 and the reaction of camphene with phenol in the presence of an alkylsulphonic acid yields mainly isobornyl phenyl ether (384).353 The di-iodocamphene (385) gives (386) and (387) when it is irradiated in methanolic solution.Similar treatment of the dibromocamphene (388) gives the vinylic bromide (389) analogous to (387) together with camphene (38 1).354When the bromo(pheny1)camphene (390) is photolysed in non-polar solvents (391) is formed via a radical pathway; however when the same compound (390) is irradiated in an alcoholic solution the ether (392) which is formed via a cationic intermediate is also The isocamphane derivative (393) which has potential sympathomimetic activity has been prepared356 and a series of endo-isocamphane compounds (394) has been made.357 The chemical shifts of 13Cin the n.m.r.spectra of each of (399) R= Cl or Br Ph /+OMgC1 OMgCl V Ph nineteen (+)-(1 R)-camphor derivatives have been measured and assigned,35s and it has been shown that methylene groups that are stereospecifically labelled with deuterium [as for example in (395)] can easily be observed by using 2H-decoupled two-dimensional proton-carbon n.m.r. shift-correlation meth- od~.~~~ The circular dichroism spectrum of (+)-camphor (373) has been examined over the range 160-210 nm in the gas phase and in trifluoroethanol solution; synchrotron radiation was Formylcamphor (396) condenses with chiral amines to give bis-enamines; for instance (397) is formed with trans-cyclohexane- 1,2-diamine. Several of these adducts have been examined by ultraviolet and circular dichroism methods with a view to probing their structures in The c.d.and n.m.r. spectra of the sterically crowded exocyclic diene (398) which was derived from camphor have been recorded and discussed.362 (+)-Camphor (373) has been converted into the camphene hydrohalides (399) and into the bornyl/isobornyl halides (400). NATURAL PRODUCT REPORTS 1988 (400)R =CI or Br I-OSOZCF (403) V kR2 Ph (411) R'R2=0 (412) R1R2=OCHzCHzO The exolendo ratio in the product mixtures depends upon the synthetic method which is applied.363 The reaction of (+)-camphor (373) with trifluoromethylsulphonic anhydride yields a mixture of (40 1)-(403). Treatment with water gives camphor (373) from (401) and the camphene derivatives (404) and (405) from (402) and (403) respectively.364 The reaction of (+)-camphor (373) with trifluoromethylsulphonic anhydride in the presence of 2,6-di-t-butyl-4-methylpyridinegives a product which contains mainly the camphene (404).364 When (+)-camphor (373) undergoes Reformatsky reaction with ethyl 2-(bromomethyl)prop-2-enoate the methylene-lactone (406) is The Ivanov reagent (407) reacts with (+)-camphor (373) to give the kinetic product (408).This is converted into the /?-lactone (409) by thionyl chloride and thermolysis of (409) yields the olefin (410).366 The reaction of the diketone (411) with 1,2-di(trimethylsilyloxy)ethane in the presence of trimethylsilyl triflate gives the mono-acetal (412) ~electively.~~' A review on the uses of camphor and its derivatives as chiral NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON R23 0E B r I (413) Br -d r-CO2R (417) (418)R = Me (419)R = H .ON& C02R' (414)R'=H,R2= Br (415)R1=Me,R2=Br (41 6) R' =HIR2=OH AN'CO2But N-Ph &-(429) R1= 0 or N -alkyl ,R2= alkyl (430) R=O or NPh [structure (432) is with (374)] starting materials for synthesis has been The 9,lO- dibromocamphor (413) reacts with KOH in aqueous THF to give the bromo-acid (414) or with NaOMe in MeOH to give the corresponding bromo-ester (41 5). When KOH and aqueous DMSO is used as the reagent the hydroxy-acid (416) is 8,lO-Dibromocamphor (41 7) gives the epimeric bromo-ester (418) with NaOMe in MeOH but a mixture of the bromo-acid (41 9) [which is rapidly converted into the S-lactone (420)] and the intramolecular alkylation product (421) when it is treated with KOH and DMSO.This bromo-ketone (421) is further converted into the acid (422) when it is treated with a base.369 The camphor oxime (423) has been hydrosilylated by using a trialkylsilane in the presence of RhCl(PPh,), PtO, or K[PtCl,(C,H,)]. Acidic hydrolysis of the product mixture gave the expected epimeric amines (424) together with the ring- &aN NH2 H (433) (4341 cleavage product (425).370 It has been demonstrated that the imine (426) can be alkylated at the pro-R face of the activated methylene group to give products (427) and (428) with enantiomeric excesses of from 0 to (+)-Camphor (373) has been converted into a series of derivatives (429) and (430) whose tautomerism has been Several compounds with the general structure (43 1) have been synthesized and their pharmacological properties evaluated.373 The oxidation of isoborneol(379) to camphor using polymer- supported CrO, has been described.374 Bornyl chloride (432) reacts with urea to give (433),375 and bornylmagnesium chloride reacts with benzaldehyde in THF solution to give bornene (434) benzyl alcohol and a small amount of benzoin.376 Camphor derivatives continue to be applied successfully as chiral auxiliaries for organic synthesis. The chiral Lewis acids NATURAL PRODUCT REPORTS,1988 &SnR' R2 R3 (435)R'= R2=Me,R3=CI R 0 (436)R1 = Me R2=R3 =CI (438)R = H,Me.Ph 1-naphthyl etc.(439) (437)R' = R2=R3=Me (444)R =Me (445) (447) (446)R =other alkyl (435) and (436) have been made from the trimethylstannyl compound (437).377 Similar systems have been prepared in the menthane and pinane series. Conjugate addition of LiBu,Cu to the crotonates (438) proceeds with high diastereoisomeric excess (d.e.) especially for the 1-naphthyl derivative. Reduction of this adduct by LiAlH leads to (-)-(S)-3-methylheptan- 1-01 of 95% e.e.378 The acrylate (439) which is derived from (+)-camphor (373) and its enantiomer have been used in several Diels-Alder ~yntheses.,'~ Addition of benzenesulphenyl chlor- ide to the acrylate (440) yields the adduct (441) wherein the stereochemistry at the newly generated carbon centre is mainly (S).The 'inverted' acrylate system (442) conversely gives (443) of mainly the (R) configurati~n.~~~ Addition of trichloromethylmagnesium chloride to the crotonate (444),followed by hydrolysis of the ester gives the (+)-($)-acid (445) in 95 YOyield.381 The same crotonate (444) and its analogues (446) react with RCuBF to give Michael adducts (447) which can be hydrolysed to the corresponding alkanoic acids of greater than 99 YOe.e.382 The analogous endo-crotonates (448) similarly yield adducts (449) with opposite enantioselectivity.The diastereoselective hydroxylation (using MOO and pyridine and HMPT) of the (E)-and the (2)-enolate derived from (450) has been (RS)-Pantolactone (45 1) has been resolved via separation of the diastereoisomeric amides that it forms with (lR)-3-endo-aminoborneol(452).The reagent can easily be recovered and recycled.384 The reaction of several aldehydes RCHO with diethylzinc in the presence of catalytic amounts of the dimethylamino-isoborneol (453) yields (9-alcohols (454) of up to 99% e.e.385 NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON Y &&:$OH Ph &/-&OH (455) (457) &Go S -== 3 PhOzS 02 (458) (459) (460) (461) (462)n = 1 or 2 (463)n = 1 or 2 Br H HO ARH 40 R SO2R (465) R = Ph napht hyl ,etc. (466)R'= alkyl R2= H (468) (469) (467)R'= alkyl R2= Br (470) The acetal (455) can be oxidized with N-chlorosuccinimide and Me$ to give the corresponding keto-acetal which yields enantiomerically pure (9-benzoin on hydrolysis.386 A synthesis of optically pure thiolactol (456) has been described.3s7 (+)-Camphor (373) has been converted into the sulphoxide (457) which epimerizes at sulphur when it is heated at 145 "C.The carbanion derived from (457) adds stereo- specifically to cyclopent-2-enone to give the Michael adduct (458).388The sulphonyl-activated dienophiles (459) and (460) have been prepared and their reactions have been The stable chiral (camphorsulphony1)oxaziridine(461) and its enantiomer each oxidize the lithium enolates of esters and amides to the corresponding a-hydroxycarbonyl derivatives with opposite stereo~hernistry.~~~ (471) Intramolecular Diels-Alder reactions of the acyl sulphon- amides (462) to give (463) are catalysed by EtAlCl at -20 "C.Treatment of these adducts with LiAlH gives enantiomerically pure bicyclic alcohols (464) and the regenerated chiral auxi-liar^.^^^ Some asymmetric induction is observed in Diels- Alder reactions of cyclopentadiene with the sulphonyl-substi- tuted isobornyl acrylates (465).392The esters (466) can be de- protonated and then enantioselectively a-brominated to give (467) which can be further transformed into optically active bromohydrins (468) and epoxides (469) of high enantiomeric excess.393 When the enamine (470) which can be obtained from (+)-camphor (373) is reduced by formic acid the predominant product is the isobornylamine (471).394The Ritter reaction of NATURAL PRODUCT REPORTS 1988 25 Ntl R (472)* Me0 (474)R = NH2 [*structure ( 382) is with (375)l (473) (476) =KY (475) (477) O& 0 &O R 0 (479) (480) (481)R=(€)-or @)-NOH (+I -(485) (482)R= 0 (-1-(486) RLOAC, R*=H (+) -(487)R’ = H R2= OAC (+) -(488)R’R*=O (537)R’= H ,RZ = SC(0)SMe (540)R1=H,R2=OC(S)SMe tricyclene (472) with MeCN yields the exo-amide (382).395 The Schiff base (473) can be deprotonated alkylated and the product then hydrolysed with aqueous acid to regenerate the chiral auxiliary together with an a-alkylated cyclohexanone of 58-99 % e.e.39s Several chiral hindered amines have been synthesized.For instance oxidation of the hydrazine (474) (using PbO,) generates the bornyl radical (479 which can be trapped by nitroso-t-octane.Reduction of the trapped products (using Na in liquid NH,) leads to the exo- and the endo-isomer of (476).397Catalytic hydrogenation of N-isobornylcamphor- imine (477) gives (478); this is a very hindered base its pK being 4.7.397 For a series of lactones (479; R = Me Et Ph etc.) the diastereotopic methylene protons are not magnetically equiva- lent. This observation has been explained in terms of a chirality-independent differential shielding of the (pro-S)-hydrogen atom by the amide carbonyl group.398 Members of a series of camphor-imides (480) have been prepared and their conformational preferences have been studied.399 The isomeric mono-oximes (481) of camphorquinone (482) react differently with diazomethane. Thus the (E)-oxime is N-methylated with this reagent whereas the (2)-oxime is 0-methylated.400 (489) Syntheses of homocamphenilone (483) and of homocam- phene (484) have been described.401 7 Pinanes The oleorosin from the xylem of Pinus rzedowskii is rich in a-pinene (485),402as are the leaf oils from western Mexican Juniperus durangensis and J.j~liscana.~~~ a-Pinene has also been found in the volatiles from flowers of Ophrys sphecodes var. atrata var. litigiosa and var. provincialis and of Ophrys splendid^.^^^ Two Mexican populations of Pinus cembroides have been chemodifferentiated. The northern chemotype is rich in a-pinene (485) whereas the southern form is rich in ~ar-3-ene.~~~ Similar chemotaxonomic differences have been observed in Soviet-grown larches.Thus the a-pinene/car-3-ene ratio in some stands of Japanese Western and American larches is 51:1 2 :1 and 1.5 :1 respectively.406 cis-Pinocarveyl acetate (486) and its trans-isomer (487) make up the characteristic aroma of the liverwort Targionia hypo- phyll~,~~’ and pinocarvone (488) is the main component of the oil from Elsholtzia str~bilifera.~~~ The novel myrtenylfuro- heliangolide (489) has been found in the aerial parts of Calea rupicola.409 NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON Rdl (+) -(490) R = HZ (+)-(491) R'= OH,R2 =H (493) R'=H or Me,R2=H (511) R=OH (514) R =O (+)-(492) R'R2= 0 (494) R' =H or Me.R2=OH (512) R = OBa (513) R="63 K+ H' CHO [structure (496) is with (37411 8 (497) (498) R =OH (499) R = OH (500) (548) R =SnPh3 (536) R = OC(S)SMe (550) R = SOzSnPh3 (538) R = SMe J?' (5011 (-1 -( 502) It was noted that Amaranthus retrojlexus could not grow and complete its normal life-cycle under the sour orange tree (Citrus ~urantium),~~~ and it has now been shown411 that a-pinene (485) P-pinene (490) limonene (1 lo) and citronellal each of which is present in the leaf oil from C.aurantium are allelopathic to A. retrojlexus. Cultures of the honey fungus (Armillaria mellea) convert a-pinene (485) into verbenol (49 1) and verbenone (492) amongst other A strain of Serratia marcescens that was isolated from sewage sludge effects a similar transformation of (485) but a-terpineol (47) becomes the major product when its source of nitrogen is altered and glucose is introduced as a second carbon source.413 Various microbial hydroxylations of the amides (493) to give alcohols (494) have been The effects of P-pinene (490) on the respiration of yeast cells have been examined.Respiration is inhibited when glucose or ethanol is a substrate and the transport of potassium is also curtailed. These effects may be due to localization of the P-pinene in or on the cell membrane.415 Cell cultures of Nicotiana tabucum enantio-selectively hydrolyse the (R)-form of isopinocampheyl acetate (495).349 A review on the synthesis of perfumery compounds from a-and P-pinenes has appeared,416 as have articles on the synthesis of camphor from a-pinene417 and on optimal conditions for conversion of a-pinene into borneol via bornyl chloro-acetate.41s Both the (+)-and the (-)-forms of [10-14C]-a- and [1O-l4C]-P-pinene have been synthesized.419 The vibrational circular dichroism and the Fourier-transform infrared spectra of (+)-a-pinene (485) as obtained for the neat liquid in a nitrogen matrix have been described.420 It has been shown that there is a correlation between the optical rotations of (+)-and (-)-a-pinene and their site-specific 2H/1H isotope ratios.These can be determined by natural-abundance 2H (539) R = SSMe (541) R = SC(0)SMe (543) R = CH~OTS (545) R = SnMe3 n.m.r. spectroscopy thus permitting an assessment of the optical purity of a sample of ~inene.~~~ a-Cyclodextrin in formamide has been used as the stationary phase in an enantioselective gas-chromatographic separation of mixtures that contain a-and P-pinenes and the four possible stereoisomers of inane.^^^ 423 The mechanism of the gas-phase pyrolysis of a-pinene (485) has been probed using various 2H-labelled forms of the te~pene.~~~ Isomerization of a-pinene (485) using trifluoroacetic acid leads to a mixture which consists mainly of limonene (1 lo) camphene (38 l) and bornyl trifluoroacetate (496).425 The pyrolysis of the latter compound has been investigated.425 Isomerization of a-pinene (485) using trifluoroacetic acid at higher temperatures provides a wide range of The rate constants for these isomerizations and for the appearance of various products have been determined.427 The use of activated Albanian clays as catalysts for the conversion of a-pinene (485) into camphene (381) and tricyclene (472) has been as has the isomerization of a-pinene to camphene which takes place over borophosphate catalysts in the presence of zinc The isomerization and hydrogenation reactions of (+)-apopinene (497) over Pt/Si02 or Pt/A1203 have been investigated.430 The 9,lO-dicyanoanthracene-sensitized photolysis of a-pinene (485) to give limonene (1 10) and cis-ocimene (25) has been studied and quantum yields have been determined.431 The photo-oxidation of a-pinene (485) is facilitated when reaction mixtures are irradiated with light of a wavelength corresponding to the absorption maximum of the charge-transfer complex that forms between a-pinene and ground-state oxygen.432 (-)-a-Pinene [the enantiomer of (485)] yields verbenol(491) and the isomeric alcohol (498) when it is exposed to oxygen in a microwave discharge.(-)-P-Pinene [the enantiomer of (490)] gives (-)-myrtenol (499) and (-)-myrtenal (500) under the same conditions.433 Photo-oxidation of a-pinene (485) in the presence of cobalt naphthenate gives verbenol (49 1) and verbenone (492). 434 The reaction of a-pinene (485) with FeC1;6H2O and HCl in 1,2-dichloroethane solution gives a mixture that contains the chlorocamphanes (501) and many other (+)-a-Pinene (485) has been converted into (-)-nopinone (502).436 NATURAL PRODUCT REPORTS 1988 [structure (503) is with (49511 [structures (511) -(513) are with (495); (504) R=CI ( 514) is with (49O)I (505) R= H (506) R = CH2CH=CH2 (507) R = CH2CH(Me)=CH2 (508) R = CH2CH=CMe2 (509) R = (2)-CH=CHMe (510) R = (€)-CH=CHMe R' (522) RLR~= H (524) RLOH RZ= H (525) R1=OH R2=Me As in the menthane and camphane series there has been further consolidation of the valuable uses of pinane derivatives as auxiliaries for asymmetric synthesis.This has been particu- larly marked in the area of organoboron chemistry. The synthesis of optically active compounds via asymmetric hydroboronation reactions using monoisopinocampheyl-borane (503) has been reviewed.437 The preparation of chloro- di-isopinocampheylborane (504) of high e.e. and its use as a chiral reducing agent have been described. The derived reagent (505) reduces acetophenone to give (S)-1-phenylethanol of 98% e.e.43s The secondary kinetic isotope effects during the enantioselective hydroboronation of deuteriated olefins by di- isopinocampheylborane (505) have been Allyl-di-isopinocampheylborane (506) transfers its ally1 residue to aldehyde carbonyl groups with an enantioselectivity that is a function of temperature.440 At lower temperatures products of up to 75% e.e.can be obtained. The methylallyl and dimethylallyl derivatives (507) and (508) behave similarly.440 The preparation of enantiomerically pure forms of all four (2)-and (E)-crotyldi-isopinocampheylboranes[for example (509) and (510)] has been described.441 These react regio- and stereo-selectively with acetaldehyde. Thus the (3-forms yield the enantiomeric (+)-erythro- and (-)-erythro-3-methylpent-4-en-2-01s of very high optical purity and the (E)-forms similarly give the (+)-threo- and (-)-threo-methylpentenols of similar (-)-Isopinocampheol (51 1) gives (512) when it reacts with 9-BBN and (512) is converted into the borohydride (513) by its reaction with potassium hydride.Reduction of acetophenone using (513) gives (9-1-phenyl-ethanol of 47 % enantiomeric excess.25o a-Pinene (490) has been synthesized via Wolff-Kishner (523) (526) reduction of P-chrysanthenone (514) which was obtained by intramolecular cyclization of the ketene that could be generated from geranoyl chloride (515) by heating it with triethylamine in refluxing toluene.,, The P-chrysanthenone (514) can be induced to isomerize to chrysanthenone (516) by using H and Pd/ CaCO,.(-)-P-Pinene [the enantiomer of (490)] has been converted into the optically pure decalin (517) which is a precursor for several morphine-related analgesics,443 and also via the epoxide (518) into oleuropic acid (519).,'' Oxidation of (+)-P-pinene (490) with pyridine-2-seleninic anhydride (which is more reactive than benzeneseleninic anhydride) gives (+)-pino-carvone (520) in 95% yield.445 The alcohol (521) that is produced by the reaction of (-)-P-pinene [the enantiomer of (490)] with C1,CCHO and FeCl has been utilized in syntheses of (R)-4-amino-3-hydroxybutyricacid [(R)-GABA] and of (R)-carni tine. 446 Epoxy-a-pinene (522) gives trans-carveol (284) when a solution in DMF is exposed to zeolites and the P-pinene epoxide [the enantiomer of (51 8)] analogously yields myrtenol (499) when sulpholane is the The reaction of the same epoxide with trichloroacetic acid in the presence of A-4 zeolite gives perillyl alcohol (298).447 The enantiomer of the epoxide (518) can be synthesized under very mild conditions by allowing the diol (523) to react with Ph,P(OEt), which is generated in situ from Ph,P and diethyl The epoxy- alcohol (524) is converted into a 25:75 mixture of myrtenal (500) and pinocarvone (520) by LiAlH and Et,N.The homologous compound (525) gives myrtenone (526) under the same conditions. 449 The tosylate (527) reacts with the sodium salt of acetophenone NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON OTs I I (527) (528) (529) (530) (534) V (535) R = Et or Pri (542) (544) [(548) and (550)are with (498)] (546)R'= SnPh3,R2 = H (547)R1=HIR2 =SnPh3 (549)R'=H,R2=CI oxime to form the ether (528) which can be reduced to give (S)-1 -phenylethylamine of rather poor enantiomeric excess.45o Treatment of cis-verbanone (529) with fluorosulphonic acid gives a mixture of the epimeric o-menthanes (530); these have been converted into (+)-(R)-mentha-2,4-diene (53l).451The reaction of a-chlorocitronelloyl chloride (532) with triethyl- amine leads to the chloroisopulegone (533) and the chloro- chrysanthanone (534).452 Myrtenol(499) has been converted into a number of juvenile hormone analogues (535).453 Myrtenyl xanthate (536) re-arranges when it is heated to give (537) which can be photolysed to a mixture of the thioether (538) and the disulphide (539).trans-Pinocarveyl xanthate (540) spontaneously re-arranges to (541) which also gives (538) and (539) on photo- lysi~.~~~ When myrtenol (499) is treated with N-lithioethylene- diamine at 120 "C it is converted into the thermodynamically less stable cis-isomer of myrtanal (542).333 The tosylate (543) of (553) R =Me (554)R =Ac homomyrtenol yields the spiro-compound (544) together with other products when it is treated with triethylal~minium.~~~ Metallation of (+)-a-pinene (485) with BuLi in TMEDA followed by reaction with chlorotrimethylstannane yields the allylic stannane (545). This is converted efficiently into (+)-p-pinene (490) when it is treated with an Other stannyl derivatives that have been prepared include the triphenyl- stannane (546) and its epimer (547).The latter may actually prove to be the tertiary allylic stannane (548). Both (546) and (547) were obtained when verbenyl chloride (549) reacted with Ph3SnLi.456 The reaction of (546) with SO yielded the rearranged insertion product (550). The tris(myrtany1)gallane (551) can be used to reduce ketones to secondary alcohols of the (R) c~nfiguration.~~' The pinadiene (552) reacts with Na2PdC14 in MeOH to give (553) or with Pd(OAc) and AcOH and NaCl to give (554).458 Compounds (553) and (554) are the first cis-oxypalladation products to have been prepared. They can be used as catalysts for asymmetric cyclization reactions.446 NATURAL PRODUCT REPORTS 1988 CI (555) (563) (568) R =O (570) (583)R =S $7: OAc (573) R' = R2= H2 (578) (574) R'= H2; R2= 0 (575) R'= 0 ; R2= H2 (576 ) R' = Hz ; R2= endo-H exo-0Ac (577 ) RLR~=O [structure (583) is with (568)] The gem-dichloride (555) reacts with Bu'OK in DMSO to give the allene (556) which forms via an intermediate chlorocyclopropene.459 Either of the peroxy-acids (557) and (558) yields the radical (559) when it is treated with H,S. This radical can then give the nor-terpineol (560) or a-and p-nopinol [(561) and (562)l. The ratio of (561) to (562) is always 1 :12 regardless of the stereochemistry of the initial peroxy- acid [(557) or (558)].460 8 Fenchanes The high-field ,H n.m.r.spectra of 6-exo-and 6-endo-deuteriofenchone have been The diffusion constants for overall and internal rotation of the methyl groups in isofenchone (563) a-fenchene (564) and some other members of this series have been Cyclofenchene (565) undergoes anodic oxidation in AcOH and NEt to give the acetate (566).463Both cyclofenchene (565) and p-fenchene (567) react with Pb(OAc) to yield a wide range of a~eto~y-~~mp~~nd~.~~~ The kinetics of the dehydration of fenchone (568) and of AcO A& (566) (5671 Aco+o (571) RJ? @ Br (580) R'= Br,R2=H (582) (581) R'= HI R2= Br camphor (373) over A1,0 catalysts of varying acidities to give aromatic products have been measured.465 Fenchone was the more reactive substance under all conditions which were examined.Experiments on the homo-enolization of fenchone (568) in (CD,),COK and (CD,),COD at 220 "Chave revealed that there is a deterioration of the reaction medium and significant loss from the 2H pool mainly because of the formation of isob~tene.~~~ The oxidation of (-)-fenchone (568) by chromyl acetate has been showng6' to provide the known diketones (569) and (570) together with the new keto-acetate (571) and the novel carbonate (572). Under similar conditions ( +)-2-endo-fenchyl acetate (573) gives a mixture of (574)-(579). Bromination of (+)-fenchone [the enantiomer of (568)] gives mainly 10-bromofenchone (580) together with lesser amounts of (58 1) and of the bromocamphor (582).467 Thiofenchone (583) reacts with diazomethane to give (584) which readily loses nitrogen to yield the episulphide (585) this being formed via the ylide (586).468 A synthesis of (+)-homofenchone (587) has been des- cribed 469 as has a route from (+)-fenchone to (+)-homo- fenchone.470 447 NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON (+)-(589) R= H (t)-(592) R1= HI R2=Me (590) R = OAC (-) -(593) R1= Me.R2= H (+)-(591) R=OH I; (+)-(594) R = H (620) R = SMe or SPh (626) R=CL (649) R=CN R' ,R2 R' ,R2 B 5? (596) R1 = Me,R2=H (598) R1= Me,R2=H (597) R1=H. R2=Me (599) R1=H,R2=Me (602) R'R2=0 (604) (603) R' =H,R2=OH PdCI/ CI (605) R =CL (606) (607) R = 0-alkyl 9 Thujanes The new compound cis-thuj-2-en-4-01 (588) has been isolated from the essential oil of Laurus nobili~,,~~ and sabinene (589) comprises 30 % of the leaf oil of Aloysia grati~sima.,~~ Sabinene also occurs in the leaf oil of Sideritis j~valambrensis,~~~ but it is absent from S.cretica Bo~ss.~~, Sabinyl acetate (590) is a major (+) -(595) R =H (608) R =OAC (631) R =OH (650) R =CH20H kBr to produce mainly P-thujone (593).479 The terpenoids that occur in the leaf oils of a number of members of the Cupressaceae have been examined.480 The circular dichroism spectra of (-)-3-isothujone (593) and of (+)-3-thujone (592) have been used to probe the con-formations of these ketones.481 The stereochemistries of the products of reduction of a number of thujyl derivatives by LiAIH have been determined.482 10 Caranes The fruit oil of Annona senegalensis var.senegalensis consists mainly of (+)-car-3-ene (594),483 and (+)-car-2-ene (595) has been found to the extent of 30 YOin an oil from the aerial parts of Cymbopogon stracheyi (Hook. f.) Raiz et Jain.484 The western larch (Larix occidentalis) is attacked by the beetle Dendroctonus pseudotsugae to a degree which is negatively correlated with the level of (+)-car-3-ene (594) in the xylem oleorosin.485 cis-Carane (596) and trans-carane (597) yield the p-menthenes (598) and (599) respectively together with other products when they are heated to 80 "C in the presence of Ze0car-2.~~~ The reaction of cis-carane (596) with hydrogen bromide in hexane is claimed to yield a mixture of the o-and p-menthane derivatives (600) and (601).487 The photoelectron spectra of the caranes and of car-2-ene and car-3-ene have been analy~ed.~~~ The reaction of (+)-car-Zene (595) with Fe(CO) leads to a mixture of p-cymene (1 89) [15YO], the insertion product (602) [50%] the alcohol (603) [20%] and the complex (604) [15 Chloropalladation of (+)-car-2-ene (599 using component of the essential oil from Plectranthus fruticos~s~~~ and it has also been found together with the free alcohol (59 l) [PdCl,(MeCN),] in chloroform (containing 2 YOof ethanol) in in the leaves of Achillea depress^.^^^ a-Thujone (592) makes up benzene or in dichloromethane yields a mixture of (605) and 56% of an Indian Artemisia vulgaris and an oil from (606) in ratios which are strongly solvent-dependent.The ethers Soviet Artemisia szowitziana contains 75 YO of P-thujone (607) are formed exclusively when alcohols are used as the (593).478A cell culture of Artemisia arborescens has been shown solvent. NATURAL PRODUCT REPORTS 1988 [structure (608) is with ( 595)) p p (612) .SR' [structure (620) is with (594) ] Be PeSR (616) R'=Ph or Me,R2=CI (619) R = Ph or Me (617) R' =Ph or Me R2 = OAc (618) R' =Ph or Me R2= OH R' I?* PR3 (621) R1=Me,R2=R3=OH (623) R1=OH ,R2=Me ,R3=Cl (627) R1=Me,R2=R3=CI (630) R1=Me,R2= OH R3=CI [structure (626) is with (594)] Epoxidation of the allylic acetate (608) yields a mixture of (609) and the product of acid-catalysed ring-opening (610). Treatment of (609) with aqueous base leads to the trio1 (611) which can be converted into the lactone (612) with Jones' reagent.491 The borate ester (613) gives a mixture of (614) (615) and 1,2-dimethyl-4-isopropylbenzene when it is pyro- ly~ed.~~ (+)-Car-3-ene (594) has been used as starting material for the synthesis of a number of optically active chrysanthemic acid deri~atives..~~~-~~~ (+)-Car-3-ene of nearly 100 YOe.e.has now been prepared via recrystallization of the derived organo- b~rane.,~' Addition of sulphenyl chlorides (R= Me or Ph) to (+)-car- 3-ene (594) gives (616) in 95 % yield. This may be solvolysed to the acetate (617). Dehydration of the derived alcohol (618) PC' (624) (625) R =CI (646) R =CH2CO2Et RPR2 (628) (629) R'= R2= H2 (635) R' =H2.R2=0 (636)R1=0,R2=H2 leads to the p-carene (619) which can also be obtained directly from (616).Heating (619) causes its rearrangement to the useful 10- thioether (620). 498 Hydroxylation of (+)-car-3-ene using I and AgOAc yields the cis-diol(621) amongst other Oxidation of (+)-car-3-ene (594) (using 0 and cobalt naphthenate) gives the enone (622).,, Dehydration of the chlorohydrin (623) (using POCl and pyridine) gives a mixture that contains the chorides (624)-(626) together with the dichloride (627).500 Epoxidation of (624) gives the epimeric epoxides (628). The a-epoxide yields (+)-3a,4a- epoxycarane (629) when it reacts with LiAlH, and the same reagent converts the P-epimer of (628) into the cis-chlorohydrin (630).501 The epoxycarane (629) rearranges to a mixture of (63 1)-(633) NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON [Structure (631) is with (595)] 7b OH (632) (633) (637) &-"' (638) R =H (634)R = OAC (640)R =OMe -Po (641) R =H (642) R = CHzOH (643) R =C02H (644) R =Me [structure (649) is with (594) ; (650) is with (595)] (652) R=Me (653) (654) R =H when it is treated with ButOK and pyridine at 115 0C.502 The acetoxy-ketone (634) which was derived from the epoxide (629) yields (+)-carvone (255) when it is heated.503 The epoxy- ketone (635) gives the allylic alcohol (632) under Wharton conditions and the isomeric epoxy-ketone (636) similarly yields (63 1).504 The reaction of the ,8-epoxide (637) with propan-2-01 in the presence of H,SO gives a wide range of products some of which possess the sabinyl The (-)-caran01 (638) can be converted into the boron hydride (639).This species reduces acetophenone to give (R)-1-phenylethanol of 34 % e.e. The analogous reducing agents prepared in the menthane and pinane series (see above) yield (s>-l-phenylethan~l.~~~ Dipole moments and Kerr constants have been measured for the methoxy-ketone (640) and for its epime~-.~O~ cis-Caran-4-one (641) has been hydroxymethylated to give (642),507 and this compound has been converted into the keto-acid (643) and into the methylated caranone (644).508 The caranone (641) has been transformed into the unsaturated esters (645) and (646) and into the unsaturated nitriles (647).509 The reaction of the chloro-nitrile (648) which was derived from ( -)-(9-perillalde-hyde with magnesium gives the carene derivative (649).510 The alcohol (650) can be dehydrated (using KOH at 250 "C) to give the diene (651) and the triene (652).511 Other workers have studied the ene reactions of the diene (651) with tetra~yanoethylene.~"If the caradiene (653) is heated it isomerizes to (654).513 NPR 5 NATURAL PRODUCT REPORTS 1988 OR' &02H 0-p -D -GIC (664) (666) R = H (668) R =OH Me Me \/ mR (671) R = (€)-CH=CHC(O)Me (672) R = C=C-C(O)Me (673) R = (€1-CH=CH(OH)Me 11 lonone Derivatives The new glucosides (655)-(657) and the novel rehmapicroside (658) have been obtained from the roots of Rehmannia gluti- nosa5l4and the glucosides (659) and (660) have been isolated from Eryngium c~mpestre.~~~ Both (661) and (662) are new natural products from Haplopappus frem~ntii,~~~ and (22,4E)-y-ionylidene-ethanol(663) has been found in mycelia of the fungus Cercospora ~ruenta.~~' p-Ionone (664) which occurs naturally in corn ears inhibits growth of the fungus Aspergillus jla~us,~'~ and (22,4E)-a- ionylideneacetic acid (665) has a plant-growth-inhibitory activity comparable to that of abscisic acid.519 There have been reviews on the synthesis of ionones and methyl ion one^^^^ and on aspects of ionone and epoxy-ionone chemistry.52 Ro- p-D-0 (659) (665) Like many monoterpenoids ionone derivatives are finding increasing application as starting materials for synthesis.For example all-trans- 19,19,19- trifluororetinal has been made from P-cyclocitral (666)522 and a-ionone (667) has been converted into 3-hydroxycyclocitral(668),which can be used in a synthesis of strig01.~~~ a-Ionone (667) has also been used in a stereospecific synthesis of abscisic acid (669),524 while p-ionone (664) is a precursor for the theaspiranes (670).525 The sila-p-ionone (671) and its derivatives (672) and (673) have been prepared526 and a new synthesis of trans-y-irone (674) has been A diffusion-kinetic model has been used to optimize experimental reactor conditions for the conversion of pseudo-ionone (675) into its di- tetra- and hexa-hydro-derivative~.~~~ The conformation of p-ionone (664) in solution has been NATURAL PRODUCT REPORTS 19sa~.H. GRAYSON 451 (678) X = 0 (679) X=O (680) X =NH (683) X = NMe (682) X = NMe OH moH (685) (686) R = 0 (687) (688) R =CH (y-,lo + 0 (691) R'= 0,R2=R3=H (692) (693) (695) R'=CH2 R*=OH R3=Me studied by n.m.r. methods,529 as has its hydrogenation over and a mixture of (689) and (690) when it is irradiated at palladium catalysts in a flow-type reactor.530 ,&Ionone (664) 254 nm.538 The (-)-epoxy-a-ionone (691) rapidly racemizes via yields the ketol (676) when it is oxidized with aqueous formation of (692) when it is irradiated at 254 nm in MeCN potassium ~ermanganate,~~~ a procedure for the con-and then gives a mixture of (679) (693) and (694) together with and version of p-ionone into the dienyne (677) has been fully other known The hydroxy-epoxide (695) undergoes triplet-state reactions to yield known product types plus (696) Flash vacuum pyrolysis of the epoxy-P-ionone (678) leads to (697) and acyclic ketones when it is irradiated at 280 nm in (679) and other The related aziridine (680) is acetone solution.Singlet-state photochemistry of (695) (in thermolysed to give (681) but the N-methylated analogue (682) MeCN; 254nm) leads mainly to (698) together with the p-Ionone (664) gives its geometric gives (683) when it is heated.534 Photolysis of the aziridine (680) epimeric P-ep~xide.~~~ gives (681) and (684).535 isomer and products arising from [1,5]-hydrogen migrations Some cyclization reactions of (685) which was obtained by when it is photolysed in organic solvents but the latter photoisomerization of its (@-isomer have been products are the only ones formed when the experiment is Photolysis (n+m* or m+-,7~*) of the epoxy-a-ionone (689) carried out on aqueous solutions that contain the P-cyclodextrin causes both (E)/(Z)isomerization and formation of the ketol complex of P-i~none.~~~ (687).537 The related dienyl-epoxide (688) gives its (2)-isomer NATURAL PRODUCT REPORTS.1988 CHO COzMe \/CHO I o- CHO @*OH 0-p-O -GIC OR R1 'R2 (699) R = P-D -Glc (700) R1=Me.R2=H (701) R1=OH R2= Me R3 = H (717) R = H (702) R1 =HI R2 = Me ( 734) R' =OH R2= H ,R 3=Me (735) R1=R2=H.R3=Me COzMe I HOGo &(O 0 .& OR (709) R=Me or Ph (710) R = p-D-Glc (733) R = H H H [structure (717) is with (699)] 12 lridanes A recent review542 includes material on the enzymes involved in the biosynthesis of secologanin (699).It has been confirmed that secologanin is formed biosynthetically via initial cyclization of 10-oxogeraniol/ 10-oxonerol to give iridodial (700) in Lonicera tatarica in a Catharanthus roseus hybrid and in suspension cultures of Rauwolfia ~erpentina.~*~ Loganic acid (701) has been confirmed to be an intermediate in the biosynthesis of seco-iridoid and iridoid glucosides in Galium mollugo and in G. spurium var. echino~permon.~~~ The bio- synthesis of iridoid glucosides in cells of Gardenia jasminoides f. grandiflora has been studied using 13C-labelled and members of the same research group have worked on the intermediacy of 8-epi-iridodial (702) in the biosynthesis of iridoids by Gardenia ja~minoides.~~~ The value of iridoid glucosides as taxonomic markers in the CHO COzMe OH OH 0*oMe H$$ -H - H OMe 0 ( 718) ( 719) genera Lippia Lantana Aloysia and Phyla has been discussed in a review article547 and there have been chemotaxonomic studies of iridoids in the genus plan tag^^^* and of seco-iridoids in various populations of BZackstonia perfoliata and of Centaurium species.549 The occurrence of seco-iridoid glycosides in the bark of Olea europaea has been and several known iridoid glycosides have been isolated from Pinguicula vulgari~,~~' from Vitex agnus-ca~tus,~~~ and from sixteen species of Verba~cum.~~~ The conformations of some iridoids from Lamium amplexi- caule have been studied by n.m.r.methods554 and h.p.1.c. techniques have been used to determine the iridoids of some Anatolian species of Gali~m.~~~ There have been stereoselective syntheses of (+)-dehydro-iridodiol (703) and of (-)-isodehydroiridodiol (704).556Base-catalysed cyclization of the dialdehyde (705) yields a mixture of (+_ )-chrysomelidial (706) and (i-)-dehydroiridodial (707). The 453 NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON 0-p-D -GIC C02Me (OEt CHO 0d 0 H o O-Q) C HO CHO ' OH C02Me HO& O:$oMe HO OH O-p-~-Glc "1 Me (724) Ho (726) OOH OH Glc HO -D-Glc OH (727) R=CHO (728) R =CH20H (711)559 and the lactone (712).560 Syntheses which have been reported include routes to mitsugashiwalactone (71 3),561 nep- etalactone (714),562 (+)-iridomyrmecin (715),563 and (+)-di- hydrosecologanin aglucon (7 16).564 The secologanin derivative (717) and the iridoid acetal (718) have both been synthesized HO 0 -p-D-Glc from genip~side.~~~ Pattenden has described a synthesis of the antileukaemic iridoid lactone (-k)-allamcin (719),566 and a preliminary account of another route to this compound has been published.567 The number of new naturally occurring iridoids continues to grow. The highly unsaturated compound (720) together with 7-hydroxy-8,9-didehydrodolichodial (72l) has been obtained from Centranthus ruber (L.) DC.568 New seco-iridoids include kingiside aglucon (722) from the unripe fruits of Strychnos spin~sa,~~' gentio-(723) from the roots of Sambucus eb~lus,~~~ flavoside (724) from Centranthus r~ber,~~' hydroxynuezhenide (725) from Fraxinus excelsior,571 both epimers of (726) from the leaves of Olea europ~ea,~~~ abelioside A (727) and abelioside B (728) from Abelia gr~ndiJEora,~~~ hiiragilide (729) from the jas-Cannizzaro reaction of either (706) or (707) leads to (-k)-l,2- leaves of Osmanthus ilicifolius (Hassk.) M~uillefert.,~~~ didehydroisoiridomyrmecin (708).557 The compound (*)-moside (730) and jasmesoside (73 1) from Jasminum me~nyi,~~~ (709) which is a synthon for chrysomelidial (706) and for and ligustrosidic acid (732) from the fruits of Ligustrum loganin (710) has been prepared,558 as have the useful aldehyde japonicum Th~nb.~~~ 454 NATURAL PRODUCT REPORTS 1988 C02Me structure (733) is with (710) (734)and (735) are with (701) OH OH (736) R = p -D -Glc (737)R = cis- or trans-coumaroyl (738)R = cis- or trans-fer uloyl (739)R = cis- or trans-caffeoyl COzMe HO H' OR OAc (742)R =4-0-[4'-hydroxy-(E)-cinnarnoyl]-~-~-glucosyl (743)(x -acetoxy (744)P -acetoxy (745)R = 2 -~-[(~)-cinnamoy~]-~-o-glucosyl OH Ph IH OH (747) ( 748) NATURAL PRODUCT REPORTS 1988-D.H. GRAYSON 455 CHOOH I HORO"$f0 I (749) R = H (750) R = p-D-Glc R20 @ R20 a-D -Gk (753) R1 =OH,R2= 4'-hydroxy -(El -coumaroyl H0 (754) RLOH,RLH OR' (755) R' = R2=H ( 7 56) R1= H ,R2= OH HO H fO-p-D-G'c v' *o RO (758) R =H ( 760) (759)R=A~ Loganetin (733) which is the aglucon of loganin has been found as a natural product in the leaves of Desfontainia ~pinosa,~~~ 8-epi-loganic acid (734) has been isolated from Cistanche de~erticola,~~~ and 8-epi-7-deoxyloganic acid (735) has been obtained from Argylia ~adiata.~~~ The same plant has also provided compound (736) which is a dimer of (735) and catalp01.~~" New loganin derivatives that have been found in the flowers and leaves of Gentiana pedicellata include (737)- (739),581 and 7-O-(p-coumaroyI)loganin (740) has been isolated from Desfontainia spinosa together with the novel triterpenoid- conjugated seco-iridoid (741).562 The new undulatin (742) (is this configuration correct?) has been obtained from Tecomella ~ndulata,~~~ and (1 R)-and (1 S)-1-acetoxymyodesert-3-ene [(743) and (744)] have been found in a chemovariety of Myoporum deserti A.CU~~.~~~ The iridoid free acids 2'-cinnamoylmussaenosidic acid (745) and 10-0-(5-phenylpenta-2,4-dienoyl)geniposidicacid (746) have been iso- (761) R1=R2=H,R3=Me (762) R'= R2= OH R3=H lated from Avicennia marina which also contains the loganin derivative (747).565 Another new free acid is senburiside I (748) from Swertia jap~nica.~~~ Some further examples are noted below.The new iridoid lactones villosol (749) and villosolside (750) have been extracted from Patrinia viI10sa.~~~ Other new iridoids include campsiside (751) from Campsis chinensi~,~~~ plantarenaloside (752) from Plantago the cachenesides I11 (753) IV (754) and V (755) from Campsis chinensis VOSS.,~~~ and 8-0-foliamenthoyleuphroside (756) and 2',8-di-O-foliamenthoyleuphroside(757) from Clerodundrum incis~m.~~" The new compound viburnalloside (758) has been found in Mbernum bet~lifolium~~~ and the related diacetyl- furcatoside (759) in V.jap~nicum.~~~ Ebuloside (760) has been obtained from the roots of Sambucus eb~1u.s.~~~ New iridoids from Nyctanthes arbor-tristis include arbortristoside A (761) and arbortristoside B (762).594 NATURAL PRODUCT REPORTS 1988 C02Me HO o-~-D-GIc 0-p -D -Glc (763) (764)R' = Me,R2= H,R3=OH (767) R1=H,R2=O-p-D-Glc R3=OH,R4=Me (765)R'=R2= R3=H (768) R1=C02H,R2=R3=H,R4=C02Me (766)R1=Me,R2= R3= OH (769) R'=R3= H,Rz=OH.R&=CHO R3 0-OR OH 0 (770) R1=OH,R2= 06'- R3=Me (774)R =~-D-GIc (771) R1=OH,R2= & ,R3=Me (772)R1=R2=H,R3=CHzOH (773)~1~ H,R*=OH,R3 = CH20-(Z)-cinnamoyl 0 0 HO OH O-p-o-Glc L (775) R1=H,R2=OH (778) (779) (776)R1 =OH,R2=CL (777) R1 =H,R2=CI AH0 c H& b,_ R2 (780)~1 = RZ=H (784). (+) -(782)R1 = OH,R2= n-pentyl 11 HO CO2H $? (785) (787) NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON R (788) R =H or Me okc (789) I (790) R = C5Hll or CHMeCHMe C5Hll ( 791) Iridoids with unsaturation in the cyclopentane ring include gentioside (763) from Centranthus r~ber,~~’ gardoside methyl ester (764) from Parentucellia viscos~,~~~ 7-deoxygardoside (765) from Argylia radiat~,~~~ and strictoloside (766) from the leaves of Penstemon strictus.597 Further new structures include 10-deoxymelittoside (767) from the aerial parts of Lamiastrum gale~bdolon,~~~ 10-methylixoside (768) from the leaves of Randia d~rnetorurn,~~~ and hygrophiloside (769) from Hygro-phila diformis.600 Some new iridoid epoxides which have been described are 6-senecioylantirrinoside (770) and 6-angeloylantirrinoside (77 1) from Linaria clementei,601 6-deoxycatalpol (772) from and Cistanchis herba,602 Utricularia australi~,~~~ Castilleja mini at^,^^^ l0-[(Z)-cinnamoyl]catalpol (773) from Pinguicula v~lgaris,~~~ and radiatoside (774) (a dimer of mussaenoside and catalpol) which was extracted from Argylia radiata605 The rehmaglutins A (779 B (776) and D (777) have been isolated from the roots of Rehmannia glutinosa,606 as have rehmaglutin C (778) and glutinoside (779).607 13 Cannabinoids A review on Cannabis sativa and its chemistry has been published.608 The hexahydrocannabinol analogue (780) has been syn- thesized from (+)-(R)-citronella1 (39) via the reaction of the aldehyde with lithium 2-lithiophenoxide to give (78 l) which cyclizes to (780) when it is heated.609 Both the (+)-and the (-)-form of hexahydrocannabinol (782) itself have also been made from (+)-(I?)-and (-)-(3-citronella1 respectively.610 A good catalyst for condensation of the menthadienol (783) with resorcinols [to give for example cannabidiol (784)] is BF Et,O on A120,.61’ The thioacetal(785) has been converted into Al-tetrahydrocannabinol-7-oicacid (786),612 and a syn- thesis of (& )-1 1 -nor-A8-tetrahydrocannabinol-9-carboxylic acid (787) has been reported.613 Some cannabinoid analogues which have been synthesized include the acids (788),614 the amine (789),615 and the variants (790).615 Syntheses of several [13C +14C]-labelled compounds of interest in this area have been described.616 The structures conformations and configurations of some synthetic cannabinoids such as (79 l) have been determined from their n.m.r.data with the aid of computer method^.^" 14 References 1 D. H. Grayson Nut. Prod. Rep. 1987 4 377. 2 H. Schilcher Therapiewoche 1986 36 1100. 3 K.Kogami Koryo 1985 145 11. 4 M. M. Litvinenko A. V. Degot M. S. Fursa and V. I. Lit- vinenko Farm. Zh. (Kiev) 1985 No. 4 p. 32. 5 H. P. Hanssen E. Sprecher and A. Klingenberg Prog. Essent. Oil Res. Proc. Int. Symp. Essent. Oil 16th 1985 (publ. 1986) 395. 6 K. Kieslich W. R. Abraham B. Stumpf and P. Washausen Top. Flavour Res. Proc. Int. Conf. 1985 405. 7 W. R. Abraham H. M. R. Hoffmann K. Kieslich G. Reng and B. Stumpf Ciba Found. Symp. 1985 111 146. 8 K. Nabeta and H. Sugisawa Saibo Kogaku 1985 4 382. 9 J. T. Brown and B. V. Charlwood FEBS Lett. 1986 204 117. 10 L. A. Anderson J. D. Phillipson and M. F. Roberts Adv. Bio- chem. Eng./Biotechnol. 1985 31 1. 11 R. Croteau in ‘Biogeneration of Aromas’ (A.C.S. Symposium Series No. 317) ed.T. H. Parliment and R. Croteau The American Chemical Society Washington D.C. 1986 p. 134. 12 V. J. Davisson A. B. Woodside T. R. Neal K. E. Stremler M. Muehlbacher and C. D. Poulter J. Org. Chem. 1986 51 4768. 13 T. Suga T. Hirata T. Aoki and T. Shishibori Phytochemistry 1986 25 2769. 14 I. Ekiel G. D. Sprott and I. C. P. Smith J. Bacteriol. 1986 166 559. 15 K. Isoi Mukugawa Joshi Daigaku Kiyo Yakugaku Hen 1985,33 1. 16 J. A. Schneider and K. Yoshihara J. Org. Chem. 1986 51 1077. 17 D. V. Banthorpe T. J. Grey I. Poots and W. D. Fordham Phytochemistry 1986 25 2321. 18 T. Yasuda and Y. Fujii Kagaku To Seibutsu 1986 24 7. 19 R. Croteau and M. A. Johnson in ‘Biosynthesis and Biodegrad- ation of Wood Components’ ed. T. Higuchi Academic Press Orlando Florida 1985 p.379. 20 R. Stepen and A. Sukhinin Izv. Sib. Otd. Akad. Nauk SSSR Ser. Biol. Nauk. 1985 No. 2 p. 47. 21 K. Ohta Geochem. J. 1986 19 269. 22 R. Atkinson S. M. Aschmann and J. N. Pitts Int. J. Chem. Kinet. 1986 18 287. 23 Actes -Colloq. Int. Plant. Aromat. Med. Maroc. Ist 1984 (publ. 1985) ed. J. Bellakhdar. 24 Essent. Oils Aromat. Plants Proc. Int. Symp. 15th 1984 (publ. 1985). 25 D. K. Mathela H. B. Kharkwal and C. S. Mathela Fitoterapia 1986 57 299. 26 Z.-G. Jian S.-Z. Chen S. Liu J.-L. Zhang Y.-Z. Yang and H.-H. Hu Huazhong Shifan Daxue Xuebao Ziran Kexueban 1986 20 169. 27 2.-K. Ma Z.-M. Lin R.-X. Xu and S.-Q. Zhong Sepu 1986 4 386. 28 Y.-Z. Chen D.-Y. Xue Z.-L. Li and H. Han Sepu 1986,4 324.29 D.-Y. Xue Z.-L. Li and Y.-Z. Chen Gaodeng Xuexiao Huaxue Xuebao 1986 7 905. 30 I. Feuerstein D. Mueller K. Hobert A. Danin and R. Segal Phytochemistry 1986 25 2343. 31 J. P. Vidal and H. Richard Flavour Fragrance J. 1986 1 No. 2 p. 57. 32 S. K. Adesina J. Nut. Prod, 1986 49 715. 33 E. von Rudloff S. Martin and R. G. McMinn Can. J. For. Res. 1985 15 801. 34 R. A. Stepen and L. S. Klimova Khim. Drev. 1985 No. 4 p. 101. 35 R. A. Stepen and G. A. Kuznetsova Lesovedenie 1986 No. 2 p. 86. 36 E. von Rudloff Flavour Fragrance J. 1985 1 No. 1 p. 33. 37 G. D. Hall and J. H. Langenheim Biochem. Syst. Ed. 1986 14 625. 38 S. Ramic D. Murko S. Alibalic and J. ZuDanec Rad. Poljopr. Fak. Univ. Sarajevu 1985 33 77. 39 D. Vokou and J.M. Bessiere J. Nut. Prod. 1985 48 498. 40 E. M. Gaydou and R. P. Randriamiharisoa Phytochemistry 1986 25 183. 41 A. M. Rizk H. I. Heiba M. Mashaly and P. Sandra Qatar Univ. Sci. Bull. 1985 5 71. 42 R. P. Doss W. H. Hatheway and B. F. Hrutfiord Phytochem-istry 1986 25 1637. 43 M. H. Boelens Perfum. Flavor. 1985 10 No. 5 pp. 21 et seq. 44 A. Akhila and H. K. Srivastava PAFAI J. 1985 7 No. 3 p. 11. 45 N. A. Kekelidze M. I. Dzhanikashvili L. V. Rusadze and A. P. Kachurina Khim. Prir. Soedin. 1985 784. 46 D. E. Lincoln M. J. Murray and B. M. Lawrence Phyto-chemistry 1986 25 1857. 47 R. Di Stefano and D. Antonacci Riv. Vitic. Enol. 1986 39 313. 48 B. Wilson C. R. Strauss and P. J. Williams J. Agric. Food Chem. 1984 32 919.49 B. Wilson C. R. Strauss and P. J. Williams Am. J. Enol. Vitic. 1986 37 107. 50 P. J. Williams C. R. Strauss B. Wilson and E. Dimitriadis Dev. Food Sci. 1985 10 349. 51 Y. Z. Gunata C. L. Bayonove R. L. Baumes and R. E. Cordon-nier J. Sci. Food Agric. 1985 36 857. 52 J. Marais and C. J. van Wyk S. Afr. J. Enol. Vitic. 1986 7 26. 53 G. Vernin Parfums Cosmet. Aromes 1986 68 83 and 93. 54 A. Rapp and H. Mandery Experientia 1986 42 873. 55 A. Carnacini and A. Del Pozzo Vignevini 1986 13 17. 56 C. R. Strauss B. Wilson P. R. Gooley and P. J. Williams in ‘Biogeneration of Aromas’ (A.C.S. Symposium Series No. 317) ed. T. H. Parliment and R. Croteau The American Chemical Society Washington D.C. 1986 p. 222 57 C. R. Strauss P. J. Williams B. Wilson and E.Dimitriadis Found. Biotech. Ind. Ferment. Res. (Publ.) 1984 3 51. 58 A. Rapp H. Mandery and M. Guentert Found. Biotech. Ind. Ferment. Res. (Publ.) 1984 3 255. 59 M. P. Romero A. Casp and J. M. Carrasco Rev. Agroquim. Tecnol. Aliment. 1986 26 338. 60 J. Marais S. Afr. J. Enol. Vitic. 1986 7 21. 61 E. Dimitriadis and P. J. Williams Am. J. Enol. Vitic. 1984 35 66. 62 E. I. Karakozova A. B. Solov’eva E. V. Ivanova and V. V. Ershov Izv Akad. Nauk SSSR Ser. Khim. 1986 214. 63 S. Suzuki Y. Fujita Y. Kobayashi and F. Sato Synth. Commun. 1986 16 491. 64 S. Suzuki Y. Fujita Y. Kobayashi and F. Sato Tetrahedron Lett. 1986 27 69. 65 F. VanMiddlesworth Y. F. Wang B. N. Zhou D. DiTullio and C. J. Sih Tetrahedron Lett. 1985 26 961. 66 Yu.B. Kal’yan M. Z. Krimer V. A. Smit A. M. Moiseenkov and A. I. Lutsenko Izv. Akad. Nauk SSSR Ser. Khim. 1985 2082. 67 Yu. N. Bubnov and M. Yu. Etinger Tetrahedron Lett. 1985 26 2797. 68 N. Kato and H. Takeshita Bull. Chem. SOC. Jpn. 1985 58 1574. 69 H. Suemune K. Ueno T. Kawahara K. Oda K. Funakoshi and K. Sakai Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 27th 1985 108. 70 H. M. R. Hoffmann Prog. Essent. Oil Res. Proc. Int. Symp. Essent. Oils 16th 1985 (publ. 1986) 329. 71 H. Kikuchi and T. Nagase Koryo 1985 145 37. 72 S. Mihara and H. Masuda Koryo 1985 145 53. 73 J. Verghese Indian Perfum. 1984 28 156. 74 B. Ravindranath Perfum. Flavor. 1985 10 No. 2 pp. 39 et seq. 75 E. Grozeva V. Angelov and D. Dimitrov Khim. Ind. (Soja) 1985 57 92.76 M. Yamashita M. Nishida and R. Suemitsu Sci. Eng. Rev. Doshisha Univ. 1986 27 74. 77 T. K. Razdan R. K. Wanchoo G. K. Raina and C. K. Jotshi Parfuem. Kosmet. 1985 66 444 and 448. 78 N. A. Klyuev V. A. Zamureenko and N. S. Evtushenko Farmat-siya (Moscow) 1986 35 76. 79 I. Laakso R. Hiltunen and T. Seppanen Prog. Essent. Oil Res. Proc. Int. Symp. Essent. Oils 16th 1985 (publ. 1986) 619. 80 T.-S.Wang and Y.-L. Sun Huaxue Tongbao 1986 No. 2 p. 19. 81 W. Herres K. H. Kubeczka and W. Schultze Prog. Essent. Oil Res. Proc. Int. Symp. Essent. Oils 16th 1985 (publ. 1986) 507. 82 B. G. Udarov Khim. Drev. 1986 No. 5 p. 100. 83 E. Bocchio Parfums Cosmet. Aromes 1985 63 61. 84 G. A. Graciela Malinskas M. N. Santi and J. A. Retamar Es-senze Deriv.Agrum. 1985 55 52. NATURAL PRODUCT REPORTS 1988 85 G. Stanley J. E. Algie and J. J. Brophy Chem. Ind. (London) 1986 556. 86 A. D. Dembitskii G. I. Krotova R. Suleeva and R. A. Yurina Khim. Prir. Soedin. 1985 332. 87 S. A. Gadir Y. Smith A. A. Taha and V. Thaller J. Chem. Res. (S) 1986 102. 88 S. Banerjee M. Grenz J. Jakupovic and F. Bohlmann Planta Med. 1985 177. 89 H. P. Hanssen and V. Sinnwell Z. Naturforsch. Sect. C 1986,41 825. 90 V. A. Kurkin G. G. Zapesochnaya and A. N. Shchavlinskii Khim. Prir. Soedin. 1985 632. 91 C. R. Strauss B. Wilson A. Rapp M. Guentert and P. J. Williams J. Agric. Food Chem. 1985 33 706. 92 J. Reisch S. K. Adesina D. Bergenthal and R. A. Hussain Sci. Pharm. 1985 53 153. 93 N. I. Lyashenko Pishch.Prom-st. (Kiev) 1985 No. 3 p. 38. 94 B. M. Lawrence R. H. Powell T. W. Smith and S. Kramer Perfum. Flavor. 1986 10 No. 6 p. 56. 95 0.C. Castro Ing. Cienc. Quim. 1985 9 94. 96 N. Kumar and M. G. Motto Phytochemistry 1986 25 250. 97 R. Di Stefano Vini Ital. 1986 28 41. 98 L.-F. Zhu B.-Y. Lu Y.-J. Li and L.-T. Mai Zhiwu Xuebao 1985 27 407. 99 R. Palic and M. J. Gasic J. Serb. Chem. Soc. 1985 50 571. 100 J. M. Bessiere J. Pellecuer and P. Allain Fitoterapia 1985 56 62. 101 M. G. Motto and N. J. Secord J. Agric. Food Chem. 1985 33 789. 102 E. Stahl-Biskup Planta Med. 1986 36. 103 U. Ravid E. Putievsky M. Bassat R. Ikan and V. Weinstein Flavour Fragance J. 1986 1 No. 3 p. 121. 104 A. Rapp H. Mandery and H. Niebergall Vitis 1986 25 79. 105 G.Bock I. Benda and P. Schreier in ‘Biogeneration of Aromas’ (A.C.S. Symposium Series No. 317) ed. T. H. Parliment and R. Croteau The American Chemical Society Washington D.C. 1986 p. 243 106 G. Bock I. Benda and P. Schreier J. Food Sci. 1986 51 659. 107 P. A. Vandenbergh and R. L. Cole Appl. Environ. Microbiol. 1986 52 939. 108 P. Winterhalter D. Katzenberger and P. Schreier Phytochem-istry 1986 25 1347. 109 R. Eberhardt and W. Pfannhauser Mikrochim. Acta 1985 1 55. 110 M. L. Maheshwari and J. Mohan PAFAI J. 1985 7 No. 3 p. 21. 11 1 M. A. Prosovskii K. S. Rybalko,V. I. Sheichenko A. N. Shchab- linskii and G. I. Oleshko Khim.-Farm.Zh. 1985 19 981. I12 G. I. Oleshko and M. A. Prosovskii Rastit. Resur. 1986 22,377. 11 3 Y.Yamada C. W. Seo and H. Okada Appl. Environ. Microbiol. 1985 49 960. 114 C. Marlot G. Langrand C. Triantaphylides and J. Baratti Bio-technol. Lett. 1985 7 647. 115 S. A. Abramov 0.K. Vlasova A. M. Makuev T. I. Daudova I. A. Egorov A. K. Rodopulo and A. A. Bezzubov Prikl. Bio- khim. Mikrobiol. 1986 22 126. 116 A. Rapp W. Rieth and H. Ullemeyer Vitis 1985 24 241. 117 N. Jourdain T. Goli J. C. Jallageas C. Crouzet C. Ghommidh J. M. Navarro and J. Crouzet Top. Flavour Res. Proc. Int. Conf. 1985 427. 118 A. Akhila Phytochemistry 1986 25 421. 119 A. Akhila Phytochemistry 1985 24 2585. 120 R. Croteau and J. Shaskus Arch. Biochem. Biophys. 1985 236 535. 121 F. Juettner B. Hoeflacher and K. Wurster J. Phycol. 1986 22 169. 122 I. S. Aul’chenko Pollena Tluszcze Srodki Piorace Kosmet.1985 29 205. 123 H. Tsukasa Koryo 1986 150 25. 124 0.Cori L. Chayet L. M. Perez C. A. Bunton and D. Hachey J. Org. Chem. 1986 51 1310. 125 H. Takeshita K. Komiyama and K. Okaishi Bull. Chem. Soc. Jpn. 1985 58 2725. 126 S. A. Floreani P. M. E. Mancini and J. A. Retamar An. Asoc. Quim. Argent. 1984 72 591. 127 H. Kumobayashi S. Mitsuhashi S. Akutagawa and S. Ohtsuka Chem. Lett. 1986 157. 128 A. M. Moiseenkov A. N. Rechnitzkii E. V. Polunin 0.N. Yu- dina and I. M. Zaks Izv. Akad. Nauk SSSR Ser. Khim. 1985 1820. NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON 129 G. Miganani D. Morel Y. Colleuille and C. Mercier Tetra-hedron Lett. 1986 27 2591. 130 P. Weyerstahl W. Zombik and C. Gansav Liebigs Ann.Chem. 1986 422. 131 K. Mori and H. Mori Tetrahedron 1985 41 5487. 132 R. J. Armstrong and L. Weiller Can. J. Chem. 1986 64 584. 133 K. C. Lam and M. L. Deinzer J. Am. SOC. Brew. Chem. 1986,44 69. 134 F. Scott and M. M. Nkwelo Synth. Commun. 1985 15 1051. 135 L. Meier and H. D. Scharf Liebigs Ann. Chem. 1986 731. 136 Z. M. Ismail and H. M. R. Hoffmann Heterocycles 1986 24 325. 137 S. krnasconi M. Colombo G. Jommi and M. Sisti Gazz. Chim. Ital. 1986 116 69. 138 K. Mori M. Waku and M. Sakakibara Tetrahedron 1985 41 2825. 139 B. Badet M. Julia and C. Marazano Tetrahedron Lett. 1985,26 2007. 140 M. Julia and C. Schmitz Bull. SOC. Chim. Fr. 1986 630. 141 S. L. Abidi J. Chem. SOC. Chem. Commun. 1985 1222. 142 S. L. Abidi J.Org. Chem. 1986 51 2687. 143 S. L. Abidi Tetrahedron Lett. 1986 27 267. 144 M. Ohwa T. Kogure and E. L. Eliel J. Org. Chem. 1986 51 2599. 145 Z.-J. Liu Z.-J. Chen W.-Y. Ding and Y. Fang Huaxue Xuebao 1985 43 1068. 146 A. N. Karavanov N. N. Mikhalenko and V. M. Gryaznov Dokl. Akad. Nauk SSSR 1986 286 908. 147 K. Uneyama T. Date and S. Torii J. Org. Chem. 1985 50 3160. 148 S. Inoue M. Osada K. Koyano H. Takaya and R. Noyori Chem. Lett. 1985 1007. 149 M. Hirama T. Noda and S. Ito J. Org. Chem. 1985 50 127. 150 P. Gramatica P. Manitto and L. Poli J. Org. Chem. 1985 50 462 5. 151 H. Paulsen Bien Le Nguyen V. Sinnwell V. Heemann and F. Seehofer Liebigs Ann. Chem. 1985 1513. 152 K. E. Ishag H. Jork and M. Zeppezauer Fresenius’ Z. Anal. Chem.1985 321 331. 153 G. Kortvelyessy Acta Chim. Hung. 1985 119 347. 154 L. I. Gvinter L. N. Suvorova S. S. Danielova and L. K. Freid-lin Zh. Org. Khim. 1986 22 79. 155 A. A. Wismeijer A. P. G. Kieboom and H. van Bekkum React. Kinet. Catal. Lett. 1985 29 311. 156 S. Sakane K. Maruoka and H. Yamamoto Nippon Kagaku Kaishi 1985 324. 157 S. Sakane K. Maruoka and H. Yamamoto Tetrahedron Lett. 1985 26 5535. 158 S. Sakane K. Maruoka and H. Yamamoto Tetrahedron 1986 42 2203. 159 A. Arcoria F. P. Ballistreri G. A. Tomaselli F. di Furia and G. Modena J. Org. Chem. 1986 51 2374. 160 T. Yokoyama M. Nishizawa,.T. Kimura and T. M. Suzuki Bull. Chem. SOC. Jpn. 1985 58 3271. 161 0.Bortolini F. di Furia and G. Modena J. Mol. Catal. 1985 33 241. 162 L.Novak L. Poppe A. Kis-Tamas and C. Szantay Acta Chim. Hung. 1985 118 17. 163 R. A. Whitney Can. J. Chem. 1986 64 803. 164 J. R. Williams C. Lin and D. F. Chodosh J. Org. Chem. 1985 50 5815. 165 P. Gramatica G. Giardina G. Speranza and P. Manitto Chem. Lett. 1985 1395. 166 J. Ahmad and K. B. Astin J. Am. Chem. Soc. 1986 108 7434. 167 S. Sakane J. Fujiwara K. Maruoka and H. Yamamoto Tetra-hedron 1986 42 2193. 168 M. Julia and C. Schmitz Tetrahedron 1986 42 2485. 169 B. Vig R. Kanwar and D. R. Arora J. Indian Chem. SOC. 1985 61 893. 170 K. Maruoka Y. Fukutani and H. Yamamoto J. Org. Chem. 1985 50 4412. 171 W. Sobotka and E. Chojecka-Koryn Bull. Pol. Acad. Sci. Chem. 1984 32 207. 172 0.P. Vig I. R. Trehan G. L. Kad S. Kumari and A.L. Bedi J. Indian Chem. SOC. 1985 62 238. 173 S. Sasaoka T. Yamamoto H. Kinoshita K. Inomata and H. Kotake Chem. Lett. 1985 315. 174 T. Cuvigny M. Julia and C. Rolando J. Organomet. Chem. 1985 285 395. 175 B. Aakermark and A.Vitagliano Organometallics 1985,4,1275. 176 V. J. Davisson A. B. Woodside and C. D. Poulter Methods Enzyrnol. 1985 110 130. 177 Y. Butsugan T. Goto and S. Araki Bull. Chem. SOC. Jpn. 1985 58 2137. 178 J. H. Oh K. Kim and Y. T. Kim Taehan Hwahakhoe Chi 1985 29 311. 179 E. J. Leopold Org. Synth. 1986 64 164. 180 A. Tanaka M. Suzuki and K. Yamashita Agric. Biol. Chem. 1986 50 1069. 181 S. Suzuki K. Kanehira Y. Fujita and J. Otera Nippon Kagaku Kaishi 1985 552. 182 F. Tateo F. Berte A. Bianchi C. Gregotti and P.Richelmi Riv. SOC.Ital. Sci. Aliment. 1986 15 23. 183 K. Hotta Nippon Kagaku Kaishi 1985 674. 184 L. P. Glushko V. N. Samsonova L. A. Yanovskaya and L. V. Dmitrikov Khim. Geterotsikl. Soedin. 1986 453. 185 E. A. Aboutabl F. M. Soliman S. M. El-Zalabani E. J. Brunke and T. A. El-Kersh Sci. Pharm. 1986 54 37. 186 J. S. H. Kueh I. A. Mackenzie and G. Pattenden Plant Cell Rep. 1985 4 118. 187 S. Takano M. Tanaka K. Seo M. Hirawa and K. Ogasawara J. Org. Chem. 1985 50 931. 188 J. Celebuski and M. Rosenblum Tetrahedron 1985 41 5741. 189 B. D. Johnston K. N. Slessor and A. C. Oehlschlager J. Org. Chem. 1985 50 114. 190 H. Frauenrath and T. Philipps Liebigs Ann. Chem. 1985 1303. 191 S. Takano M. Sato M. Akiyama and K. Ogasawara Hetero-cycles 1985 23 2859.192 A. Krief M. J. Devos and M. Sevrin Tetrahedron Lett. 1986,27 2283. 193 R. L. Funk and J. D. Munger J. Org. Chem. 1985 50 707. 194 A. G. Cameron and D. W. Knight Tetrahedron Lett. 1985 26 3503. 195 M. Franck-Neumann M Sedrati J. P. Vigneron and V. Bloy Angew. Chem.; 1985 97 995. 196 J. D’Angelo G. Revial R. Azerad and D. Buissov J. Org. Chem. 1986 51,40. 197 M. Saljoughian J. Labelled Compd. Radiopharm. 1985 22 1093. 198 T. Aratani Kagaku Zokan (Kyoto) 1985 No. 105 p. 133. 199 G. Stufflebeme K. T. Lorenz and N. L. Bauld J. Am. Chem. SOC.,1986 108 4234. 200 M. Franck-Neumann and M. Miesch Bull. SOC.Chim. Fr. Part. 2 1984 362. 201 A. Krief L. Hevesi G. Chaboteaux P. Mathy M. Sevrin and J. J. De Vos J. Chem. SOC.Chem. Commun. 1985 1693. 202 J. H. Babler and K. P. Spina Tetrahedron Lett. 1985 26 1923. 203 S. Muramatsu Y. Nakada and J. Ide Agric. Biol. Chem. 1985 49 751. 204 T. Hirao Y. Harano Y.Yamana Y. Hamada S. Nagato and T. Agawa Bull. Chem. SOC. Jpn. 1986 59 1341. 205 I. Reichelt and H. U. Reissig Liebigs Ann. Chem. 1985 650. 206 M. Ohno S. Matsuoka and S. Eguchi J. Org. Chem. 1986 51 4553. 207 H. A. Taher G. 0.Ubiergo and E. C. T. Talenti J. Nat. Prod. 1985 48 857. 208 A. G. Mekkawi Fitoterapia 1985 56 181. 209 C. H. Brieskorn and G. Krauss Planta Med. 1986 305. 210 P. Maupetit Perfum. Flavor. 1984 9 No. 6 pp. 19 et seq. 21 1 S.-J. Tian Yaowu Fenxi Zazhi 1985 5 4. 212 Y. S. Hwang K. H. Wu J. Kunamoto H. Axelrod and M. S. Mulla J. Chem. Ecol.1985 11 1297. 213 K. Grzunov J. Mastelic and N. Ruzic Acta Pharm. Jugosl. 1985 35 175. 214 F. Demarne J. Garnero and J. M. Mondon Parfums Comet. Aromes 1986 70 57. 215 A. Nahrstedt D. Economou and F. J. Hammerschmidt Planta Med. 1985 247. 216 S. Shimizu Kiyo -Iida Joshi Tanki Daigaku 1986 No. 8 p. 13. 217 M. Abbas-Saleh Biochem. Syst. Ecol. 1985 13 265. 218 H. L. de Pooter L. F. de Buyck and N. M. Schamp Phytochem-istry 1986 25 691. 219 S. Fujita and K. Nezv Nippon Kagaku Kaishi 1985 59 703. 220 E. Sezik and G. Tumen Doga Bilim Derg. Seri C 1986 10 59. 221 M. Kubo H. Sasaki T. Endo H. Taguchi and I. Yosioka Chem. Pharm. Bull. 1986 34 3097. 222 J. J. Brophy M. Rahmani R. F. Toia K. D. Croft and E. V. Lassak Flavour Fragrance J. 1985 1 No.1 p. 17. 223 M. Koepsel A. Krempel and H. Surburg Prog. Essent. Oil Res. Proc. Int. Symp. Essent. Oils 16th 1985 (publ. 1986) 241. 224 T. Hayashi T. Shinbo M. Shimizu M. Arisawa N. Morita M. Kimura S. Matsuda and T. Kikuchi Tetrahedron Lett. 1985,26 3699. 225 A. D. Dembitskii R. A. Yurina and G. I. Krotova Khim. Prir. Soedin. 1985 510. 226 D. Lemordant Int. J. Crude Drug Res. 1986 24 107. 227 M. A. Saleh J. Agric. Food. Chem. 1986 34 192. 228 F. Yu. Kasumov and S. E. Davidenko Khim. Prir. Soedin. 1985 840. 229 M. Melegari A. Albasini A. Provisionato A. Bianchi G. Vampa P. Pecorari and M. Rinaldi Fitoterapia 1985 56 85. 230 H. Hendriks R. Bos. and A. P. Bruins Planta Med. 1985 541. 231 M. Metwally A.-A. Dawidar and S. Metwally Chem.Pharm. Bull. 1986 34 378. 232 M. A. Metwally and R. M. King Indian J. Chem. Sect. B 1985 24 982. 233 T. S. Wu M. Niwa H. Furukawa and C. S. Kuoh Chem. Pharm. Bull. 1985 33 4005. 234 M. A. Metwally and A. M. Dawidar Phytochemistry 1985 24 1377. 235 B. K. Brookes H. A. Candy and K. H. Pegel Planta Med. 1985 32. 236 A. B. Gonzalez J. B. Barrera F. E. Rosas A. C. Y. Hernandez J. Espineira and P. Joseph-Nathan Phytochemistry 1986 25 2889. 237 J. D. Hernandez L. U. Roman M. J. Rodriguez J. Espineira and P. Joseph-Nathan Phytochemistry 1986 25 1743. 238 R. M. Carman L. K. Lynette W. T. Robinson and J. M. A. M. van Dongen Aust. J. Chem. 1986 39 1843. 239 H. Kipphardt and D. Enders Kontakte (Darmstadt) 1985 No. 2 p. 37. 240 J.K. Whitesell C.-L. Liu C. M. Buchanan H.-H. Chen and M. A. Minton J. Org. Chem. 1986 51 551. 241 H. Herzog and H. D. Scharf Synthesis 1986 420. 242 J. K. Whitesell and M. A. Minton J. Am. Chem. Soc. 1986 108 6802. 243 J. K. Whitesell R. M. Lawrence and H.-H. Chen J. Org. Chem. 1986 51 4779. 244 G. Boireau A. Korenova A. Deberly and D. Abenhaim Tetra-hedron Lett. 1985 26 4181. 245 E. J. Corey and R. T. Peterson Tetrahedron Lett. 1985 26 5025. 246 A. Misumi K. Iwanaga K. Furuta and H. Yamamoto J. Am. Chem. Soc. 1985 107 3343. 247 T. Esaki S. Sakane and H. Yamamoto Tetrahedron Lett. 1986 27 1359. 248 J. K. Whitesell D. James and J. F. Carpenter J. Chem. SOC. Chem. Commun. 1985 1449. 249 V. Prelog and M. Dumic Hdv. Chim. Acta 1986 69 5.250 H. C. Brown W. S. Park and B. T. Cho J. Org. Chem. 1986,51 3278. 251 K. Hiroi and S. Sato Chem. Pharm. Bull. 1985 33 4691. 252 T. Fuchigami A. Sato and T. Nonaka Chem. Express 1986 1 363. 253 R. Boese G. Haegele W. Kueckelhaus J. Seega and G. Tos- sing Chem.-Ztg. 1985 109 2233. 254 G. Haegele W. Kueckelhaus J. Seega G. Tossing H. Kessler and R. Schuck Z. Naturforsch. Teil B 1985 40,1053. 255 R. Boese G. Haegele W. Kueckelhaus and G. Tossing Phos-phorus Sulfur 1985 25 103. 256 T. J. Brocksom E. T. Canevarolo and F. T. Lopes An. Acad. Bras. Cienc. 1985 57 159. 257 N. G. Kozlov L. A. Popova and M. G. Novikova Zh. Org. Khim. 1986 22 536. 258 D.Young M. Jones and W. Kitching Aust. J. Chem. 1986,39,563. 259 H. J. Bestmann U. Kobold and 0.Vostrowsky Liebigs Ann.Chem. 1986 234. 260 Z. A. Filippenko 0.M. Baranov G. N. Roganov and G. Ya. Kabo Khim. Prir. Soedin. 1985 51. 261 R. R. Juo and W. Herz J. Org. Chem. 1985 50 700. 262 J.-M. Fang and Y.-W. Wang Proc. Natl. Sci. Counc. Repub. China Part A Phys. Sci. Eng. 1985 9 95. 263 F. Nicotra L. Panza F. Ronchetti G. Russo and L. Toma J. Org. Chem. 1986 51 1272. 264 K. Mori and M. Kato Tetrahedron Lett. 1986 27 98 1. 265 J. Kula and J. Podlejski Liebigs Ann. Chem. 1985 2098. 266 W. R. Abraham K. Kieslich H. Reng and B. Stumpf Eur. Congr. Biotechnol. 3rd 1984 1 245. 267 W. R. Abraham B. Stumpf and K. Kieslich Appl. Microbiol. Biotechnol. 1986 24 24. NATURAL PRODUCT REPORTS 1988 268 V. I. Lysenkov T. I. Pekhk and G. N. Bazhina Vestsi Akad.Navuk B.SSR Ser. Khim. Navuk 1985 No. I p. 60. 269 B. Ravindranath and P. Srinivas Zndian J. Chem. Sect. B 1985 24 163. 270 H. A. Taher and G. 0.Ubiergo Essenze Deriv. Agrum. 1984,54 122. 271 M. Nomura and Y. Fujihara Yukaguku 1985 34 352. 272 S. S. Ullah M. E. Molla and N. Begum Indian J. Chem. Sect. A 1985 23 992. 273 M. Andrianome and B. Delmond Tetrahedron Lett. 1985 26 6341. 274 R. M. Carman J. J. de Voss and K. L. Greenfield Aust. J. Chem. 1986 39 441. 275 T. Kurata T. Koshiyama and H. Kawashima Yukagaku 1985 34 1032. 276 K. N. Gurudutt M. A. Pasha and B. Ravindranath Indian J. Chem. Sect. B 1985 24 820. 277 V. V. Bazyl’chik P. I. Fedorov N. A. Klyuev and E. K. Dank Zh. Org. Khim. 1985 21 1450. 278 V. V.Bazyl’chik P. I. Fedorov E. D. Skakovskii and N. A. Klyuev Zh. Org. Khim. 1985 21 1446. 279 M. Beldowicz A. Malasiewicz M. Jarosewska W. S. Brud and M. Pilecki Parfuem. Kosmet. 1986 67 445 and 448. 280 A. F. Thomas and C. Perret Tetrahedron 1986 42 33 11. 281 R. M. Carman K. L. Greenfield and W. T. Robinson Aust. J. Chem. 1986 39 21. 282 E. F. Buinova T. I. Pekhk V. I. Lysenkov N. G. Yaremchenko and T. L. Sen’ko Zh. Obshch. Khim. 1985 55 2751. 283 M. V. Mir H. L. G. de la Serrana M. C. L. Martinez and R. Garcia-Villanova An. Bromatol. 1984 36 133. 284 M. V. Mir H. L. G. de la Serrana M. C. L. Martinez and R. Garcia-Villanova An. Bromatol. 1984 36 61. 285 R. H. Crabtree and M. W. Davis J. Org. Chem. 1986 51 2655. 286 M. Ouertani J. Collin and H.B. Kagan Tetrahedron 1985 41 3689. 287 B. M. Trost and T. N. Nanninga J. Am. Chem. Soc. 1985 107 1075. 288 H. Szalkowska-Pagowska and K. Piatkowski Pol. J. Chem. 1985 59 531. 289 S. G. Hegde D. Beckwith R. Doti and J. Wolinsky J. Org. Chem. 1985 50 894. 290 A. Monkiewicz and J. Gora Acta Biotechnol. 1985 5 263. 291 F. Chatzopoulos-Ouar and G. Descotes J. Org. Chem. 1985 50 118. 292 M. Rubio A. V. Bunge and E. M. Jiminez Rev. Latinoam. Quim. 1985 16 69. 293 R. Emberger and R. Hopp Top. Flavour Res. Proc. Int. Conf. 1985 201. 294 S. A. Haut J. Agric. Food Chem. 1985 33 278. 295 E. Gacs-Baitz and C. Rossi J. Chem. Res. (S) 1985 350. 296 P. P. Chernov and V. V. Bazyl’nik Zh. Org. Khim. 1986 22 323. 297 I. K. Brookes M. D. Lilly and J.W. Drozd Enzyme Microb. Technol. 1986 8 53. 298 L. B. Ionov S. M. Reshetnikov L. L. Makarova and T. M. Flegontova Zh. Obshch. Khim. 1985 55 862. 299 P. Rollin Synth. Cornrnun. 1986 16 61 1. 300 Y. Asakawa R. Matsuda and M. Tori Experientia 1986 42 201. 301 R. L. Varma and C. S. Narayanan Indian J. Chem. Sect B 1985 24 302. 302 H. Tsukasa Yukagaku 1985 34 959. 303 M. N. Santi H. A. Taher and G. Malinskas Essenze Deriv. Agrum. 1985 55 62. 304 K. P. Jotani V. N. Khunt and A. R. Parikh Acta Cienc. Indica Ser. Chem. 1984 10 255. 305 J. Lub M. L. Beekes and T. J. de Boer Red. Trav. Chim. Pays- Bas 1986 105 22. 306 H. Takayanagi E. Hirose,K. Furuhata andH. Ogura Bull. Chem. SOC.Jpn. 1985 58 745. 307 R. Croteau and K. V. Venkatachalam Arch.Biochem. Biophys. 1986 249 306. 308 D. L. Grundy and C. C. Still Pestic. Biochem. Physiol. 1985 23 378. 309 M. Berrada M. Rombourg A. Hakiki and J. Y. Vidal Bull. SOC. Chim. Fr. 1985 937. 310 R. D. Bach and R. C. Klix Tetrahedron Lett. 1985 26 985. 31 1 E. Sprecher and H. P. Hanssen Forum Mikrobiol. 1985 8 17. 312 N. Lindquist M. A. Battiste W. M. Whitten N. H. Williams and L. Strekowski Phytochemistry 1985 24 863. NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON 313 A. Mironowicz and A. Siewinski Acta Biotechnol. 1986 6,141. 314 M. J. Taschner and A. Shahripour J. Am. Chem. SOC.,1985 107 5570. 315 P.A. Wender and D. A. Holt J. Am. Chem. Soc. 1985 107 777 1. 316 E. C. Angel] F. Fringuelli F. Pizza B. Porter A. Taticchi and E.Wenkert J. Org. Chem. 1985 50 4696; the structure for carvone is given wrongly in this paper and in the related entry in Chemical Abstracts. 317 M. Miyashita T. Suzuki and A. Yoshikoshi J. Org. Chem. 1985 50,3377. 318 0.Louis-Andre and G. Gelbard Tetrahedron Lett. 1985 26 831. 319 T. Cohen and L. C. Yu J. Org. Chem. 1985 50,3266. 320 J.-L. Shi F.-L. Li Q.-X. Bi X.-Q. Shen J.-L. Gu J.-X. Yao Z.-Z. Zhou G.-P. Shen and M.-X. Qui Huaxue Xuebao 1986 44,681. 321 B. M. Trost and S. R. Angle J. Am. Chem. Soc. 1985 107 6123. 322 A. Tungler T. Mathe Z. Bende and J. Petro Appl. Catal. 1985 19,365. 323 P. Baeckstroem U. Jacobsson B. Koutek and T. Norin J. Org. Chem. 1985 50,3728. 324 E. R. Dockal Q. B. Cass T. J. Brocksom U. Brocksom and A.G. Correa Synth. Commun. 1985 15 1033. 325 R.M. Carman and J. M. A. H. van Drongen Aust. J. Chem. 1986 39,817. 326 A. Liptak J. W. Kusiak and J. Pitha J. Med. Chem. 1985 28 1699. 327 T. Fujita S. Watanabe K. Miharu K. Itoh and K. Sugahara J. Chem. Technol. Biotechnol. Chem. Technol. 1985 35A,57. 328 W. Giersch R. Brauchli W. Thommen and K. H. Schulte-Elte Helv. Chim. Acta 1986 69,996. 329 W. R. Abraham B. Stumpf and K. Kieslich Appl. Microbiol Biotechnol. 1986 24,31. 330 D.Pauluth and H. M. R. Hoffmann Liebigs Ann. Chem. 1985 756. 331 H. M. R. Hoffmann and D. Pauluth Liebigs Ann. Chem. 1985 396. 332 D. Pauluth and H. M. R. Hoffmann Liebigs Ann. Chem. 1985 403. 333 H. M. R. Hoffmann A. Koever and D. Pauluth J. Chem. Soc.Chem. Commun. 1985 812. 334 F. S. Sharipova L. A. El’chibekova E. S. Nedel’ko and V. Yu. Averina Izv. Akad. Nauk Kaz. SSR Ser. Khim. 1986 No. 1 p. 86. 335 J. J. Brophy E. V. Lassak and R. F. Toia Planta Med. 1985 170. 336 S. S. Mishurova T. A. Malinovskaya I. B. Akhmedov and D. G. Mamedov Rastit. Resur. 1986 22,526. 337 G. Ubiergo H. A. Taher and E. C. Talenti An. Asoc. Quim. Argent. 1986 74,567. 338 J. J. Brophy E. V. Lassak and R. F. Toia J. Proc. R. Soc. N.S. W. 1985 118,101. 339 J. Adam and M. Belley Tetrahedron Lett. 1986 27,2075. 340 M.Nomura and Y. Fujihara Nippon Kagaku Kaishi 1986 217. 341 G. C. Uniyal A. K. Singh N. C. Shah and A. A. Naqvi Planta Med. 1985 457. 342 J. Sanz I. Martinez-Castro and M. Pinar J. Nut. Prod. 1985,48 993.343 A. Villar R. M. Giner and J. L. Rios J. Nut. Prod. 1986 49 1143. 344 J. J. Brophy I. A. Southwell and I. A. Stiff J. Nut. Prod. 1986 49,174. 345 R. P. Adam T. A. Zanoni and L. Hogge J. Nut. Prod. 1985 48,678. 346 J. Kumarnoto R. W. Scora and W. A. Clerx J. Agric. Food Chem. 1985 33,650. 347 B. A. Sharipova M. R. Rasulova M. K. Kurbanov and Yu. N. Nuraliev Rastit. Resur. 1986 22,237. 348 V. M. Hernandez R. Miranda M. Martinez and P. Joseph- Nathan J. Nut. Prod. 1986 49,1173. 349 T. Suga T. Hirata and S. Izumi Phytochemistry 1986 25 279 1. 350 H. C. Brown F. J. Chloupek and K. Takeuchi J. Org. Chem. 1985 50,826. 351 J. Caram M. E. Martins C. M. Marschoff and E. G. Gros Rev. Latinoam. Quim. 1986 17,39. 352 N. G.Kozlov G. V. Nesterov and S. A. Makhnach Zh. Obshch. Khim. 1985 55,2099. 46 I 353 A. I. Sedel’nikov T. S. Tikhonova N. P. Polyakova and V. P. Larionov Gidroliz. Lesokhim. Prom-st. 1985 No. 4 p. 12. 354 H. R. Sonawane B. S. Nanjundiah and M. D. Panse Tetra-hedron Lett. 1985 26,3507. 355 H.R. Sonawane B. S. Nanjundiah M. Udaukumar and M. D. Panse Indian J. Chem. Sect. B 1985 24 202. 356 G. Buchbauer W. Pernold M. Ittner M. T. Ahmadi R. Dobner and R. Reidinger Monatsh. Chem. 1985 116,1209. 357 R. Vitek and G. Buchbauer Monatsh. Chem. 1985 116,801. 358 G. B. Crull A. R. Garber J. W. Kinnington C. M. Prosser P. W. Stone J. W. Fant and J. H. Dawson Magn. Reson. Chem. 1986 24 737. 359 P. B. Reese L. A. Trimble and J. C. Vederas Can. J. Chem. 1986 64 1427.360 A. Gedanken H. D. Lagier J. Schiller A. Klein and J. Hormes J. Am. Chem. Soc. 1986 108,5342. 361 H.P. Jensen Tetrahedron 1985 41,2867. 362 B. V. Crist S. G. Rodgers J. K. Gawronski and D. A. Lightner Spectroscopy 1985 4 19. 363 M. Falorni L. Lardicci and G. Giacomelli J. Org. Chem. 1986 51 5291. 364 A. G. Martinez E. T. Vilar M. M. Gomez and C. R. Franco Chem. Ber. 1985 118,1282. 365 G. Ruecker and W. Gajewski Eur. J. Med. Chem. Chim. Ther. 1985 20,87. 366 M. Momtchev V. Vassilev and B. Blagoev Bull. SOC.Chim. Fr. 1985 844. 367 J. R. Hwu and J. M. Wetzel J. Org. Chem. 1985 50,3946. 368 T. Money Nat. Prod. Rep. 1985 2,253. 369 J. W. Hutchinson T. W. Money and S. E. Piper Can. J. Chem. 1986 64 854. 370 H. Brunner and R.Becker Angew. Chem. 1985 97,713. 371 J. M. McIntosh and P. Mishra Can. J. Chem. 1986 64 726. 372 R. Knorr and F. Ruff Chem. Ber. 1985 118,4486. 373 E. Occelli L. Fontanella A. Diena and P. Schiatti Farmaco Ed. Sci. 1985 40,86. 374 M.-Q. Li R.-C. Ran and X.-R. Jia Huaxue Tongbao 1985 No. 12 p. 15. 375 M. E. Spiridonova 0.I. Korobkova and L. I. Olishevets Khim. Prir. Soedin. 1985 841. 376 M.-D. Ruan Y.-M. Zhang X.-D. Chen and L. Huang Hangzhou Daxue Xuebao Ziran Kexueban 1986 13,66. 377 R. Krishnamurti and H. G. Kuivila J. Org. Chem. 1986 51 4947. 378 P. Somfai D. Tanner and T. Olsson Tetrahedron 1985 41 5973. 379 W. Oppolzer C. Chapuis D. Dupuis and M. Guo Helv. Chim. Acta 1985 68 2100. 380 F. Effenberger T. Beisswenger and H.Isak Tetrahedron Lett. 1985 26,4335. 381 G. Helmchen and G. Wegner Tetrahedron Lett. 1985 26 6047. 382 G. Helmchen and G. Wegner Tetrahedron Lett. 1985 26,6051. 383 R. Gambino P. Mohr N. Waespe-Sarcevic and C. Tamm Tetra-hedron Lett. 1985 26,203. 384 C. Fizet Helv. Chim. Acta 1986 69,404. 385 M. Kitamura S. Suga K. Kawai and R. Noyori J. Am. Chem. Soc. 1986 108,6071. 386 C. R. Noe M. Knollmueller G. Steinbauer and H. Voellenkle Chem. Ber. 1985 118,4453. 387 C. R. Noe M. Knollmueller E. Wagner and H. Voellenkle Chem. Ber. 1985 118,3299. 388 M. R. Binns R. J. Goodridge R. K. Haynes and D. D. Ridley Tetrahedron Lett. 1985 26,6381. 389 0.de Lucchi V. Lucchini C. Marchioro G. Valle and G. Modena J. Org. Chem. 1986 51 1457. 390 F. A. Davis M.S. Haque T. G. Ulatowski and J. C. Towson J. Org. Chem. 1986 51,2402. 391 W. Oppolzer and D. Dupuis Tetrahedron Lett. 1985 26,5437. 392 W. Oppolzer M. J. Kelly and G. Bernardinelli Tetrahedron Lett. 1984 25,5889. 393 W. Oppolzer and P. Dudfield Tetrahedron Lett. 1985 26 5037. 394 R. Carlson and A. Nilsson Acta Chem. Scand. Ser. B 1985 39 181. 395 N. G. Kozlov and T. E. Kozlova Zh. Obshch. Khim. 1986 56 233. 396 N. Ikota H. Sakai H. Shibata and K. Koga Chem. Pharm. Bull. 1986 34 1050. 397 E. J. Corey and A. W. Gross J. Org. Chem. 1985 50,5392. 398 D. Parker R. J. Taylor G. Ferguson and A. Tonge Tetrahedron 1986 42 617. 399 Vandana R. M. Singh and S. M. Verma Indian J. Chem. Sect. B 1986 25 724. 400 A. V. Prosyanik Ya.Z. Zorin A. I. Mishchenko V. M. Negri- movskii and A. B. Zolotoi Izv. Akad. Nauk SSSR Ser. Khim. 1985 1840. 401 H. Spreitzer C. Schiffer and G. Buchbauer Liebigs Ann. Chem. 1986 1578. 402 J. P. Perry and X. M. Sanchez Nav. Stores Rev. 1986 96 18. 403 R. P. Adams T. A. Zanoni and L. Hogge J. Nut. Prod. 1985 48 673. 404 A. K. Borg-Karlson and I. Groth Phytochemistry 1986 25 1297. 405 E. Zavarin and K. Snajberk Biochem. Syst. Ecol. 1985 13 89. 406 L. V. Krasnoboyarova R. D. Kolesnikova and V. G. Latysh Izv. Vyssh. Uchebn. Zaved. Lesn. Zh. 1985 No. 2 p. 85. 407 Y. Asakawa M. Toyota and A. Cheminat Phytochemistry 1986 25 2555. 408 J. C. Bisht A. K. Pant C. S. Mathela U. Kobold and 0.Vos-trowsky Planta Med. 1985 412. 409 G. Schmeda-Hirschmann R.Boeker J. Jakupovic and F. Bohl- mann Phytochemistry 1986 25 1753. 410 I. S. AlSaadawi M. B. Arif and A. J. AlRubeaa J. Chem. Ecol. 1985 11 1527. 41 1 I. S. AlSaadawi and A. J. AlRubeaa J. Chem. Ecol. 1985 11 1515. 412 B. Draczynska C. Cagara A. Siewinski A. Rymkiewicz A. Zabza and A. Leufven J. Basic Microbiol. 1985 25 487. 413 S. J. Wright P. Caunt D. Carter and P. A. Baker Appl. Micro- biol. Biotechnol. 1986 23 224. 414 A. Archelas J. D. Fourneron B. Vigne and R. Furstoss Tetra-hedron 1986 42 3863. 415 S. Uribe J. Ramirez and A. Pena J. Bacteriol. 1985 161 1195. 416 W. Schmidt-Renner Wiss. 2. Tech. Hochsch. Chem. “Carl Schorlemmer” Leuna-Merseburg 1986 28 21 5. 417 M.-X. Qian Huaxue Tongbao 1985 No. 12 p. 28. 418 S.-X.Li S.-C. Gu and C.-H. Chen Linchan Huaxue Yu Gongye 1984 4 No. 4 p. 10. 419 V. C. 0.Njar and D. V. Banthorpe J. Labelled Compd. Radio- pharm. 1985 22 615. 420 D. 0.Henderson and P. L. Polavarapu J. Am. Chem. Soc. 1986 108 7110. 421 G. J. Martin P. Janvier S. Akoka F. Mabon and J. Jurczak Tetrahedron Lett. 1986 27 2855. 422 T. Koscielski D. Sybilska S. Belniak and J. Jurczak Chromato-graphia 1984 19 292. 423 T. Koscielski D. Sybilska S. Belniak and J. Jurczak Chromato-graphia 1986 21 413. 424 J. J. Gajewski and C. M. Hawkins J. Am. Chem. SOC. 1986 108 838. 425 R. M. Markevich A. I. Lamotkin and V. M. Reznikov Khim. Drev. 1985 No. 5 p. 96. 426 R. M. Markevich A. I. Lamotkin and V. M. Reznikov Khim. Drev. 1985 No. 2 p. 103. 427 R. M.Markevich A. I. Lamotkin and V. M. Reznikov Khim. Drev. 1985 No. 3 p. 106. 428 S. Kullaj Bul. Shkencave Nut. 1985 39 47. 429 S. B. Battalova T. R. Mukitanova N. R. Bukeikhanov and L. V. Li Izv. Akad. Nauk Kaz. SSR Ser. Khim. 1986 No. 5 p. 82. 430 F. Notheisz M. Bartok D. Ostgard and G. V. Smith J. Catal. 1986 101 212. 431 Y.-Q. Shen H.-P. Liu Y. Cao and Z.-Z. Zhang Huaxue Xuebao 1986 44 971. 432 L. Zhi B.-W. Zhang S.-K. Wu X.-D. Feng Ganguang Kexue Yu Kuang Huaxue 1985 No. 1 p. 40. 433 M. Nomura and Y. Fujihara Yukagaku 1985 34 367. 434 S. C. Sethi A. D. Natu and M. S. Wadia Indian J. Chem. Sect. B 1986 25 248. 435 V. I. Lysenko B. G. Udarov and T. I. Pekh Vestsi Akad. Navuk BSSR Ser. Khim. Navuk 1985 No. 4 p. 62. 436 P. Lavallee and G.Bouthiller J. Org. Chem. 1986 51 1362. 437 Anonymous Youji Huaxue 1986 133 and 1007. 438 J. Chandrasekharan P. V. Ramachandram and H. C. Brown J. Org. Chem. 1985 50 5446. 439 B. E. Mann P. W. Cutts J. McKenna J. M. McKenna and C. M. Spencer Angew. Chem. 1986 98 567. 440 P. K. Jadhav K. S. Bhat P. T. Perumal and H. C. Brown J. Org. Chem. 1986 51 432. NATURAL PRODUCT REPORTS 1988 441 H. C. Brown and K. S. Bhat J. Am. Chem. SOC. 1986 108 293. 442 Y. S. Kulkarni and B. B. Snider J. Org. Chem. 1985 50 2809. 443 D. L. Boger and M. D. Mullican J. Org. Chem. 1985 50 1904. 444 R. Pellegata P. Ventura M. Villa G. Palmisano and G. Lesma Synth. Commun. 1985 15 165. 445 D. H. R. Barton and D. Crich Tetrahedron 1985 41 4359. 446 R. Pellegata 1. Dosi M.Villa G. Lesma and G. Palmisano Tetrahedron 1985 41 5607. 447 M. Nomura and Y. Fujihara Nippon Kagaku Kaishi 1985 990. 448 P. A. Robinson C. N. Barry J. W. Kelly and S. A. Evans J. Am. Chem. SOC. 1985 107 5210. 449 M. M. El Gaied and A. Selmi J. SOC. Chim. Tunis. 1985 2 27. 450 S. Itsuno K. Tanaka and K. Ito Chem. Lett. 1986 1133. 451 J. M. Coxon G. J. Hydes and P. J. Steel Tetrahedron 1985 41 5213. 452 B. B. Snider R. A. H. F. Hui and Y. S. Kulkarni J. Am. Chem. Soc. 1985 107 2194. 453 L. Borowiecki A. Kazubski and E. Reca Liebigs Ann. Chem. 1986 1428. 454 G. A. Tolstikov A. Yu. Spivak L. M. Khalilov E. V. Vasil’eva and S. I. Lomakina Izv. Akad. Nauk SSSR Ser. Khim. 1985 1814. 455 M. Andrianome and B. Delmond J. Chem. Soc. Chem.Commun. 1985 1203. 456 D. Young and W. Kitching J. Org. Chem. 1985 50 4098. 457 M. Falorni L. Lardicci and B. Giacomelli Tetrahedron Lett. 1985 26,4949. 458 T. Hosokawa Y. Imada and S. Murihashi Bull. Chem. SOC.Jpn. 1985 58 3282. 459 M. S. Baird S. R. Buxton and H. H. Hussain J. Chem. Res. (S) 1986 310. 460 J. Fossey D. Lefort and J. Sorba J. Org. Chem. 1986 51 3584. 461 N. H. Werstiuk G. Timmins and B. Sayer Can. J. Chem. 1986 64 1465. 462 J. M. Bernassau M. Fetizon and J. A. Pinheiro J. Phys. Chem. 1986 90 1051. 463 Y. Matsubara T. Uchida T. Ohnishi K. Kanehira Y. Fujita T. Hirashima and I. Nishiguchi Tetrahedron Lett. 1985 26 45 13. 464 T. Uchida M. Nomura Y. Fujiwara and Y. Matsubara Nippon Nogei Kagaku Kaishi 1986 60 443.465 V. Krishnasamy and K. Balasubramanian J. Indian Chem. SOC. 1985 62 213. 466 N. H. Werstiuk and G. Timmins Can. J. Chem. 1985 63 526. 467 W. Cocker R. L. Gordon and P. V. R. Shannon J. Chem. Res. (S) 1985 172. 468 R. Huisgen G. Mloston and A. Proebstl Tetrahedron Lett. 1985 26 4431. 469 W. Kreiser P. Below and L. Ernst Liebigs Ann. Chem. 1985 194. 470 W. Kreiser and P. Below Liebigs Ann. Chem. 1985 203. 471 M. Novak Phytochemistry 1985 24 858. 472 E. Soler E. Dellacassa and P. Moyna Phytochemistry 1986 25 1343. 473 A. Villar M. C. Zafra-Polo M. A. Bonnanad A. Navarro and J. L. Rios Pharm. Acta Helv. 1985 60 351. 474 M. E. Komaitis A. Falirea and E. C. Voudouris J. Sci. Food Agric. 1985 36 970. 475 G. Fournier M. Paris S. H. Dumitresco N.Pages and C. Bou- dene Planta Med. 1986 486. 476 E. Tsankova and I. Ognyanov Planta Med. 1985 180. 477 L. N. Misra and S. P. Singh J. Nut. Prod. 1986 49 940. 478 A. N. Aleskerova G. A. Fokina and S. K. Serkerov Khim. Prir. Soedin. 1986 116. 479 A. Codignola Actes -Colloq. Int. Plant Aromat. Med. Maroc. Zst 1984 (publ. 1985) 159. 480 M. Yatagai T. Sato and T. Takahashi Biochem. Syst. Ecol. 1985 13 377. 481 D. A. Lightner C. S. Pak B. V. Crist S. L. Rodgers and J. W. Givens Tetrahedron 1985 41 4321. 482 M. Walkowicz and B. Laczynska-Przepiorka Pol. J. Chem. 1985 59 801. 483 0.Ekundayo and B. Oguntimein Planta Med. 1986 202. 484 H. Lohani J. C. Bisht A. B. Melkani D. K. Mathela C. S. Mathela and V. Dev Indian Perfum. 1986 30 447.485 A. N. Reed J. W. Hanover and M. M. Furniss Tree Physiol. 1986 1 277. 486 G. V. Khalechits and M. F. Rusak Zh. Obshch. Khim. 1986 56 2132. NATURAL PRODUCT REPORTS 1988-D. H. GRAYSON 487 E. F. Buinova B. G. Udarov L. V. Izotova and I. A. Shingel Zh. Org. Khim. 1985 21 2015. 488 V. A. Chuiko E. N. Manukov Yu. V. Chukhov and M. M. Timoshenko Khim. Prir. Soedin. 1985 639. 489 C. Santelli-Rouvier M. Santelli and J. P. Zahra Tetrahedron Lett. 1985 26 1213. 490 D. Wilhelm J.-E. Baeckvall R. E. Nordberg and T. Norin Organometallics 1985 4 1296. 491 R. H. Naik G. D. Joshi and G. H. Kulkarni Indian J. Chem. Sect. B 1986 25 306. 492 E. N. Manukov 0.G. Vyglazov V. A. Chuiko and E. D. Skak- ovskii Zh. Org. Khim. 1986 22 1105.493 R. H. Naik G. H. Kulkarni and R. B. Mitra Indian J. Chem. Sect. B 1985 24 154. 494 S. S. Bhosale G. H. Kulkarni and R. B. Mitra Indian J. Chem. Sect. B 1985 24 1008. 495 S. S. Bhosale G. H. Kulkarni and R. B. Mitra Indian J. Chem. Sect. B 1985 24 543. 496 G. Godbole and S. P. Pathak Sci. Cult. 1985 51 278. 497 P. K. Jadhav J. U. N. Prasad and H. C. Brown J. Org. Chem. 1985 50 3203. 498 K. Takabe M. Inamori R. Nashiki T. Yamada and T. Katagiri Shizuoka Daigaku Kogakubu Kenkyu Hokoku 1984 35 25. 499 A. Hendrich K. Piatkowski and J. Gora Perfum. Flavor, 1986 11 No. 5 p. 85. 500 Z. G. Isaeva G. I. Kovylyaeva G. A. Bakaleinik and G. S. Bikbulatova Zzv. Akad. Nauk SSSR Ser. Khim. 1985 919. 501 Z. G. Isaeva G. A. Bakaleinik G. 1. Kovylyaeva and A.N. Vereshchagin Zzv. Akad. Nauk SSSR Ser. Khim. 1985 2808. 502 E. N. Manukov and T. R. Urbanovich Vestsi Akad. Navuk B. SSR Ser. Khim. Navuk 1985 No. 3 p. 70. 503 M. H. Shastri D. G. Patil V. D. Patil and S. Dev Tetrahedron 1985 41 3083. 504 Z. G. Isaeva A. N. Karaseva and I. S. Ikhtonova Izv. Akad. Nauk SSSR Ser. Khim. 1985 2628. 505 Z. G. Isaeva and G. A. Bakaleinik Zzv. Akad. Nauk SSSR Ser. Khim. 1985 648. 506 E. K. Kazakova G. Davletshina G. A. Bakaleinik and A. N. Vereshchagin Zzv. Akad. Nauk SSSR Ser. Khim. 1986 842. 507 C. H. Brieskorn and C. K. Ryu Arch. Pharm. (Weinheim Ger.) 1985 318 261. 508 C. H. Brieskorn and C. K. Ryu Arch. Pharm. (Weinheim Ger.) 1985 318 788. 509 Z. Kubica Z. Burski and K. Piatkowski Pol. J. Chem.1985,59 827. 510 T. F. Braish and P. L. Fuchs Synth. Commun. 1985 15 549. 51 1 E. N. Manukov 0.G. Vyglazov V. A. Chuiko and I. A. Shingel Zh. Org. Khim. 1985 21 2089. 512 R. Askani and M. Wieduwilt Liebigs Ann. Chem. 1986 1104. 513 V. A. Chuiko E. N. Manukov and 0.G. Vyglazov Dokl. Akad. Nauk BSSR 1986 30 158. 514 M. Yoshikawa Y. Fukuda T. Taniyama B. C. Cha and I. Kitagawa Chem. Pharm. Bull. 1986 34 2294. 515 C. A. J. Erdelmeier and 0.Sticher Phytochemistry 1986 25,741. 516 S. Banerjee J. Jakupovic and R. M. King Pharmazie 1986 41 157. 517 T. Oritani M. Niitsu T. Kato and K. Yamashita Agric. Biol. Chem. 1985 49 2819. 518 R. C. Gueldner D. M. Wilson and A. R. Heidt J. Agric. Food Chem. 1985 33 411. 519 T. Oritani K. Yamashita and T.Oritani Nippon Noyaku Gak- kaishi 1985 10 535. 520 J. Gora and D. Kalemba Pollena Tluszcze Srodki Piorace Kosmet. 1985 29 236. 521 C. H. Eugster Pure Appl. Chem. 1985 57 639. 522 Y. Hanzawa A. Yamada and Y. Kobayashi Tetrahedron Lett. 1985 26 2881. 523 J.-F. He and Y.-L. Wu Synth. Commun. 1985 15 95. 524 0.S. Park W. Y. Lee and J. C. Park Saengyak Hakhoechi 1986 17 67. 525 H. Masuda and S. Mihara Agric. Biol. Chem. 1985 49 861. 526 U. Wannagat R. Muenstadt and U. Harder Liebigs Ann. Chem. 1985 950. 527 0.Takazawa K. Kogami and K. Kayashi Bull. Chem. SOC. Jpn. 1985 58 389. 528 A. Ermakova E. M. Sul’man 0.S. Popov 0.B. Sannikov A. I. Gontar and A. B. Dolzhenko React. Kinet. Catal. Lett. 1985,29 409. 529 K. Muellen H. Schmickler B.Frei and H. R. Wolf Tetrahedron Lett. 1986 27 477. 530 D. V. Sokol’skii T. 0.Omarkulov and S. V. Goncharova Zzv. Akad. Nauk Kaz. SSR Ser. Khim. 1986 No. 2 p. 10. 531 N. Ragoussis N. Argyriadis and P. Mamos Synthesis 1985 489. 532 E. Negishi A. 0.King and J. M. Tour Org. Synth. 1986 64 44. 533 A. O’Sullivan N. Bischofberger B. Frei and 0.Jeger Helv. Chim. Acta 1985 68 1089. 534 E. P. Mueller Helv. Chim. Acta 1985 68 1107. 535 E. P. Mueller Helv. Chim. Acta 1986 69 692. 536 W. H. Okamura R. Peter and W. Reischl J. Am. Chem. SOC. 1985 107 1034. 537 P. Mathies B. Frei and 0.Jeger Helv. Chim. Acta 1985 68 192. 538 P. Mathies B. Frei and 0.Jeger Helv. Chim. Acta 1985 68 207. 539 A. O’Sullivan B. Frei and 0.Jeger Helv. Chim. Acta 1986 69 555.540 U. Goldener M. E. Scheller P. Mathies B. Frei and 0.Jeger Helv. Chim. Acta 1985 68 635. 541 P. Arjunan and V. Ramamurthy J. Photochem. 1986 33 123. 542 R. Verpoorte Pharm. Weekbl. 1986 121 248. 543 S. Uesato S. Kanomi A. Iida H. Inouye and M. H. Zenk Phytochemistry 1986 25 839. 544 S. Uesato M. Miyauchi H. Itoh and H. Inouye Phytochemistry 1986 25 2515. 545 K. Kobayashi S. Uesato S. Ueda and H. Inouye Chem. Pharm. Bull. 1985 33 4228. 546 S. Uesato S. Ueda K. Kobayashi M. Miyauchi H. Itoh and H. Inouye Phytochemistry 1986 25 2309. 547 H. Rimpler and H. Sauerbier Biochem. Syst. Ecol. 1986 14 307. 548 E. Andrzejewska-Golec and L. Swiatek Herba Pol. 1984 30 9. 549 W. G. van der Sluis Plant Syst. Evol. 1985 149 253. 550 H.Tsukamoto S. Hisada and S. Nishibe Shoyakugaku Zasshi 1985 39 90. 551 J. L.Marco J. Nat. Prod. 1985 48 338. 552 K. Goerler D. Oehlke and H. Soicke Planta Med. 1985 530. 553 K. Seifert J. Schmidt N. T. Lien and S. Johne Planta Med. 1985 409. 554 S. Kobayashi A. Mima M. Kihara and Y. Imakura Chem. Pharm. Bull. 1986 34 876. 555 F. Ergun and B. Sener Gazi Univ. Eczacilik Fak. Derg. 1986 3 59. 556 M. Yamaguchi K. Hasebe S. Tanaka and T. Minami Tetra-hedron Lett. 1986 27 959. 557 F. Bellesia F. Ghelfi U. M. Pagnoni and A. Pinetti Tetrahedron Lett. 1986 27 381. 558 A. T. Hewson and D. T. MacPherson J. Chem. Soc. Perkin Trans. 1 1985 2625. 559 J. C. Caille M. Farnier and R. Guilard Can. J. Chem. 1986,64 824. 560 H. J. Knoelker and E.Winterfeldt Liebigs Ann. Chem. 1986,465. 561 W. A. Nugent and F. W. Hobbs J. Org. Chem. 1986 51 3376. 562 S. E. Denmark and J. S. Sternberg J. Am. Chem. SOC. 1986 108 8277. 563 W. Oppolzer and J. E. Jacobson Tetrahedron Lett. 1986 27 1141. 564 R. T. Brown and M. F. Jones J. Chem. SOC. Chem. Commun. 1985 699. 565 S. Isoe T. Takemoto H. Inaba Q. Han K. Nakatani S. Kat-sumura K. Yamamoto S. Fujiwara and K. Hori Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 27th 1985 160. 566 K. E. B. Parkes and G. Pattenden Tetrahedron Lett. 1986 27 1305. 567 B. M. Trost M. K.-T. Mao J. M. Balkovec and P. Buhlmayer J. Am. Chem. SOC. 1986 108 4965. 568 G. Schneider and J. Veith Arch Pharm. (Weinheim Ger.) 1985 318 515. 569 J. D. Msonthi C. Galeffi M. Nicoletti I.Messana and G. B. Marini-Bettolo Phytochemistry 1985 24 771. 570 G.-A. Gross and 0.Sticher Helv. Chim. Acta 1986 69 1113. 571 N. Marekov S. Popov and N. Khandzhieva Khim. Znd. (Sofia) 1986 58 132. 572 P. Gariboldi G. Jommi and L. Verotta Phytochemistry 1986 25 865. 573 F. Murai M. Tagawa S. Matsuda T. Kikuchi S. Uesato and H. Inouye Phytochemistry 1985 24 2329. 574 M. Kikuchi and Y. Yamauchi Yakugaku Zasshi 1985 105 442. 575 K. Inoue T. Tanahashi and H. Inouye Phytochemistry 1985,24 1299. 576 M. Kikuchi and Y. Yamauchi Yakugaku Zasshi 1985 105 142. 577 P. J. Houghton and L. L. Ming Phytochemistry 1985 24 1841. 578 S.-F. Luo Y. Gu and Y.-H. Liu Zhongyao Tongbao 1986 11 681. 579 A. Bianco P. Passacantilli G. Righi J.A. Garbarino V. Gam- baro M. Serafini and M. Nicoletti Planta Med. 1986 55. 580 A. Bianco P. Passacantilli G. Righi M. Nicoletti M. Serafini J. A. Garbarino and V. Gambaro Phytochemistry 1986 25 946. 581 J. Garcia and A. J. Chulia Planta Med. 1986 327. 582 P. J. Houghton and L. M. Lian Phytochemistry 1986 25 1907. 583 K. S. Verma A. K. Jain and S. R. Gupta Planta Med. 1986 359. 584 H. G. Grant C. A. Russell-Maynard and M. D. Sutherland Aust. J. Chem. 1985 38 325. 585 G. Koenig and H. Rimpler Phytochemistry 1985 24 1245. 586 Y. Ikeshiro and Y. Tomita Planta Med. 1985 390. 587 C.-J. Xu X.-Y. Zeng and D.-Q. Yu Yaoxue Xuebao 1985 20 652. 588 Y. Imakura M. Tagawa and F. Murai Chem. Pharm. Bull. 1985 33 2220. 589 Y. Imakura and S.Kobayashi Heterocycles 1986 24 2593. 590 E. Stenzel H. Rimpler and D. Hunkler Phytochemistry 1986 25 2557. 591 S. R. Jensen B. J. Nielsen and V. Norn Phytochemistry 1985 24 487. 592 T. Iwagawa and T. Hase Phytochemistry 1986 25 1227. 593 G.-A. Gross 0.Sticher and C. Ankh Helv. Chim. Acta 1986 69 156. 594 K. K. Purushothaman M. Venkatanarasimhan and A. Sarada Phytochemistry 1985 24 773. 595 A. Bianco P. Passacantilli G. Righi and M. Nicoletti Phyto-chemistry 1985 24 1843. 596 A. Bianco P. Passacantilli G. Righi M. Nicoletti M. Serafini J. A. Garbarino and V. Gambaro Gazz. Chim. Ital. 1986,116,67. NATURAL PRODUCT REPORTS 1988 597 P. Junior Planta Med. 1985 229. 598 A. Bianco P. Passacantilli G. Righi M. Nicoletti and M. Sera- fini Phytochemistry 1986 25 1981.599 0. P. Sati D. C. Chaukiyal M. Nishi K. Miyahara and T. Kawasaki Phytochemistry 1986 25 2658. 600 S. R. Jensen and B. J. Nielsen Phytochemistry 1985 24 602. 601 J. L. Marco Phytochemistry 1985 24 1609. 602 H. Kobayashi H. Karasawa T. Miyase and S. Fukushima Chem. Pharm. Bull. 1985 33 3645. 603 S. Damtoft S. R. Jensen and B. J. Nielsen Phytochemistry 1985 24 2281. 604 R. L. Arslanian G. H. Harris and F. R. Stermitz J. Nat. Prod. 1985 48 957. 605 A. Bianco P. Passacantilli C. Rispoli M. Nicoletti I. Messana J. A. Garbarino and V. Gambaro J. Nat. Prod. 1986 49 519. 606 I. Kitagawa Y. Fukuda T. Taniyama and M. Yoshikawa Chem. Pharm. Bull. 1986 34 1399. 607 M. Yoshikawa Y. Fukuda T. Taniyama and I. Kitagawa Chem.Pharm. Bull. 1986 34 1403. 608 D. J. Iglesias i Angles Rev. R. Acad. Farm. Barcelona 1986 2 43. 609 J. J. Talley J. Org. Chem. 1985 50 1695. 610 G. Casiraghi M. Cornia G. Casnati G. Gasparri-Fava and M. F. Bellichi J. Chem. SOC. Chem. Commun. 1986 271. 611 S. H. Baek M. Srebnik and R. Mechoulam Tetrahedron Lett. 1985 26 1083. 612 E. Mago M. Szirmai A. Ohlasson and S. Agurell Marihuana '84 Proc. Oxford Symp. Cannabis 1984 (publ. 1985) 191. 613 A. Schwartz and P. Madan J. Org. Chem. 1986 51 5463. 614 R. F. Borne and S. C. Mauldin J. Heterocycl. Chem. 1985 22 693. 615 V. S. Jorapur Z. H. Khalil R. P. Duffley R. K. Razdan B. R. Martin L. S. Harris and W. L. Dewey J. Med. Chem. 1985 28 783. 616 J. P. Porwoll and E. Leete J.Labelled Compd.Radiopharm. 1985 22 257. 617 W. Offermann W. Kuhn J. Stelten D. Leibfritz G. von Kie-drowski and L. F. Tietze Tetrahedron 1986 42 2215.

ISSN:0265-0568    

DOI:10.1039/NP9880500419

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Trends in Protease Inhibition G. Fischer Department of Biochemistry Martin- 1uther University DDR-402 Halle German Democratic Republic -~ Reviewing the literature published between November 1984 and January 1987 1 2 2.1 2.1.1 2.1.2 2.1.3 2.1.3.1 2.1.3.2 2.1.4 2.1.4.1 2.1.4.2 2.1.4.3 2.2 2.2.1 2.2.2 3 3.1 3.2 4 4.1 4.1.1 4.1.2 4.1.3 4.2 4.2.1 4.2.2 4.2.3 5 5.1 5.1.1 5.1.2 5.1.2.1 5.1.2.2 5.I .2.3 5.1.2.4 5.1.2.5 5.1.2.6 5.1.2.7 5.1.3 5.2 5.2.1 5.2.2 6 Introduction Serine Proteases -General Considerations Useful Classes of Inhibitors Compounds that form Non-covalent Complexes Tetrahedral-Intermediate-like Inhibitors Acylating Inhibitors Acyclic compounds Heterocyclic compounds Latent Electrophiles Halomethyl ketones Alkylating heterocyclic compounds Latent nitrenes and carbonium ions The Main Target Serine Proteases Elastases Trypsin-like Enzymes Cysteine Proteases -General Considerations Reversible Inhibitors Irreversible Inhibitors Metalloproteases -General Considerations Useful Classes of Inhibitors Phosphorus-containing Amino-acid and Peptide Mimics Carboxylate- and Thiol-containing Inhibitors Inhibitors that contain the Keto-function or an Alcohol Function The Main Target Metalloproteases Angiotensin-converting Enzyme Enkephalin-degrading Enzymes Collagenases Aspartic Proteases -General Considerations Useful Classes of Inhibitors Variation of Pepstatin Modified Statine Residues 2-Alkylstatines 3-Methylstatine 4-Alkylstatines Difluorostatine Aminostatine Statone Phosphorus-containing statine derivatives Peptide- bond Isosteres The Main Target Aspartic Proteases Pepsins and Cathepsin D Renin References I Introduction The inhibition of proteolytic activity by low-molecular-weight synthetic inhibitors serves mainly to control undesirably high levels of proteases within biological systems.Other efforts to achieve specific and potent inactivation are concerned with the evaluation of the role of the targeted enzyme in the living cell. In several other cases investigations of enzyme-inhibitor complexes are exploited to give more detailed knowledge about enzyme chemistry and catalysis.One of the most satisfying aspects of research in the field of protease inhibition is the high level of interest that is shown by researchers in chemistry medicine biology and biotechnology. k k EtSeES$?TI k-a -1 E= enzyme; S= substrate; hedral intermediate; EA= *EA-%EtPz -3 p1 ES= Michaelis complex; TI= tetra-acyl-enzyme; P and P are products Scheme1 The great majority of the enzyme inhibitors that are used therapeutically are centred on a few enzymes belonging to the classes of metalloproteases [e.g.metalloproteinases ;E.C. class 3.4.241 and serine proteases [e.g.serine proteinases; E.C. class 3.4.2 I] although inactivation of aspartic proteases [aspartic proteinases ; E.C. class 3.4.231 is becoming increasingly important in regulating blood pressure.The aim of this Report is to provide a supplement to earlier reviews' and an update to the scope of selective and efficient inhibition of proteases by novel approaches concerning transition-state analogues suicide inhibitors and bi-product mimics. Additionally suitable synthetic routes to several of the most interesting synthons have been noted. 2 Serine Proteases -General Considerations The mode of catalytic acceleration and inhibition of hydrolysis of a peptide bond by serine proteases has been studied intensively for more than 30 years. A substantial part of the knowledge about single steps concerning proteolytic events has come from studies of the action of inhibitors on chymotrypsin and trypsin.Obviously in turn mechanistic aspects have stimulated the development of new strategies to inactivate specifically the more than 130 serine proteases that have been classified up to now. Although it has been elucidated that the different enzymes in this class possess the same chemistry of the active centre (which includes the triad ofAsp His and Ser residues) and that the enzymes have the same intermediates Michaelis complex (ES) tetrahedral intermediate (TI) and acyl-enzyme (EA) during the minimal catalytic cycle (see Scheme l) the particular free-energy profile of the reaction is a matter of controversy.lo This occurs despite the fact that there is probably more knowledge about this class of enzymes than about any others.One of the major concepts in current use is the stereo- electronic control of hydrolytic reaction^.^^-^^ Assuming that serine proteases are able to establish the optimal orientation of the lone pair^^^.'^ for both formation of the tetrahedral intermediate and expulsion of nitrogen a conformational change of the oxygen in the side-chain of a serine residue must occur. Truncated substrates that lack the machinery to perform timed conformational changes during enzyme catalysis have unusual partition ratios of intermediates. Despite the release of strain energy upon formation of the sulphonyl enzyme from the highly strained cyclic compound toluene-o,a-sultone reversion to the substrate is preferred over hydrolysis by about ten- fold.l6 Examination of possible candidates that might give rise to 465 NATURAL PRODUCT REPORTS 1988 ... 1 -+. H"7j H (Ser -195) (Ser -195) (a) (b) Figure 1 Conformational states of the tetrahedral intermediate in the reaction of serine proteases. (a) The stereoelectronically favourable conformation of the addition step. (b)The same for the expulsion of R-NH,. The developing negative charge on the oxygen atom triggers by deprotonation of the NH group of Ser- 195 the conformationai change at the Ser-04 linkage. Thereby the energetically unfavourable negative charge of the oxyanion is spread among solvated groups in the neighbourhood of the active site. Table 1 Some important biological processes that are performed by serine proteases Type of reaction Activation of zymogensZo Fibrinol ysis Degradation of highly cross- linked proteins Conversion of prohormones Development regulation and degradation k k + E 1 EI & El* 3 EI** ... k-1 k-2 k-3 E = enzyme; I = inhibitor; EI EI* etc. are enzyme-inhibitor complexes Scheme 2 the trigger signal for such a change led to the mechanism in Figure 1 .173 In this way the kinetically controlled protonation of the developing negative charge of the hemi-orthoamide by an NH group in the peptide backbone has to be crucial. Thus by shortening the backbone C-N bond of the Xaa-Ser moiety which serves invariantly as the NH hydrogen-bond donor in the entire family of serine proteases 0-4of the serine residue is pulled towards a favourable conformation for the forward reaction.Subsequently tautomerization of the hydroxy-imine and expulsion of the leaving group can occur. The residence timeslg of the intermediates that are shown in Scheme 1 have a major impact on the potency of several of the classes of inhibitor that are described below. In contrast to the mechanistic similarities of the various serine proteases their biological functions are very broad (Table 1). The regulation of the serine protease activity in tissue is mainly mediated by separate families of protein protease inhibitor^.^' Their common inhibitory mechanism exhibits slow binding and several tightly bound complexes E13*(see Scheme 2) which are slowly hydrolysed. Usually the tightness of Enzyme(s) involved Trypsin kailikrein chymotrypsin and many others Plasmin plasminogen activator Elastases cathepsin G Mast-cell proteases tonin trypsin-like enzymes dipeptidyl peptidase IV Acrosin Artemia pr~tease,~~ mast-cell proteases prolyl endopeptidase k - Physiology Coagulation of blood digestion complement pathway Destruction of blood clots," neoplastic transformation22~24 Proteolysis of elastins,25- 26 turnover of cartilage proteoglycans Angiotensin I," proenkephalin,"* 30 promelittin31 Fertili~ation,~' hormone ina~tivation,~~ histamine release3'*36 Pathology Thrombosis pancreatitis anti-complement action Cell invasion Pulmonary emphysema arthritis inflammation'' Hypertension Infertility anaphylaxis binding increases with the formation of subsequent EI complexes.The inhibition of eight different serine proteases by turkey ovomucoid third domain occurs by interaction with the same peptide bond between Leu-18 and Glu-19 regardless of the substrate specificity of the enzyme.39 In the enzyme- inhibitor complex that has recently been studied by X-ray crystallography and by n.m.r. 42 the reactive peptide bond is still intact. Interestingly the degree of pyramidalization is also relatively weak. The designs of new synthetic inhibitors of serine proteases using the principles of the naturally occurring compounds are based mainly on peptide aldehydes,'. 43 although peptides from streptomycetes (e.g.chymostatins and related aldehydes) have enjoyed widespread use in the study of diverse cellular func- tion~.~~.45 Short-chain 4-nitroanilide substrates that are models for the reactive site of naturally occurring protein inhibitors are generally much less reactive than the most reactive tripeptide 4- nitroanilides available but are nevertheless reasonable sub- strate~.~~. 47 Cyclic nonapeptides corresponding to the v-sequence of soybean Bowman-Birk inhibitor are active against a series of serine protea~es.~~ A related approach to inhibitors of human leucocyte elastase and cathepsin G has resulted from the fragmentary data49 that are available for their natural substrate elastin. 6-(2-Picolinoyl)lysine which may act as a synthetic model for a desmosine residue gives rise to strong binding effects when introduced in various positions of 4-nitroanilide The even more closely related com- pound 2-amino-4-(3-pyridyl)butyric acid which contains the 3-pyridyl feature of desmosine is active in the micromolar range for inhibition of human leucocyte elastase when it is introduced into a penta~eptide.~~ NATURAL PRODUCT REPORTS 19884.FISCHER More progress in the evaluation of biological functions and medical use should I anticipate result in the preparation of low-molecular-weight synthetic inhibitors that are designed specifically to bind to the appropriate target enzyme. Earlier work in the field of serine proteases has been reviewed by Powers and Harper.51 2.1 Useful Classes of Inhibitors 2.1.I Compounds that form Non-covalent Complexes The work of Ashe and Zimmerman5 on the specific inhibition of leucocyte elastase by cis-unsaturated fatty acids has been extended to rat mast-cell chyma~e.~ The long alkyl chains that are present in cells mainly as components of acylglycerols phosphoglycerides sphingolipids and waxes appear to interact with hydrophobic regions of the enzyme affecting the con- formation around the active site.The unsaturated compound 1,2-dioleoylglycerol 3-phosphate is 20 times more inhibitory than the distearoyl Anchoring of substrate-like peptide fragments by hydrophobic terminal residues on the enzyme is responsible for the strong competitive inhibition of human leucocyte elastase by N-alkylated peptides and peptide C-alkylamide~.~~ Oleoyl-Ala-Ala-Pro-Val-OH does not inhibit pancreatic elastase whereas a Ki value of 4000 nmol dm-3 has been estimated for human leucocyte ela~tase.~~ For the same enzyme Boc-Val-Val-Val-NH[CH,],,CH (Ki = 210 nmol dm-3) is the best within a series comprising homologues in which the alkyl chain ranges from [CH,] lip to [CH,],,.57 The mode of action of N-trifluoroacetylated peptide anilides with elastases is characterized by considerable affinity associated with a very low turnover.Therefore those alternate substrates can function as strong inhibitor^.^^ investigation^,^^ using 13C n.m.r. spectroscopy indicate that for the most potent of the compounds that contain the trifluoroacetyl-Lys-Ala moiety both the trifluoroacetyl groupGo and the side-chain of the lysine residue59 are rigidly bound to the protein.This mode of binding brings the peptide chain into a favourable position for formation of a parallel pleated-sheet structure. The highly hydrophobic nature of the heptafluorobutyryl side-chain of (1) is responsible for its effective inhibition (Ki = 81 nmol dm-,) of a-chymotrypsin.61 Fluorine- 19 n.m.r. studies of ring-fluorinated analogues of (1) suffer from the extreme insolubility of the compounds. The inhibitory potency of structure (1) is in doubt. There is no enzyme-catalysed hydrolysis at either the amide or the thioester linkage.62 The 4-hydroxypyran-2-one inhibitor elasnin (2) is also neither as specific nor as potent towards leucocyte elastase as was suggested earlier.63 Analogues with various substituents in the pyrone ring have been studied and the results indicate that there is a non-covalent mode of binding mediated mainly by hydrophobic There is evidence that the 4-hydroxy- pyran-2-one moiety binds to the S subsite with the 6-substituent covering subsites S to S,.The elasnin analogue (3) is the most potent inhibitor of this type for human leucocyte elastase (Ki = 4600 nmol dm-3).65 The 3-acyl residue appears to be important for inhibition since simple 6-alkyl-4-alkoxy-2- pyrones and the congeneric 5,6-dihydropyrones do not inhibit human leucocyte elastase.66 A highly sulphated dextran sulphate with a molecular weight of 131 kDa exhibits potency against human leucocyte elastase at the subnanomolar Peptides that are derived from a-aza-amino acids e.g.(4) being substituted by poor leaving groups do not acylate serine proteases but simply act as reversible inhibitors. Due to the location of the a-aza-alanine residue at position P and by varying the amino-acid residues at positions P, P, and PI,over a wide range the inhibition of porcine pancreatic elastase could be optimized; compound (5) (Ki = 100 nmol drn-,) was the most potent of many derivatives.68 The benzyl ester moiety in position PI,seems to be essential for inhibitory activity. None of the compounds that were investigated has any significant effect against human leucocyte elastase. Thus to target this p OH H Val -Gly -Azala -0821 HOZC H 0 (5) enzyme the aza-alanine residue was replaced by the side-chain- branched residue a-azanorvaline leading to (6) as the most potent of these structures (Ki = 20 nmol dm-3).69 Replacing the peptide bond by a thiomethylene linkage did not greatly affect the potency regardless of its position within the P subsites.Aromatic residues in the C-terminal position are necessary for potent inhibition of serine proteases. For example whereas Suc- Tyr-D- Leu-D-Phe 4-me t h ylpiperidide does not show any inhibitory effect on chymotrypsin the 4-nitroanilide is an efficient inhibitor. The same principle holds true for other elastase-like enzyme^.^^-'^ More specific inhibitors of trypsin thrombin plasmin kallikrein complement subcomponent C1r complement sub- component Cls and others have been developed using the concept of cationic ES-type inhibitors.74-76 Arginine derivatives that have two hydrophobic groups within the molecule exhibit highly specific inhibition of thrombin among trypsin-like H HN HO,C I Me (7) 0 CH3SOf HNYNH2 (9) u hNH (10) T proteases.The (2R74R)-enantiomer of (7) shows a value of Ki of 19 nmol dm-3 and inhibits coagulation factor Xa 1.1 x lo4 times more weakly than it inhibits Related compounds have been investigated in the blood clotting system Thc in ~itro.~~ therapeutically used non-antigen gabexate mesylate (8) inhibits serine proteases competitively. On the basis of the Ki values the affinity towards a number of proteases can be arranged as follows human urinary kallikrein M porcine pancreatic P-kallikrein 4 bovine P-trypsin M bovine coagulation factor Xa M human [Ly~~~lplasmin M human uro- kinase M bovine a-thrombin.The selective inhibition of the enzymes that are involved in the coagulation system without influencing the blood-pressure-controlling kallikreins may result from the distinct nature of residue 226 located at the primary specificity site of the enzymes.79 Quantitative structure-activity relationships using X-ray data have shown the important role of electron-donating substituents in the inhibition by substituted benzamidinesaO of trypsin.al,82 Additionally the molar refractivity which is primarily a measure of the volume of substituents is a significant parameter as this accounts for about 20% of the variance in l/log Ki in the benzamidine series.s4 Unfavourable NATURAL PRODUCT REPORTS 1988 HN4-'0 (SW -195) 0 168A COf HZN 0-2 97i/ ..(Ser -195) (b) Figure 2 The tetrahedral structure of the reactive carbonyl carbon within protease-inhibitor complexes. (a)From the 1.8 A structure of the Streptomyces griseus protease A-chymostatin complex.92 Only the (S) configuration of equally populated enantiomers is drawn showing that the a1d:hydic oxygen is directed into the oxyanion hole. (b) From the 1.4 A structure of the bovine trypsin-p-amidino- phenylpyruvate complex.95 The C-0 bond that is formed is considerably longer than in the chymostatin complex. desolvation of some substituents of the inhibitor is also important.83 Bis-(5-amidinobenzimidazol-2-yl)methanecan be used for blocking the invasion of tumour cells across basement membranes in ~itro,~~ although trypsin-like proteases are not strongly inhibited.Similar results have been found for the inhibition of growth of HeLa cells by substituted phenyl esters of amidinopiperidine- 4-propionic acid. The proteolytic activity that can be isolated from these cells is not affected by soybean trypsin inhibitor. However the inhibition of this activity by the corresponding amidinopiperidine-4-carboxylic esters roughly parallels their inhibition of the growth of HeLa cells.86 The most potent inhibitor of thrombin that has been described is (9) (Ki = 6 nmol dm-3); it is a useful antithrombotically effective com- pound in various experimental models of thrombosis.87-88 The semi-synthetic approach that has been applied to the trypsin inhibitor from bovine mast cells allows replacement of the residue Lys-15 at position P,,by a different amino acid. For this purpose a cascade of proteolytic and peptide-synthetic steps must be carried The effectiveness of the excellent inhibitor aprotinin (Ki = 6 x nmol dm-3 for trypsin) has been upgraded by more than four orders of magnitude in Ki by preparing [Val15]aprotinin (Ki = 0.1 1 nmol dm-3) as an in-hibitor of human leucocyte elasta~e.~~ 2.I .2Tetrahedral- Intermediate- like Inhibitors The carbonyl function can exist in an activated state as has been realized in aldehydes halomethyl ketones pyruvates and other derivatives.Therefore these compounds are able to inactivate proteases in a specific transition-state-like manner. These are mechanism- based inhibitors." 'l For example chymostatin A (10) forms a hemiacetal adduct with the catalytic residue Ser- 195 of Streptomyces griseus protease A (Figure 2a).92393The role of the active-site serine residue in NATURAL PRODUCT REPORTS 1988-G. FISCHER RH I \/ Ac-Leu-Leu-Arg-H -+ Ac- Leu -Leu -N DL CH(OBU)z /c\ H RH \/ J.'. (R = [CH,],NH:NHz Z = PhCHzOCO ) NH Reagents i BuOH TosOH; ii Pronase E pH 8.0 at 40 "C for 72 h; iii Z-Xaa-OSuc CH,Cl, for 20 h then chromatography on silica gel for separation of diastereoisomers; iv H, Pd/C for 5 h; v dicyclohexylcarbodi-imide,HOBt CH,Cl, at 0 "C Z-Yaa-OH Scheme 3 Table 2 Reversible inhibition of serine proteases by peptidyl fluoromethyl ketones and related compoundsa~ ' Ki/ nmol Ketone Enzyme dm- Ref.Ac- Leu-Phe-CF chymotrypsin 560 112 Ac-Leu-Phe-CF,H chymotrypsin 2.5x 104 112 Ac-Leu-Phe-CFH chymotrypsin 2.0x lo6 112 113 Ac- Leu-Phe-H chymotrypsin 1.7~10~ Z-Lys(Z)-Val-Pro-Val-CF leucocyte elastase 0.1 114 Z-Val-Pro-Val-CF leucocyte elastase 1.6 114 Ac- Ala- Ala-Pro- Ala-CF pancreatic elastase 250 112 MeOSuc-Ala-Ala-Pro-Val-leucocyte elastase 104 115 CH,Cl Z-Ala- Ala-Pro-Val-CF leucocyte elastase 1 116 (a) Racemic fluorine-containing amino acids were used in several cases; (h) In this Table the experimental conditions are not the same throughout inhibition is shown by the 250-fold difference between values of Kl for the binding of elastatinal with intact porcine pancreatic elastase and with the chemically modified congener anhydro- elastase in which Ser- 195 has been converted into dehydro- alanine.94 On the other hand the carbonyl group is not fully tetrahedral in the trypsin-p-amidinophenylpyruvatecomplex (Figure 2b).95 The stabilization of the hemiketal complex that is formed by thrombin and p-amidinophenylpyruvate may be achieved by a hydrogen-bond between a carboxylate oxygen of the inhibitor molecule and N of Hi~-57.~~ Carbon-13 n.m.r.experiments on a-chymotrypsin that is complexed with the aldehyde inhibitor N-acetylphenylalaninal show two signals for the hemiacetal at pH values > 7." These could arise from slowly interconverting conformations of the complex probably connected with the protonation of the hemiacetal anion.98 Tripeptide aldehydes (Z-Arg-Leu-Phe-H) fulfil many of the criteria for inhibitory activity towards chymotrypsin that are found in the chymostatin reaction although the potency is decreased by a factor of 2.7." There have been several reports of new peptide aldehyde inhibitors of elastases,lnOv lol proline-specific pro tease^,^^^-ln4 and urokinase.In5The semi-synthesis of peptidyl-argininals 469 Ci H Iii (11) Reagents i LiCHCl, ZnCl, at 2100 "C; ii LiN(SiMe,), at -78 "C; iii RIC(0)OC(O)Et F- DMF-THF at -20 "C; iv BCI, at -78 "C CH,Cl, then aqueous HF at 0 "C Scheme 4 using leupeptin dibutyl acetal as the precursor has led to a simple route to many kinds of inhibitors of trypsin-like enzymes (Scheme 3).ln6 Peptidyl methyl ketones though not activated in their carbonyl function show a high inhibitory potency against thermitase (e.g.for Ac-Ala-Ala-Ala-Phe-CH, Ki = 40 nmol dm-3).1n7-11n In contrast to the analogous halomethyl ketone inhibitor a significant thermostabilizing effect on the protein by reversible inactivation is not Elastases and cathepsin G are also susceptible to inhibition by peptidyl ketones and peptidyl keto-esters.lll Among the halomethyl ketones the peptidyl trifluoromethyl ketones are exceptional in exhibiting only reversible competitive inhibition toward the serine protease that is the target of inhibition.'12 The simple compound Ac-arnbo-Phe-CF is approximately twenty-fold more effective towards chymotrypsin than the corresponding optically pure aldehyde.Several inhibition constants for the fluorinated compounds are listed in Table 2. The potent peptidyl trifluoromethyl ketones are of the slow-binding type according to Scheme 2. Not all of the transition-state analogues share this property. Whether or not the structural matching of the enzyme (in its ground state) and the transition-state- analogue inhibitor constitutes an appreciable kinetic barrier to its binding appears to be dependent on minor changes in peptide conformation. 288 The most efficient inhibitor in Table 2 i.e. Z-Lys(Z)-Val-Pro-Val-CF, binds relatively fast (Icon = 8 x lo4 dm3 mol-l s-'); when this value is corrected for the low carbonyl content of the inhibitor in aqueous solutions it shows the magnitude of other associative reactions between enzymes and small ligands.Acylaminoboronic acids and their precursor amino-acid difluoroborane analogues (1 I) competitively inhibit serine pr~teases.~'~? 118 It is assumed that these compounds mimic the tetrahedral intermediate. The appropriate boronic acids are active against chymotrypsin (Ki = 300-3000 nmol dm-3) and porcine pancreatic elastase (Ki = 100-3500 nmol dm-3). Much NATURAL PRODUCT REPORTS 1988 more effective are those peptide substrate structures which possess the boronic acid moiety on their respective C-terminal end.'19 MeOSuc-Ala-Ala-Pro-boro-Val-OH (Ki = 0.57 nmol dmP3 towards human leucocyte elastase) achieves the same potency as the 70-residue polypeptide inhibitor eglin iso- lated from the leech Hirudo medicinalis.12' This peptide boronic acid is the first example of a reversible synthetic protease inhibitor that prevents emphysema in an animal mode1.12' The more easily purified difluoroboranes were synthesized as described for the phenylglycine derivative in Scheme 4.2.1.3 Acylating Inhibitors 2.1.3.1 Acyclic compounds. Many experiments in protease chemistry have demonstrated that the enzymes perform acylation slowly and deacylation more rapidly when using amide and peptide substrates. Recently exceptions were found for nitroanilides and even for non-activated amines acting as If the the leaving gr~up.'~~-'~~ acylated enzyme exhibits reasonable stability the quasi-irreversible inactivation of the enzyme can be monitored.This type of inhibition is manifested by many well-known active-site titrants of serine proteases including arylsulphonyl fluoride~,'~~-'~~ phosphorofluori-dates,128 and phosphonates. 129 Studies with organophosphorus inhibitors of serine hydrolases suggest that truncated simulators of natural substrates recruit only a single site of the multi- proton catalytic capability that is involved in the hydrolysis of natural substrates.'30. 13' A fully functional acyl-enzyme intermediate but exhibiting sufficient stability to produce a 13C n.m.r. signal has been n N-N (12) 'I I 0 Reagents i Me,CHNH, I- EtOH at 65 "C; ii RSC(O)Cl THF at 5 "C Scheme 5 established with (5-n-propyl-2-furoyl)-a-chymotrypsin.132~133 This derivative is more suitable for assessing the properties of acyl-enzymes under native conditions than the acetyl-a-chymotrypsin that was reported previously.The 13C chemical shift of the carbonyl carbon of the acylated enzyme has a pH dependence that corresponds to a titration curve with a pKa of 7.0. There is controversy about the ability of the enzyme to maintain a distorted conformation of the acyl moiety. There appear to be at least two active acylated enzymes in a temperature-dependent conformational equilibrium.134 How- ever the 13C chemical shift of the acyl-enzyme does not indicate an unusual hybridization of the carbonyl group.'32 Different rates of deacylation of acylated trypsin-like enzymes may result from the concept of inverse substrates.'35* 136 Simple acyl groups introduce only moderate discrimination effects in the temporary inactivation of human thrombin human plasmin and bovine trypsin.137 The 4-methoxybenzoyl residue for example affords a relatively stable acyl-plasmin (ti x 15 h) while the t; of 4-methoxybenzoyl-thrombin is 35 minutes. A series of potent temporary inhibitors of vitamin-K-dependent proteases result from 4-amidinophenyl esters of cinnamic Despite their relatively low ability to discriminate between the enzymes of the blood clotting system their low degree of toxicity makes these compounds of interest for studies in V~VO.'~~ Thrombin-like snake venom proteinases are also susceptible to this type of ina~tivation.'~' Electron-withdrawing substituents at position 4 of the phenolic moiety of the slightly toxic aryl 4-guanidinobenzoates enhance the inactivation of human acrosin and human trypsin.14' The 4-guanidinobenzoylated enzyme is a stable intermediate in the urokinase reaction but not in the reaction of tissue-type plasminogen activator preventing titration of the active site of the latter enzyme by 4-methylumbelliferyl 4-guanidino-ben~0ate.l~~ Slow deacylation of the carbamoyl enzyme [' Enz'-OC(0)NR1R2] must also be a component of the inactivation of elastases by peptidyl carbamates although the mechanism of inactivation is not yet ~lear.'~~.'~~ The onset of the apparently uncompetitive inhibition of porcine pancreatic elastase by (12) (K = 2400 nmol dm-3) occurs very rapidly.The inhibitors with various aryl groups in position PI were found to be specific towards elastases as demonstrated by their lack of activity (13) against trypsin chymotrypsin and acetylcholinesterase. Scheme 5 give some details of the synthetic route to peptidyl carbama tes. Stable carbazate enzymes i.e. 'Enz'-OC(O)N(R)NHC(O)- (kdeacylation < 1.8 x s-') are formed by the reaction of serine proteases with azapeptides that carry both an aza-amino-acid residue in position P and a good leaving group in position Pl,. Trifluoroethyl esters and phenyl esters exhibit both suitable specificity and sufficient rates of acylation when using aza- peptides as active-site titrants of chymotrypsin-like enzymes and elasta~es.'~~.146 2.13.2 Heterocyclic compounds. Heterocyclic acylating agents are increasingly being used in the specific inactivation of serine proteases. N-Acylsaccharins (13 ; R = acyl) and N-acyl-benzisothiazolone derivatives (14; R = acyl) are powerful acylating agents for human leucocyte elastase [if R = 2-furoyl in (13) kdeacylation = 7 x lo-' s-' and IC, = 360 nmol dm-3].147 This compound if administered in a dose of 10.8 mg per kg of body weight completely protects against the emphysematous lesion in an acute animal m0de1.l~~ If the substituent R in (13) is an electron-withdrawing aryl group the inactivation of several chymotrypsin-like enzymes is also significant but perhaps mechanistically different.149 Bio-logical effects on chemotaxis of leucocytes were reported for these inhibitors. 150 Appropriate substituents [R1 = CH2NH3+ R2 = CH2Ph] can be introduced into the isatoic anhydride structure (1 5) to direct the anthranoyl-enzyme-producingme~hanism'~' of inactivation towards thr~rnbin.',~ Under conditions that have been chosen to ensure that thrombin is inactivated with 2500 nmol dm-3 of (15; R' = CH,NH3+ R2 = CH2Ph) and with a half-time of NATURAL PRODUCT REPORTS. 1988-G. FISCHER 0 (15) (16) 0 0 + 'Enz'-OH &CR H HN I R co2- + 'En 2'-OH NH HN I R Scheme 6 0 Cl (18) (19) inactivation of 2.6 minutes (kdeacylation < 1.5 x s-l) no detectable inactivation of trypsin chymotrypsin or plasmin takes place.However the inhibitor molecule is destroyed by an unknown enzyme activity in serum. While the approach leading to stable anthranoyl-enzymes is due to the electron-donating properties of the NH linkage it has been postulated153 that 5-alkyl-substitution in 4H-3,l- benzoxazin-4-ones [R2in structure (1 6)]15' should produce a 2,6-disubstituted benzoyl-enzyme upon hydrolysis stabilized by steric crowding. In fact replacing 5-methyl for hydrogen enhances the inhibitory potency by a factor of 4.4 in inactivation of human leucocyte elastase. Even more favourable in efficacy are the 2-alkylamino- substituted benzoxazinones (17).156 The alternative routes [k and k3]155for cleavage of the acyl-enzyme that are outlined in Scheme 6 can be partially blocked by bulky 5-alkyl and 2- aminoalkyl substituents.These substituents produce an enor- mous increase in the lifetime of acyl-elastase (by a factor of 770) in comparison to the unsubstituted 2-amino-3,1 -benzoxazin-4- ones. An insight into the stabilization factors that are responsible for the cleavage of acyl-enzymes comes from an X-ray analysis of the covalent adduct that is formed when 3-benzyl-6-chloropyran-2-one (18) inactivates chymotrypsin. 157 A halo- 47 1 enol-derived acid chloride functions as an intermediate. 15*3 159 The carboxylate group of the hydrolysed inhibitor bound within the active site of the protease forms a salt bridge to the protonated imidazole ring of His-57.This linkage precludes a water molecule from attacking the acyl group. For deacylation to occur a conformational change within the active site is necessary.lG0 Several 3-alkoxy-4-chloroisocoumarins show transient inactivation of chymotrypsin and elastases but exhibit only a limited hydrolytic stability in aqueous solution especially in the presence of g1utathione.l6' A central feature of the mechanism of inactivation by 3,4- dichloroisocoumarins (19)16 is that upon formation of the acyl-enzyme a reactive acid chloride (or ketene) is released. Therefore diacylation can occur with His-57 and the diacylated enzyme remains stable because of the low rate constant for deacylation of about 2 x s-l regardless of the type of enzyme.Since the rate of acylation is also very rapid for most of the nineteen serine proteases that have been investigated the range of values of kobs/clnhlbitor spans little more than two orders of magnitude. Two exceptions are bovine coagulation factor Xa and human thrombin which exhibit greater stability towards the inhibitor. 2.1.4 Latent Electrophiles 2.1.4.1 Halomethyl ketones. Halomethyl ketone derivatives of specific substrates are potent irreversible inhibitors of serine proteases though of limited use because of the intrinsically high chemical reactivity of the halogen- bearing carbon. 16' The mechanism of inactivation suggests that at least two reversible complexes are formed between an enzyme and its inhibitor prior to the direct attack of the methylene carbon on N' of the active-site histidine residue.ll5.163 For inhibitors that are derived from specific peptides the second complex i.e. the hemiketal is stable relative to the Michaelis complex and dissociates more slowly than it alkylates the active-site histidine residue. Therefore ki/Ki describes the rate-limiting formation of the hemiketal for specific and the rate-limiting alkylation for non- specific chloromethyl ketones. Recent X-ray diffraction data of the complex from the subtilisin-like fungal enzyme proteinase K [Tritirachium alkaline proteinase] with Z-Ala-Ala-CH,CI confirm a number of earlier investigations which indicated that the inhibitor is attached to the enzyme by two covalent bonds.lG4 Within the Z-Lys-CH,Cl-trypsin complex the tetra- hedral structure of the reactive carbonyl group in the final EI complex could be observed directly by 13C n.m.r.in both solution and the solid state (by cross-polarization magic-angle spinning).165 166*16* Protonation of the hemiketal is perturbed within the trypsin complex due to the formation of the imidazolium ion of His-57 leading to the unusual relationship that pK (tetrahedral oxyanion) Q pKa (Hi~-57).l~~ The undesirably high general reactivity of the chloromethyl ketones has been slightly overcome by replacing chlorine by fluorine. For simple fluoromethyl ketones the second-order rate constant of the irreversible inactivation is reduced about 40- fold whereas the reversible term is more efficient for the fluoro- compounds.163,169.170 The advantage of halomethyl ketones with their predictable requirement for optimal inhibitory potency (utilizing subsite fitting by appropriate substrates) has been used to differentiate between several chymotrypsin-like protease~'~~ and human plasma serine protea~es.'~~* 172 2.1.4.2 Alkylating heterocyclic compounds.A new strategy of irreversible inhibition of serine proteases is depicted in the ynenol lactone reaction in Scheme 7.173 The key steps namely acylation of the enzyme formation of a tethered allenone and finally alkylation comprise truly suicide inactivation. The synthetic route to these compounds is described in Scheme 8-174.175Compound (20; R1= R2 = H) inhibits human leuco- cyte elastase with a Ki of 5300 nmol dm-3 in a non-time-dependent manner by an alternate-substrate mechanism.The NATURAL PRODUCT REPORTS. 1988 R’ 0wR2 + ‘Enz’-OH -02c R’ + ‘Enz’-OH Scheme 7 I Reagents i R’CECH CuI (PPh,),PdCI, Et,N at 35 “C Scheme 8 Q H Tos-Phe-N OMe Cl (22) ‘Enz’-HIS + ‘EnzLOH ____) O-‘Enz’ + 0-‘En z’ l-Cl-1 ..,& CO2R OR COZR Cl His -‘Enz’ (23) Scheme 9 0 R ‘Enz’ Rq-+ ‘EnzLOH 0-‘Enz’ Br (24) \ + ‘EnzlOH Scheme 10 benzylic structure (20; R1= CH,Ph R2 = H) however irre- important factor in inactivation since the pyran-2-one deriv- versibly inactivates human leucocyte elastase (kinact.= atives show even more efficacy in kinact..The pyran-2-one ring 7.6 x lo3 dm3 mol-’ s-l) porcine pancreatic elastase (kinact,= in the 5-halomethyl derivative (21) is of interest in the 7.3 x lo2 dm3 mol-l s-l) and trypsin (kinact,= 17 dm3 mol-’ s-l) mechanism-based inactivation of chymotrypsin. Considering with a partition ratio Y of 1.6 for leucocyte elastase indicating the partition ratio there is a very high efficiency because of the that nearly every inhibitor molecule is consumed by the few turnovers that are required for complete inactivation. inactivation pathway. The size of the lactone ring is also an However the rate of the reaction is relatively low. The NATURAL PRODUCT REPORTS 1988-G. FISCHER 0 Inactivation / t R' C02NH rnodif ied enzyme + 'Enz '-0H Scheme 11 Hm Q inhibitors due to the hidden 4-quinone imine methide structure which is a potent alkylating agent for enzymic nucleophiles.Only partial re-activation of inhibited enzyme by hydroxyl-amine can be achieved indicating that several inactivated enzyme species may exist. This finding accords with the X-ray diffraction study of the inhibitor-porcine pancreatic elastase complex which showed that His-57 was not alkylated."' Previous investigations on five- and six-membered-ring halo- enol lac tone^,'^^ e.g. (24) have suggested the suicide mechanism for the inactivation of chymotrypsin (Scheme 10). The long- term inactivation is resistant to the nucleophile-mediated recovery of enzyme activity. Furthermore scavenger experi- ments and the persistent 1 1 ratio of the inhibitor to the inactivated enzyme even during denaturation experiments rule out an alternate-substrate mechanism of inacti-vation."' ''I In some cases however slight changes in the structure of the inhibitor (for example by shifting the aryl residue R from position 3 to position 4) cancel the suicide pathway but provide potent inhibitors.The inhibition now occurs reversibly perhaps by the intermediacy of a stable acyl- enzyrne.l8* Appropriately substituted cephalosporins e.g. (25) are among the most potent and hydrolytically resistant inhibitors of elastases that have yet been reported.''3 In the earlier phases of the inhibition re-activation of the enzyme could be achieved by treating it with hydroxylamine. With a half-time of about I20 minutes however the inactivation becomes irreversible.In fact the /$factam antibiotics which have often been described as slow deacylating compounds for u-alanyl-D-alanine pep- tidase,lx5 are able to alkylate (in a suicide pathway) His-57 of porcine pancreatic elastase if they are substituted in the 7r- position by appropriate substituents and bear ester or amide functions at position 4.1H4The inhibitory potency of the reversible step depends largely on the formation of an adduct to the hydroxyl group of Ser-195 as exemplified by simple boronic acids1" and the lowered binding energy of cephalo- sporins to anhydro-elastase.g4 2.1.4.3 Latent nitrenes and carbonium ions.The use of peptide- derived masked isocyanates or nitrenes (26) in inactivation of proteases was introduced by Fischer et ~1.''~ The appropriate specificity towards the target enzyme is achieved by utilizing the N-terminal recognition region of favourable substrates.Thus RYNKN+N Me0$ 0 dipeptidyl peptidase IV is specifically inactivated by N-(Xaa- (28a) 0bo I II 0 (2 7) (28b) mechanism of inactivation is still unknown although an exposed disulphide bridge near the active site of chymotrypsin appears to be inv01ved.l'~ The basic structure of 3-alkoxy-7-amino-4-chloroiso-coumarinslii in compound (22) has opened up the interesting possibility by a proteolytic cascade of designing a pro-suicide inhibitor since the 7-amino-group is necessarily liberated upon proteolytic hydrolysis of (22).16' Although not active against the targeted chymotrypsin-like proteases (22) is most successful in inactivating human leucocyte elastase.As shown in Scheme 9 the 7-aminocoumarins (23) themselves are powerful suicide Pro-)-O-(4-nitrobenzoyl)hydroxylamine.N-Terminally pro-tected peptides cannot be cleaved by the enzyme and co nseq ue n t 1y N-termi na1I y protected h yd ro xy 1amines N-(Boc-Xaa-Pro-)-O-(4-nitrobenzoyl)hydroxylamine are not able to inactivate dipeptidyl peptidase lV.Isi As expected for enzyme-activated inhibitors the rate of irreversible inactivation decreases in the presence of competitive inhibitors. A highly reactive nitrene intermediate has been suggested to be involved in the mechanism of inactivation (Scheme 11).Depending on the amino acid Xaa in the case of inactivation of dipeptidyl peptidase IV the partition ratio changes from 2 x lo5 for Gly to 8 x lo3 for Lys(Z) whereas in the inactivation of thermitase by Boc-Ala-Ala-NHO-(4-nitro-benzoyl) nearly every molecule of inhibitor leads to inacti- vation.1*8 The lifetime of the tetrahedral intermediate is thought to allow a choice to be made between the alternative reaction routes that are depicted in Scheme 1 I with inactivation being favoured if the lifetime is prolonged. Obviously compound (27) extends this principle.'" However the full reaction cycle including Lossen rearrangement of the inter- mediate nitrene does produce an isocyanate within the active site of the target enzyme. Aliphatic isocyanates are known to inactivate serine proteases irreversibly.'9n 19' Activity has been observed to be regained albeit incompletely after an enzyme has been inactivated by (27); Itrph~,ICr,tl,,l = 1.9 x 10 s '."" On the basis of latent isocyanates amino-acid-derived azolides (28)lYJ lS4 and sulphonate salts (29)'" were designed specifically to obtain potent irreversible inhibitors of human NATURAL PRODUCT REPORTS 1988 0 (30) -NH-CH-0-'Enz' + I R II N \ 0-r 1 inactivation Scheme 12 Table 3 Reversible inhibitors of porcine pancreatic elastase (PPE) and human leucocyte elastase (HLE)" Inhibitor Z-Ala-NH[CH ,],,CH Boc-Ala-NH[CH,],,CH Boc-Val-NW[CH2] ,CH HO,CCH(Me)NHC(O)-Val-GIy-Azala-OBzl wal'']Aprotinin [t-L,eu'']Aprotinin MeOSuc- Ala-Ala-amho- boro-Val-OH Z-Val-CF Z-Pro-Val-CF Z-Val-Pro-Val-CF Elastatinal (16; R' = CF, R2 = Me) (13 ; R = 2-furoyl) K,/nmol dm-3 PPE* HLE Ref.12x 103 190 x lo3 57 N. I. 10.6 57 N. I. 4.5 57 100' 400 x 10' 68 69 57 0.11 89 N. I. 15 89 0.25 0.57 119 N. D. 13x lo3 114 N. D. 1.8~10' 114 N. D. 1.6 114 200 50 x 10' 94 207 N. D. 29 153 580 360 149 (a) In this Table the experimental conditions are not the same throughout; (h) N. D. = Not determined. N. I. = No inhibition; (c) IC, value leucocyte elastase. The value of klnact./~,nhlblt~,,. was 2070 dm" molk's-' if (28a; R = CH,Ph) was used. Interestingly none of the descarboxymethylated derivatives of (28) showed any inhibitory activity towards porcine pancreatic elastase.The active-site-directed N-nitroso-amide (30) inhibits a-chymotrypsin due to a suicide mechanism that is characterized by the release of benzyl carbonium ions according to Scheme 12.1S5The highly reactive carbonium ion inactivates the enzyme by a scattered alkylation of amide linkages at both oxygen and nitrogen. The final ratio of benzylic groups to enzyme molecules is 1.O indicating the perfect efficacy of inhibition.lS6 2.2 The Main Target Serine Proteases 2.2.I Elastam The main target serine proteases that are released from polymorphonuclear leucocytes and alveolar macrophages are leucocyte elastase and the more chymotrypsin-like cathepsin G. There is a relationship between the activity of these enzymes and the chronic destruction of tissue that is associated with inflammation arthritis and emphysema (see Table IUy Both of the enzymes have major plasma inhibitors these being a,-antichymotrypsin z,-antitrypsin and z2-macro-globulin.200201 Onset of destructive diseases can occur if the balance between a protease and the corresponding antiprotease has been disturbed.Therapeutic intervention by administering synthetic inhibitors can achieve an artificially elevated level of inhibitory capacity. Obviously the design of the inhibitor needs to be fitted to the subsites of enzymes in several cases. The fibronectin-degrading enzyme cathepsin G utilizes subsites P through P to enhance k,,,. The enzyme has a preference for substrates in which there is Phe or Met at position Remote interactions between human leucocyte elastase and its substrate have a profound influence on acylation rates particularly in the region of P through to P .The preference is for Val in position P, whereas catalysis by porcine pancreatic eiastase is enhanced if Ala is in position P1.203 *04 In effect comparable preferences have been observed for inhibitors that contain a peptide chain and additionally a reactive linkage that is responsible for inactivation.68 6s ,05 206 Some values of K for the reversible inhibition of elastases are summarized in Table 3. The data in Table 3 also indicate that the relationship between subsite mapping and inhibition is not so simple. From the parameters in Table 4 it appears that generally speaking irreversible inhibitors do not exhibit specificity at the same high level as is shown by reversible ones.More representative of conditions in vivo is the hydrolysis of elastin mediated by human leucocyte elastase compared with the chromogenic substrate assay that was used to determine the values of K in Table 3. Table 5 summarizes several of the values of IC, that have been derived from the elastin assay. Table 4 Irreversible inactivation of three tissue-degrading enzymes by various compounds Compound 2-(C,F,CONH)C,H,SO,F MeOSuc-Ala-Ala-Pro-Val-CH2C1 (28a; R = n-propyl) (20 R' = n-butyl R' = H) (29; R = n-butyl) (23; R = Et) 3,4-Dichloroisocoumarin (uj PPE = porcine pancreatic elastase HLE (k,,,,,/K,)/dm"mol-' s PPEfl.h 1300' 1560" 6.3 260 N.I. 700' 2500' = human leucocyte elastase; (b)N. D. HLE",* 1700" N. D. 500 12 x lo3 9 20 9420" 8920' = Not determined N. I. Cathepsin G" Ref. 13' 47 N. I. 47 N. D. 194 N. D. 175 N. D. 192 195' 161 28' 162 = No inactivation; (c)k,"*,. NATURAL PRODUCT REPORTS 1988-G. FISCHER (31) Table 5 Inhibition of the hydrolysis of elastin by human leucocyte elastase Inhibitor IC,,/nmol dm-3 Ref. Z-Ala- Ala-Pro-urnho-Val-CF 110 1 I6 Suc- Ala- Ala-Pro-Val-CH ,C1 292 116 Suc-Ala- Ala-Pro-urnho-boro-Val-OH 130 116 (31) 1200 101 Eglin C 43 208 Table 6 Irreversible inactivation of three trypsin-like enzymes by chloromethyl ketones"' kil,:,,.(/dm3 mol-' s-' Ketone Factor XIa B-Factor XIIa Kallikrein Dns-Glu-Gly-Arg-CH,CI 63 462 15.6 x lo3 o-Phe-Pro-Arg-CH,C1 227 1 1160 2299 o-Phe-Phe-Arg-CH,CI I10 I389 118 x lo3 HNYNH2 HN /)\NH2 Table 7 Reversible inhibition of five trypsin-like enzymes K,/nmol dm- In hi bi tor Thrombinb Trypsin" (2R74R)-(7) (2S74S)-(7)(32) 19 280 x lo3 1000 5 500 x 103 90 (33) 30 800 (8)D-Phe-Pro- Arg-H 800" 50 2600 100 (u)Bovine enzyme; (h)human enzyme; (c) N.D. = Not determined 2.2.2 Trj'psin-like Enzymes Numerous enzymes which play an important role in haema-tological phenomena such as coagulation fibrinolysis and inflammation exhibit trypsin-like specificity. Relevant here are the very potent inhibitors for trypsin thrombin coagulation factor Xa and others.However in several cases the antitryptic activities of low-molecular-weight inhibitors fail to exhibit sufficient specificityi4 since these enzymes display only subtle differences in subsite interactions. In this respect Table 6 shows a striking example of the discrimination effects that can be achieved. However it is probable that the complex biological effects that are introduced by a plasmin-inhibitory drug should not be explained simply in terms of inactivation of a distinct protease.481 Careful studies on the temporary blockade of bovine trypsin human trypsin and human plasmin by 4- amidinophenyl esters in which the acyl group varies have been performed.211 Despite the considerable number of acyl groups that have been tested only a 100-fold difference in deacylation rate could be found to differentiate between plasmin and thrombin.Comparable results have been reported with 4- guanidino-benzoates and -thiobenzoates as active-site titrants for trypsin-like enzymes."' Some of the typical inhibitory specificities are shown in Table 7. 3 Cysteine Proteases -General Considerations In contrast to the enzymes in the previous section the number of available structural units to optimize the affinity of the inhibitor toward the individual cysteine protease is very limited. Although catalysis by these enzymes proceeds by a mechanism that is related to that of the serine proteases (Scheme 1 3),219attempts to utilize their common structural requirements for the design of inhibitors are rare.However the lack of a variety2'" of synthetic inhibitors does not result from the insignificance of cysteine proteases in biological events. Scheme 13 Factor Xa" Plasmin". ' Kallikrein" Ref. 210 800 1500 77 500 x lo3 500 x 10" 500 x lo3 77 N. D. 900 10 x 10" 209 N. D. 400 1000 209 2200 N. D. 500 x lo3 79 2000 2000 20 x lo3 210 NATURAL PRODUCT REPORTS 1988 Table 8 Some biological processes that involve cysteine proteases Type of reaction Enzyme(s) involved Cleavage of viral protein215 Picornavirus protease2I6 Cleavage of signal sequences Calpains and others and activation of proteins233 Turnover of peptides and Cathepsins pyroglutamyl proteins2'* peptide hydrolase*" n H (34) 0 H I II 111 J.Q (35) Reagents i (CF,CO),O THF Et,N at 5 "C; ii deprotection with CF,CO,H then ethyl chloroformate N-methylmorpholine THF Boc-Gly at -15 "C; iii deprotection with CF3C0,H Scheme 14 Table 8 lists the most widely studied physiological processes involving cysteine proteases. It is typical that attempts to probe the antiviral activity of inhibitors of cysteine proteases were made with members of the naturally occurring cystatin superfamily. 3.1 Reversible Inhibitors Recently the amino-acid sequence of human plasma a,-thiol proteinase inhibitor (molecular weight = 70 kD) was deter-mined by analysing the base sequence of cDNA. Its identity with low-molecular-weight kininogen was established.222 There are several highly conserved amino-acid sequences among the cysteine protease inhibitors of plasma tissues and kininogens including those in human ~ystatin,,,~ human ~tefin,*,~ and chicken cystatin.225 The common sequence -Gln-Val-Val-Ala- Gly- was thought to be located within the reactive site of these inhibitors.Indeed a weak inhibition in the millimolar range arises when papain and cathepsin B are incubated with these pep tide^.^^^.^^' Z-Gln-Val-Val-Ala-Gly-OMe which is the most active compound protects papain significantly from T- kininogen-induced inhibition indicating that both of the inhibitors may share their binding sites. Some new details about the catalytic pathway of cysteine proteases come from '"C n.m.r. studies22M-232 229 that were performed with well-known230.peptide aldehyde inhibitors. The inhibition of papain by IT- enriched Ac-Phe-Gly-H (K,= 26 nmol dm-"; value not cor-Physiology Pathology Replication of viruses Viral diseases Activation of secretory Implantation proteins resorption of bone"' -Muscular dystrophy2"' rected for hydration)228 is characterized by the stereospecific formation of a thiohemiacetal with both the L-Phe and the D-Phe enantiomer. The D-isomer is bound only five-fold less tightly than the Lampound supporting a binding model in which in both of these inhibitor complexes the phenyl ring is located at the S hydrophobic pocket of papain. Computer modelling studies suggest that the hydroxyl function of the thiohemiacetal-bound papain does not point towards the oxyanion hole but instead to the indole ring of Trp-26 and to the backbone polypeptide-chain residues Gly-65 and Gly-66.This would correspond with the proposals that stabilization of a tetrahedral intermediate by backbone hydrogen-bonding is negligible in catalysis by papain.228 A similar range of potency is found for 5-oxoprolinal (34) using pyroglutamyl peptide hydrolase as the target enzyme.234 5-Oxoprolino1 by comparison competitively inhibits with a K,value that is four orders of magnitude higher than that of the aldehyde analogue. The use of 5-oxoprolinal in vivo suffers from its rapid metabolic inactivation. Recently it has been found that peptidyl methyl ketones are potent inhibitors for cysteine proteases.For example Z-Ala- Ala-Phe-Ala-CH exhibits the following Kl values papain 2 nmol drn-,; cathepsin B 8 nmol drn-,; cathepsin L 0.7 nmol dmF3. Cathepsin H is not inhibited.237 In contrast to peptide aldehydes the corresponding nit rile^,^^. 236 are solely powerful inhibitors for cysteine pro- teases lacking any effect on serine proteases. Papain that is inhibited by N-(N-acetylphenylalanyl)aminoacetonitrile (for which values of Kl have been obtained of 730,232 1100,238 and 6800 nmol dm-3 23y) is protected from S-alkylation by chloro- acetic The covalent nature of the binding of nitrile inhibitors to papain has been demonstrated recently by direct n.m.r. observation of the thioimidate resulting from the attack of the enzymic thiol group on the nitrile moiety.239 241,242 Since the inhibitory principle will be extended to other cysteine proteinases as already demonstrated by the inhibition of cathepsin C [dipeptidyl peptidase I; E.C.3.4.14.11 (K,= 2700238or 1100 nmol dm 3241) with (39 the synthetic route to the amino-nitrile synthon is given in Scheme 14.238 3.2 Irreversible Inhibitors Affinity labelling of cysteine proteases by peptidyl halomethyl ketones blocks the essential thiol group by alkylation. Because of the proximity effect within the Michaelis complex the rate of this type of alkylation is enhanced up to lO"-fold compared with the bimolecular-model reaction.243 Although selectivity can be achieved by varying the peptidyl residue the high chemical reactivity of the halomethyl moiety towards general nucleophilic attack causes severe toxic effects in cellular Attempts were made to overcome these unspecific side-reactions by replacing chlorine or bromine by fluorine.24S.246 Using glutathione as an unspecific nucleophile the decrease in reactivity of fluoro-ketones has been determined to be 500-fold compared with their chlorine congener~.'~~ Fluoro-substitution however does not diminish the efficiency of inactivation of cathepsin B to a similar extent. In summary the second-order rate constant is decreased to about half that of the corresponding chloromethyl ketone and kl/Kl= 3700 dm3 rno1-I s1at 37 "C for Z-Phe-Phe-CH,F."O Even NATURAL PRODUCT REPORTS 1988-G. FISCHER 477 0 (36) (37) BocN-I -iii H H H iiV .CO2 Me Reagents i O, MeOH Me$ at -78 "C; ii trimethyl phosphonoacetate NaH THF ; iii deprotection by CF,CO,H ; iv Ac-L-Phe ethyl chloroformate N-methylmorpholine THF at -15 "C Scheme 15 I + ( Arg-127 Figure 3 Several possible enzyme-substrate interactions that have been proposed for the tetrahedral intermediate of the general acid/ general base mechanism of catalysis by carboxypeptidase A.more active against cathepsin B is Ala-Phe-Lys-CH,F (ki/Ki = 3 x lo5 dm3 mol-I s-' at 25 "C) whereas the rate of unspecific alkylation remains unchanged in comparison to the N-protected inhibitor.169 Some new inhibitors of calpain based on the chloromethyl ketone concept have been reported.247 Leu-Leu-Phe-CH,C1 that is dansylated on the N-terminal leucine residue distinguishes between calpains and papain by a 100-fold difference in their rates of inactivation.Diazomethyl ketones are much more selective in their inactivation of cysteine proteases because of the inertness of the diazo-group against thiol-containing and their general lack of reactivity towards other classes of proteases. The specific inactivation in vivo of pyroglutamyl peptide hydrolase by pyroglutamyl diazomethyl ketone in a dose as low as 0.1 mg per kg of body weight administered intraperitoneally to mice has been rep~rted.~~~~~~~ A second-order rate constant of 1.5 x lo5dm3 mol-I s-l for the inactivation of the bovine brain enzyme in vitro has been calculated. The diazomethyl compound is a long-lasting drug since 24 hours after a single dose of 0.1 mg per kg of body weight approximately 50 % of the enzyme is still inactivated in various mouse tissues.Based on the epoxide inhibitor E-64 (36) which was isolated from cultures of Aspergillus japonic~s,~~' several synthetic and semi- synthetic analogues have been developed250 and te~ted~~l-~~~ against papain and the various cysteine cathepsins. Generally cathepsin H is poorly inactivated by epoxide inhibitors whereas papain is mostly sensitive with apparent second-order rate constants in the range of lo5 dm3 mol-' s-' at 40 "C. The proposed model for the binding of epoxide inhibitors is characterized by a reversed mode of attachment when compared with peptidyl diazo-ketones.E-64 (36) covers the Sl site with its leucyl moiety whereas the agmatine group points towards the S,. position. Calpains are also inactivated by epoxide inhibitors but with greatly reduced potency.255 Hydrophobic chains which could be located into the S,. binding pocket give rise to increased efficacy of epoxides. The synthetic inhibitor (2R,3R)-(37) diminishes the rate of proteolysis in ischaemia providing evidence that the inactivation of calcium-activated neutral proteinase and/or cathepsin B is involved in these processes.256 By covalently coupling an epoxide inhibitor to an acrylamide copolymer the value of K is decreased with respect to the free inhibitor.258 Replacing the trans-epoxide group in an analogue of (36) by the nucleophile-trapping fumaryl residue leads to 100-fold less active inhibitors.251 The vinylogous amino-acid ester (38) however shows a higher potency (Kl = 26000 nmol dm-3; k,= 1.8 x s-l) against papain.23sv257 Molecular graphics demonstrate that the P-carbon of the double-bond of (38) lies directly above the sulphur of Cys-25 of papain at an appropriate distance to form a covalent bond.The inactivation parameter does not greatly change if the carboxy- methyl residue in (38) is replaced by methyls~lphonyl.~~~ With serine proteases and metalloproteases appropriate analogues of (38) exhibit only very weak competitive inhibition. This reflects the fact that the vinylogue principle constitutes a promising starting point for the design of more specific inhibitors of cysteine proteases.The synthetic route to (38) is given in Scheme 15.238 4 Metalloproteases -General Considerations There is evidence that several zinc-dependent proteases have strong similarities in their catalytic action and therefore in their sensitivity towards inhibitors. Considerable attention has been focussed on the X-ray crystallography of a variety of enzyme-inhibitor complexes including thermolysin bound to N-(1-carboxy-3-phenylpropyl)-Leu-Tr~,,~~ to Leu-NHOH,260 to chloroacetyl-DL-(N-OH)Leu-OCH3,261 to phosphoramidon (42),262 and to N-phosphoryl- Leu-NH and (2-benzyl-3-mercaptopropionyl)-Ala-Gly-NH,.263 Other work was performed on carboxypeptidase A complexed with (-)-2-benzyl-3-(4-methoxybenzoyl)propanoic with the aldehyde inhibitor 2-benzyl-3-formylpropanoic with 2-benzyl-5,5,5-trifluoro-4-oxopentanoic acid,266 and with N-[(benzyloxycarbonylaminomethyl)hydroxy-pho~phinyl]-Phe.~~~ Our knowledge of the spatial arrangement of the catalytic groups during hydrolysis of a peptide bond is based mainly on these data (Figure 3).It has been suggested that the y-carboxylate of Glu-270 acts as a shuttle. Thus the negative charge promotes the attack of a zinc-bound water molecule on the zinc-co-ordinated carbonyl group in the substrate. After Table 9 The role of metalloproteases in biological systems Type of reaction Enzyme(s) involved Release of physiologically Angiotensin-converting active peptides enzyme2s8*2ss Degradation of connective tissue C~llagenase~'~* 271 Inactivation of polypeptide Enkephalinases,273 meprin,272 angiotensin-converting enzyme Supramolecular assembly metal lo en do pro tease^^^^ Digestion Carboxypeptidases A and B Asp -Arg -Val-Ty r -Ile -His-Pro-Phe-His-Leu (Angiotensin I ) J Asp-Arg-Val-Tyr-Ile-His-Pro-Phe ( Angiotensin n) Scheme 16 (39) OR OH (40) in2+ 1 m\ Figure 4 Proposed contacts of enalaprilate in the active site of angiotensin-converting enzyme.HS NATURAL PRODUCT REPORTS 1988 Physiology Pathology Production of a vasoconstrictor Hypertension Destabilization of collagen Arthritis275 Analgesic function Hypertension Fusion of myoblasts exocytosis -fusion.of adipocyte membranes277 H protonation Glu-270 serves as the proton donor to the nitrogen of the leaving group.Tyrosine-248 has no crucial role in catalysis.267 The correct binding of substrate is further. enhanced by the salt bridge between Arg-145 and the C-terminal carboxylate moiety of the substrate. As indicated in Table 9 metalloproteases are involved in a variety of biological events. By far the most important example from the standpoint of clinical use has been the inhibition of angiotensin-converting enzyme (peptidyl-dipeptidase A2'*). This zinc-dependent enzyme converts angiotensin I into angiotensin I1 (Scheme 16). Bradykinin which is a potent nonapeptide vasopressor is also degraded by this enzyme. Truncated sequences of angiotensin I generated by the enzymes of blood platelets are able to inhibit angiotensin-converting enzyme in the submicromolar range.486 Elucidation of the minimal inhibitory unit of natural angiotensin-converting-enzyme inhibitors of snake venom279 stimulated the develop- ment of the powerful inhibitor D-3-mercapto-2-methyl-propanoyl-L-Pro (captopril) (39).280 Also orally active in the treatment of hypertension is enalapril (40; R = Et),281 resulting from the bi-product concept282 of inhibitor design.The low IC, values of 23 nmol dm-3283 and 1.2 nmol dm-3 [for enala- prilat which is the dianion of (40; R = H)Iz8l are due to the optimal mode of binding to the enzyme as demonstrated in Figure 4.284 The enkephalin-degrading enzyme endopeptidase 24.11 (brain enkephalinase) [membrane metallo-endopeptidase ;E.C.3.4.24.113 is inactivated by the binding of thiorphan (41) (Ki = 40 nmol dm-3).286 Taking into account the different sub- sites of both enzymes the binding scheme within the enzyme- inhibitor complex is similar to that which has been suggested for the inhibition of angiotensin-converting enzyme by capto- pril. Another approach to potent synthetic inhibitors results from the naturally occurring efficient zinc protease inhibitor phos- phoramidon (42),287 which is thought to function as a transition- state analogue. NATURAL PRODUCT REPORTS 1988-G. FISCHER Table 10 Phosphoric-acid- phosphonic-acid- and phosphinic-acid-derived inhibitors of zinc proteases Structure Enzyme Ki/nmol dm-3 Ref. H,O,P-Phe H,O,PCH,CH(CH,Ph)CO,H H,O,P-Leu-Trp Me[CH,],CH,P(O) (0-)-Gly-Pro-Ala ZNHCH,P(O) (0-)-Leu-Ala-Gly ZNHCH,P(O) (0-)-Leu-Leu AcNHCH,P(O) (0-)-Phe-Met Me[CH ,],CH(NH ,)PO,H PhCH,CH(NH,)PHO,H Ph[CH ,],P(O) (0-)-Ala-Pro (PhO),P(O)- Ala-Pro (HO),P(O)- Ala-Pro ZNH[CH ,J,P(O) (0-)-Phe Phosphoramidon (42) Phosphoramidon (42) Carboxypeptidase A Carboxypeptidase A Elastaseb Collagenasec Collagenased Thermolysin Enkephalinasee Leucine aminopeptidase Leucine aminopeptidase ACEf ACE ACEf Carboxypeptidase A En kephalinase" Elastaseb 240" 298 220 298 26 300 800 301 14000 302 9.1 297 140 303 470 304 59000 304 0.Y 306 42000 307 1.4 307 7 308 4 303 250 300 (a) Compare earlier values of 5000 (ref.294) and 2100 nmol dm-3 (ref. 299); (6) from Pseudomonas aeruginosa; (c) from Clostridium histolyticurn; (d) from human neutrophils; (e) endopeptidase 24.1 1 ; (f) ACE is angiotensin-converting enzyme; (g) TC, = 7 (ref. 305) The mode of inhibition for several of the reversible inhibitors of metalloproteases is rather complicated. The kinetics of inactivation of angiotensin-converting enzyme by phosphorus- containing inhibitors have been studied extensively.288 In some cases the inhibition constant depends markedly on the substrate employed.289 The apparent K values do not represent true dissociation constants and they are substantially decreased (70- to 250-fold) in the presence of 300 mmol dm-s of chloride ion. The EI* complex is stabilized by the halide ion which decreases the k- Few specific irreversible inactivators of metalloproteases have been developed although recent examples of this class are sulphinamoyl esterszg1.292 and cyclopropyl peptides (43).293 4.1 Useful Classes of Inhibitors 4.I .I Phosphorus-containing Amino-acid and Peptde Mimics The tight binding of phosphoramidon towards thermolysin has caused the development of a number of related phosphor- aflE1~Iates~~* 295 as potent transition- and phosphonamidatesZ8l. state-analogue inhibitors of several zinc proteases. The multi- substrate ground-state-inhibition concept that was suggested for (2RS)-2-benzylsuc~inate~~~been rejected for these has derivatives since the values of k,,,/K,,, and not the values of Km,of the corresponding substrates correlate with the K values of the phosphonamidates.296 "' Significant differences are observed in the X-ray structure of the phosphoramidon-thennolysin complex compared with that of H,O,P-Leu-NH bound to the same enzyme. The zinc ion in the phosphoramidon complex appears to be quadridentate. As a further difference the nitrogen of the P-N bond in the phosphoryl-Leu-NH complex seems to be protonated.2E2. 263 The potencies of several phosphorus-containing inhibitors are summarized in Table 10. Masking one P-OH group in 2-benzyl-3-phosphono-propionic acid does not considerably change the K value for carboxypeptidase A.298 However the closely related structure ZNH[CH,],P(O) (0-)-Phe undergoes a 70-fold increase in K upon O-methylati~n.~~~ It follows that at least a single negative charge must be located on the phosphorus moiety.On the other hand monoesterification of H,O,P-Leu-NH decreases the effectiveness in inhibiting thermolysin by about 1OO-f~ld.~~~ Substitution of OH by SH in the P-ethoxy-derivative of H,O,P-Phe leads to a ten-fold higher Kivalue. This sulphur effect had previously been demonstrated in )the inhibition of thermolysin. ,09 However endopeptidase 24.1 1 and angiotensin- converting enzyme are insensitive to the replacement of P=O with P=S.,03 Although studies with model compounds suggest that the replacement of phosphorus by an arsenic atom should lead to more active inhibitors in fact a large decrease in (44) X = NH (46) X = 0 ZNH ' ZNH ..... 11, 111 (471 Reagents i Me,SiCl Et,N ; ii 1-alkoxycarbonyl-3-methylbutyl isocyanate ;iii deprotection Scheme 17 effectiveness is observed for the arsono-derivative of 2-phosphonoacetyl-Pro in inactivating angiotensin-converting enzyme presumably due to the longer bond distances around the arsenic atom.310 As shown in Table 10 a large scatter of inhibition constants is sometimes observed. One reason may be the hydrolytic instability of the P-N bond.300 The P-OR linkage is also hydrolysed non-enzymatically to regenerate the P-OH group. In this way a prolonged release of the potent converting- enzyme inhibitor (HO),P(O)-Ala-Pro from the weakly inhibi- tive diphenyl ester has been suggested." Cleavage of the P-O bond is not accelerated by the enzyme but the nitrogen group of the P-N linkage can be transferred under very mild conditions by nucleophilic assistance to carboxylate groups.311 Several novel phosphorus-containing dipeptide analogues (44)and (46) product analogues (45) and mimics of bestatin (47) have been developed by Bartlett et None of these is very effective against leucine aminopeptidase.However they are valuable tools for the evaluation of the contribution of a single hydrogen- bond to the binding energy between ligands and proteins. Hydrogen-bonding interactions contribute to the inhibition of thermolysin by the phosphonate esters (46; R' = H R2= Z Xaa = Leu) and (44; R' = H R2 = Z Xaa = Leu) (in which oxygen of P-O-C is replaced by NH).Both compounds have the same mode of binding to thermolysin as determined by X-ray analysis,,12 whereas the inhibitory potency is about 840 times stronger for the NH-comp~und.~~~ The difference of 16.7 kJ mol-' in the intrinsic binding energy appears to result from a hydrogen-bond interaction (3.0 A) between the P-NH proton and C=O of Ala-113. A value of 17.6 kJ mol-' was calculated from a thermodynamic pertur- bation method and molecular dynamics. The calculation shows two important factors that are responsible for the different inhibitory efficiency namely attractive and repulsive interactions and relative solvation effects.314 The latter favours the oxygen analogue in the inhibition of thermolysin. The preparation of the phosphine surrogate (47) of bestatin is shown in Scheme 17.4.1.2 Curboxylute-and Thiol-containing Inhibitors The most prominent example of the carboxyalkyl dipeptides enalapril (40; R = Et) has been subjected to an enormous wealth of structural m~dification.~~~.~'~ A similar statement is true for captopril (39) as the parent compound of thiol inhibitors,283 although there is some evidence to suggest that there are alternative binding modes for sulphydryl and non- sulphydryl inhibit01-s.~~~ Obviously the carboxylate function protected as an ester in (40; R = Et) contributes substantially to the affinity of enalaprilate [the dianion of (40; R = H)] for angiotensin-converting enzyme"' and for other metallo-proteases. The carboxylate function of N-(I -carboxy-3-phenyl-gropy1)-Leu-Trp (Kl M 50 nmol dm-,) binds to the active-site zinc ion of thermolysin by bidentate co-~rdination.~~~ This finding explains why the binding energy of the dianion of (40; R = H) is 25 kJ mol-1 less for the apoenzyme of angiotensin- converting enzyme than for the enzyme.317 Replacement of the carboxyl group in (40; R = Et) by 2- and 4(5)-imidazolyl residues yields inhibitors with only marginal The a-carboxylate of y-dipeptides of glutaminic acid can replace the carboxylate group of (40; R = Et) and is therefore useful in designing new inhibitors.319 The absolute configuration of the carboxylate- bearing carbon in (40; R = Et) has been determined to be (S)whereas the (R)-enantiomer is less active.281 The state of protonation of the secondary amine nitrogen in (40; R = Et) is not important for its strong binding since the azapeptide (48) which is largely unprotonated above pH 7 is strongly bound to the enzyme.32o In summary the NH group is not critical but is favourable for high activity.,,' A favourable pattern of substitution within the remainder of molecule can compensate for the absence of this A broad spectrum of alkyl groups and arylalkyl chains can replace the phenylethyl residue in (40; R = Et) without altering IC, to a value outside the nanomolar range.Extending the peptide chain of enalapril to cover the S and S subsites of angiotensin-converting enzyme may lead to tighter binding as observed for simple peptide inhibitors and ketomethylene tripeptide analogues.323 But irrespective of the length of the spacer between the critical carboxylate group and the N-terminal aminoacyl moiety none of these compounds achieves the low K value of enalapril- ate.324 Replacement of the alanine residue by a variety of L-amino acids results in inhibitors which show similar activity to (40;R = Et).Thus the Lys analogue is the orally active compound li~inopril.~~~ Numerous proline surrogates have been reported. Many of them are highIy active against angiotensin-converting enzyme when introduced into an appropriate basic structure indicating that there can be considerable structural latitude of the C-terminal end. Considering the difficult chemical synthesis of the proline derivatives the advantage with respect to the existing inhibitors is not obvious.NATURAL PRODUCT REPORTS 1988 168) (49) 0 OH HO,C 00 (50) (51) OH (52) Alternative inhibitor structures have come from the analysis of the active-site conformation of the most potent of the currently known Captopril and related com- pounds all have a common low-energy conformation.326 Benz~lactams~~~ and the lactam analogues (49),,15 which are simplified versions of (40; R = Et) in which the angle w of the imidic peptide bond is fixed at a value corresponding to the trans conformation exhibit very good inhibitory properties. The trans conformation of (40; R = Et) predominates in aqueous and readily binds to the active site of the enzyme. The optimal value of the angle $ responsible for promoting a favourable spatial arrangement of the dipeptide structure must lie within a 30 " window encompassing 130" to 170".The value of $ of the most potent eight-membered lactam inhibitor (49; n = 4) is virtually identical to that found in the crystal structure of enalaprilate itself (143 O).,,* Therefore it appears that the dipeptide unit of (40; R = Et) binds to angiotensin-converting enzyme in a conformation that is close to the minimum-energy conformer. The bicyclic lactam (50) having all the conformational and hydrophobic329 330 advantages yields a K value as low as 0.076 nmol The free rotation around a carbon-carbon single bond is prevented by methylene bridges in (5 1). These cyclic compounds are as effective as captopril in inhibition,332 and several bicyclic dipeptide mimics have been reported.The structures are represented by benzazepines,333 1,5- benzo thiazepines 334*484 triazolo- pyrazolo- and pyridazo-pyrida~ines,~~~-~~~ octahydro-in dole^,^^^ pyridazo-dia~epines,~~~ Be-and pyridazinedi~nes.~~~ cause of their synthetic advantages being derivable from the asymmetric synthesis of thiorphan (41),341 N-substituted gly- cine derivatives (52) and N-substituted 4-aminobenzoic are increasingly being used in inhibiting zinc-dependent proteases. The preferable conformation of the dipeptide unit can be realized by choosing the N-substituents on glycine and by NATURAL PRODUCT REPORTS 1988-G. FISCHER n 0 J. H*N) (53) Reagents i (CF,SO,),O C,H,N CH,CI, Walden inversion; ii H-Lys(Boc)-OMe CH,Cl, at -15 OC; iii Pd/C propylphosphonic acid anhydride H-Ala-Oalkyl CH,CI, at -12 "C then NaOH for 32 h Scheme 18 appropriate replacements in the Ala position.Advantages have been shown for compounds with Lys instead of Ala and with the 2,3-dihydro-lH-inden-2-~1 moiety linked to the nitrogen of the glycine residue.,? The favourable lysine side-chain is also found in (53) (IC, = 10 nmol dm-3 for angiotensin-converting enzyme) which is readily synthesized according to Scheme 18,344The most potent mer~aptoalkanoyl-~~~ and 2-mercapto- aroyl-glycine inhibitors346 usually contain the N-cyclopentyl residue as in pivopril. In these structures the mercapto-group cannot be replaced by NO or by carboxyl.Even more truncated in chain length are the thiol inhibitors of aminopeptidases ;for example L-leucinethiol inhibits leucine aminopeptidase with Kl = 51 nmol dm-,.,,' 4.1.3 Inhibitors that contain the keto-function or an alcohol function It is well known that the introduction of the aldehydic or ketonic carbonyl group into an appropriate substrate structure yields strong reversible inhibitors of metalloproteases. A'-Ray studies of the metalloenzyme carboxypeptidase A have shown that in contrast to serine and cysteine proteases the geminal highly potent ketomethylene structures. The kinetics of their inhibition are complex.3E1 Assuming that the slow-binding compound ketoace (54)362 binds to angiotensin-converting enzyme in its hydrate form a value of <0.018 nmol dm- has been calculated for Ki.361 Ketoace has less than 3 % hydrate content in aqueous solution since the 13C n.m.r.spectrum lacks any resonance from geminal diol carbons.3R1 Surprisingly the benzamido-group of (54) and related structures must be an essential structural component. Instead of the NH linkage an electronegative atom may be present although in this case the potency drops consider- ably.363 Replacement of the benzamido-group in (54) by a 2-furoylamido-group or N-terminally lengthening the peptide chain gives a further increase of The concept of carbonyl and ketomethylene inhibitors has been applied to substrate congeners of other zinc protea~es.~~~,~~~ The keto- methylene isostere has been discovered in arphamenines which are strong inhibitors of aminopeptidase B and of carboxy- peptidase that have been isolated from the culture filtrate of Chromobacterium violace~m.~~~ As indicated above the benz- amido-group also plays a significant role in the activity of these structures.4.2 The Main Target Metalloproteases 4.2.1 Angiotensin-converting Enzyme Considering the great body of patent literature and the different assays that are used direct comparison of the IC, values that have been determined for interaction of enzymes with inhibitors of non-related chemical classes often gives no satisfactory information. Furthermore despite high inhibitory efficiency in several cases the number of compounds that have been employed in antihypertensive therapy is very limited.369-371 Marked species differences for several of the inhibitors must diol form of the carbonyl inhibitors binds to the en~yme.?~~.'~~ also be ons side red.^'? Interestingly both of the hydroxyl groups of the diol point to the zinc ion.Oxygen- 18-exchange experiments using leucine aminopeptidase with bestatin as the inhibitor also imply that the enzyme catalyses the addition of water to carbonyl groups.34s Electron-withdrawing substituents in the neigh- bourhood of the ketonic carbonyl increase both its activity as a competitive inhibit~r~~~-~~I and the equilibrium constant for hydration3,* relative to the activity of the congeneric halomethyl ketone. Fluorinated ketones should have K values ca.103-fold smaller than those for the non-fluorinated ketones.353 However isosteric peptide alcohols that lack the second hydroxyl group Some differences in potency between the inhibition of angiotensin-converting enzyme in vitro and competitive inhibi- tion by captopril when it binds to membrane-bound enzyme have been observed for inhibitors that contain peptide-bond mimics.488 Appropriate structures have been developed for the affinity-chromatographic purification of the enzyme.373 N-(1-Carboxy-5-aminopentyl)-dipeptideslinked to Sepharose 6B3?* or to Agaro~e,'~ possess large binding capacities for angio- tensin-converticg enzyme. Reducing the length of the spacer from 28 to 22 A diminishes the amount of enzyme that can be loaded by 350-fold.Additional structures have been tested for are devoid of the inherent efficacy of geminal diol~.~~~,~~~ inhibitory activity of angiotensin-converting enzyme such as Non-isosteric secondary peptide that are partially derived from the naturally occurring compound be~tatin,,~ are as their (5')-enantiomers potent inhibitors of various zinc proteases including angiotensin-converting en- zyme. The tertiary alcohol moiety causes a 2000-fold decrease in inhibition of angiotensin-converting enzyme compared with the secondary derivative.360 Various ketonic substrate ana-logues of angiotensin-converting enzyme have been investigated that occupy different subsites of the enzyme.361 Inhibitors whose structure spans subsites S,. and S,. or S through to S are rather weak (>micromolar range).Covering subsites S through to S,. on both sides of the zinc ion however yields peptides that contain retro-inverso peptide 443 meta-bolites of a~partame,~'~ 4-nitrobenzyl esters of malonyl-amino acids and carbonylbis-amino acids,," triterpene~,~~' and perimidine~.~~, In several cases the potency of these compounds is only moderate but further improvement might be achieved in the future. 4.2.2 Enkephalin-degrading Enzymes The enzyme which is responsible for degradation of enkephalins and has been isolated from kidney brush-border membrane NPR 5 OH (55) NHOH / HONH (56) (57) R H or Me fractions is identical with brain enkephalinase and exhibits thermolysin-like 378 Measured in various tissues [Met5]enkephalin is almost exclusively hydrolysed by three distinct enzymes namely an aminopeptidase angiotensin- converting enzyme and endopeptidase 24.1 1.380-382 Recently it has been reported that a metal-dependent dipeptidyl peptidase also rapidly degrades [Met5]enkephalin.389 Among them endopeptidase 24.1 1 is strongly inhibited by thiorphan (41).286 Both of the enantiomers are active at the same level but the analgesic properties that have been reported for racemic thiorphan are largely associated with the (R)-enanti~mer.~~~ In this series the values of K parallel the binding affinity of the corresponding substrates.342 Compound (55) (K,= 21 nmol dm-3) which is derived from the carboxyl type of inhibitors is the most potent derivative.Incorporation of the metal-co-ordinating hydroxamate moiety in place of sulphur or a N-hydroxylated peptide bond to cover the S,. subsite into the thiorphan molecule leads to new bidentate inhibitors. Kelatorphan [(RS)-(56)] inhibits the enkephalin-degrading enzymes in the micromolar up to the nanomolar range.384-388 Kelatorphan is also efficient in poten- tiating the analgesia that is induced by a sub-analgesic dose of [Met5]enkephalin. A very sensitive tool for estimating degrada- tion of enkephalins in vivo uses the propioxatins (57) which are naturally occurring hydroxamic acids that specifically inhibit (> 104-fold) the cleavage of the Gly-Gly bond in [Met5]- enke~halin.~~~ Besides the well-known inhibitor bestatin of the enkephalin-degrading aminopeptidase a boronic acid analogue of phenylalanine ester inhibits in the nanomolar range.391 Several of the aminopeptidases that have been investigated exhibit slow binding properties with the aminoboronic acids.391 It has been suggested that a tetrahedral boronate ion is bound to the active site of aminopeptidases.Certainly the boronic acids undergo strong interactions with the metal ion within the active In contrast the complexing properties of boronic acids to free metal ions in solution are not significant. 4.2.3 Collagenases Collagenase cleaves collagen at the Gly-Leu or the Gly-Ile peptide bond to yield two fragments which are then readily degraded by non-specific pr~teases.~~~ Human neutrophil collagenase shares many mechanistic features with bacterial collagenases and other zinc protea~es.~~~ The enzyme from Clostridium histolyticum can readily be inhibited by phosphon- NATURAL PRODUCT REPORTS 1988 (58) collagenase inhibitors must be large to be able to interact with the many enzymic s~bsites.~~? Among the thiol compounds that were studied in this work HS[CH,],C(O)-Pro-Arg gave rise to a K of 500 nmol dm-3.The artificial substrate Z-Pro-Ala-Gly- Ile-Ala-Gly-OEt for mammalian collagenase was chosen to generate a binding moiety which contains additionally a ketomethylene isostere. The resulting competitive inhibitor is only moderately active (K,= 6 x lo4nmol dm-3).366 Substrate- derived peptide hydroxamic acids show the same range of potency (K,= 4 x lo3nmol dm-3) whereas the corresponding compounds without the hydroxamic acid moiety lack any significant inhibitory More successful is carboxy- alkyl substitution within an appropriate peptide chain;398 for example [(1R)-3-benzyloxycarbonylamino-1-carboxypropyll-Leu-Tyr(0Me)-Tyr-NHMe inhibits a number of mammalian collagenases in the micromolar range.Subjected to human rheumatoid synovial collagenase the compound exhibits competitive kinetics with K = 300 nmol dm-3.3gg This com- pound also significantly decreases the rate of resorption of explanted mouse bone. Because of its low toxicity and high affinity for cartilage La3+ ion which shows values of K of 80&3000 nmol dm-3 for various collagenases may be useful for studies in ~ivo.~OO The extraordinarily high potency of gold(1) complexes on human neutrophil collagenase is exemplified by the chrysotherapeutic drug myocrisin (58) for which the K,value is 3.5 nmol dm-3 and which is the best known synthetic inhibitor of a collagenase.401 Similarly some metallocenes show reversible competitive inhibition of type I procollagen N-proteinase.The most active compound is ferrocenium tetrachloroferrate exhibiting K = 4000 nmol dm-3 which probably results from formation of a charge-transfer complex between the cylindrical inhibitor molecule and the areas of the enzyme in which there is a high electron density.402 5 Aspartic Proteases -General Considerations Aspartic proteases have been isolated from five major sources.4o3 Three different types of gastric enzymes have been found in the stomachs of a number of species; these are the pepsins chymosins and gastricsins.Cathepsin D and cathepsin E have been found in lysosomes and renin is a product of the juxtaglomerular apparatus of the kidney and the submaxillary gland. Micro-organisms contain proteinase A (yeast) [Sac- charomyces aspartic proteinase] and some pepsin-analogue enzymes (examples being the microbial aspartic proteinases from Endothia parasitica Rhizopus chinensis and Penicillium janthinellum). In contrast to mammalian enzymes the fungal aspartic proteases are able to split off the pro-part of trypsinogen that recognizes a Lys-Xaa bond.404 Some plants contain aspartic proteases (examples being Nepenthes aspartic proteinase and Sorghum aspartic proteinase).Retroviral pro- teases may also belong to this Renin is a highly specific enzyme and cleaves a specific Leu-Val bond of the human a-globulin angiotensinogen (59) to form the decapeptide angiotensin I.405 The blockade of renin should therefore indirectly affect the concentration of the potent vasoconstrictor angiotensin I1 in plasma. Thus an antihypertensive effect of inhibitors of renin has been shown in a large majority of patient^.^^^,^^' Most of the recent work on the inhibition of aspartic proteases has been with renin as the target enzyme. Phos-amidates (see Table 10) and mercapto-peptide~.~~~,~~~ Naturally occurring inhibitors of aspartic proteases are not phonamidates that carry long alkyl chains on their N-terminus involved in the regulation of the enzyme activity within the host tend to inhibit more strongly.By contrast studies with the cell with the exception of the renin-binding protein and the enzyme from Achromobacter iophagus indicate that powerful yeast proteinase A inhibitor.408 NATURAL PRODUCT REPORTS 1988-G. FISCHER 1 5 10 Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-l~e-His~ P3 P P P,. Py P3/ (59) (-'Xaa'-represents a part of a residue -Xaa- to which -N-or -C- is attached) H II 0 Scheme 19 Classical examples of inhibitors of aspartic proteases are the affinity labels N-diazoacetyl-norleucine methyl ester and 1,2- epoxy-3-(4-nitrophenoxy)propane.409~411The inactivation is attributed to their specific modification of the P-carboxyl groups of the Asp residues at the active site.Good inhibition (K = 250 nmol dm-3) of those enzymes which possess a Glu residue in position 13412 has been observed by using the pro-part of porcine pepsinogen (Leu-Val-Lys-Val- Pro-Leu-Val-Arg-Lys-Lys-Ser-Leu-Arg-Gln-Asn-Leu).The peptide exhibits slow-binding inhibition and requires approxi- mately one hour for developing full inhibitory activity at 25 "C. Residues 13 to 16 can be removed without any loss of inhibitory potency.*13 The pro-segment of human renin has also been used to develop inhibitors of rer~in.~~~ Considering the exceptionally high substrate specificity of renin synthetic peptides that are related to the sequence of horse angiotensinogen have been synthesized as potential (63) inhibitors of primate renin.The decapeptide Pro-His-Pro-Phe- His-Phe-Phe-Val-Tyr-Lys represents an example of moderate inhibitory activity and good aqueous sol~bility.~~~.~~~ mol-l of energy favouring the binding of the inhibitor. Scheme Further-more the actinomycete peptide pepstatin [Iva-Val-Val-Sta- Ala-Sta (60)] is a specific competitive and tight-binding inhibitor of most aspartic protease~.~~' Pepstatin contains the unusual y-amino acid statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (61)] in two positions. 5.1 Useful Classes of Inhibitors 5.1.1 Variation of Pepstatin Pepstatin has been proposed to be a transition-state-analogue inhibitor of aspartic pr~teases,~~~,"~ although a collected-substrate mechanism for inhibition has been suggested for statine-derived inhibitors.420 The 3(S)-hydroxyl group of statine displaces an enzyme-bound water molecule (Scheme 19).The return of a single molecule of water that was bound to the active site of the enzyme to the bulk solvent produces 10-20 kJ 19 shows how the 3-hydroxyl group of the central statine residue points to the two active-site aspartine residues [Asp-32 and Asp-215) replacing the interaction of the water that has been displaced. In fact bisdeoxystatine-derived pepstatin [deoxystatine = (62)] has an approximately 4000-fold higher value of K on porcine pepsin than pepstatin itself.421~422 The (S)configuration of the 3-hydroxyl group of statine is required for maximal inhibition Iva-Val-Val-(3R,4S)-Sta-Ala-Iaa being a poor inhibitor of porcine pepsin (K,= 2000 nmol dm-3).421 Besides the 3(S)-hydroxyl of statine-3 the interaction of the leucine-type side-chain of this residue with a hydrophobic cleft in the enzyme is important for its tight binding.X-Ray crystal structures of enzyme complexes of statine-containing inhibitors support these Some heteroatoms of the acyl-Val and Sta-5 moiety can be replaced by hydrogen so that (63) is strongly active (K = 2.9 nmol dm-3 with porcine 19-2 NATURAL PRODUCT REPORTS 1988 ~ ~~~_____ pepsin425). The full effect of chain length on the efficiency of Table 11 The effect of chain length of statine-containing inhibition is shown in Table 11. compounds" on the inhibition of penicillopepsin4*6 It is possible to introduce the hydrophilic lactoyl residue and porcine pepsin"' instead of acyl-Val to increase the solubility of pepstatin in Penicillopepsin water.lZ8 This modified compound is as effective as pepstatin in inhibiting porcine and human pepsin and porcine gastricsin but Compound KJnmol dm-3 is less effective against other aspartic proteases.ha-Val-Val- Sta- Ala-Sta 0.15 From a comparison of the sequences of pepsin s~bstrates~~~ Iva-Val-Val-Sta- Ala-OEt 1.6 and from X-ray data for pepstatin that is bound to Rhizopus Iva-Val-Val-Sta-OEt 24 aspartic pr~teinase,"~ it has been suggested that the statine Iva-Val-Sta-OEt 105 residue mimics a dipeptide unit in the restricted conformation Porcine pepsin of the tetrahedral intermediate.This aspect is illustrated in structure (64) using the substrate nomenclature of Berger and Compound KJnmol dm-3 S~hechter.~~~ It appears that strong and selective inhibitors of Iva-Val-Val-Sta- Ala-Sta 0.046 the aspartic proteases will be obtained if one statine residue is Iva-Val-Val-Sta- Ala-Iaa 0.1 introduced instead of the residues at positions P and P,. of a Iva-Val-Sta-Ala-Iaa l.lb Iva-Sta- Ala-Iaa 340' Xaa-Yaa-Val-Sto -Aka-Xaa Iva-Val-Sta 1OOOd Ac-Sta 1.2 x 106 P4 P3 P2 Pl PI/ PZ' P3' (a)Statine has the (3S,4S)-configuration throughout (6) compare K = 2.9 nmol (64) dm-3 (ref. 425); (c)compare K = 350 nmol dmF (ref. 425); (d)from ref. 421 Table 12 Modified statine residues within peptide chains Structure" Notation Abbreviation used Ref.R' I -CH-CH-CHz-C-NH-IOH II 0 statine Sta 417 R' I -CH -CH-IOH R JH -fI-"-0 2-alkylstatine 435 436 R' :H3 -CH -c- ~H,-C -NH- II 3-methylstatine Me3Sta 431 OHI 0 RZI -CH- CH-I OH 'dCH2-C-NH - 4-alkylstatine 438 439 -p'CH- CH-I CF2 -C-NH I1 - difluorostatine 353 440 OH 0 R' I -CH- CH -CHt-C-NH I II NH2 0 - aminostatine Asta 44 1 R' R2 I -CH-CH-CHz-NH-CH-I OH I amino-alcohol Leu-$[CHOHCH,NH]-Xaa 442 R' I -CH-CH- CHz-S-CHz- thiomethylene 443 AH -CH-CH-I R' I CHZ- 0 II S-CH,-I1 sulphonylmethylene 443 OH 0 R' I -CH-C -CHz-C-NH-Id Id statone Sto 444 R'I -CH- 0II P-CH2-C-NHI I1 OH 0 - phosphinic acid analogue StaP 433 R2I -CH- 0 I1H CHz-P-NH-5-I OH OH phosphonic acid analogue 445 R2 I -CH-CH-OH I [CHIn-R2 1 OH peptide glycols 446 447 (a) R' and R2represent the side-chain of leucine and various alkyl groups respectively NATURAL PRODUCT REPORTS 1988-G.FISCHER naturally occurring enzyme substrate43z or if there is a strongly binding peptide chain. There is a remarkable increase in the degree of inactivation during the incubation of pepstatin and some of its derivatives with pepsin Rich et al. 420.421,425 have suggested a two-stage reaction sequence (see Scheme 2) with a slow k step and kJk < 1. The conversion EI* -t EI** may be the displace- ment of the water molecule that is bound at the active site. Typically lag phases are in the range of minutes but increase to hours in the case of pepstatin analogues that contain modified statine residues.433 5.1.2 Modijied Statine Residues Structural changes that have been realized for statine are summarized in Table 12.In addition to the recommended nomenclature regarding replacement of amide a diversity of abbreviations have been used some of which are noted in Table 12. Among the structural elements in Table 12 the amino-alcohol analogues do not appear to be promising inhibitors of renin. Similarly the IC, values of peptide glycols are not very satisfactory [for Boc-Phe-His-NH-( 1S,2R)-CH-(benzyl)CH(OH)CH,OH the value of IC, is 2600 nmol dm- for human renin).446 Recently angiotensinogen analogues that contain the 1,2-glycol dipeptide isostere (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid have been synthesized and found to be active in the subnanomolar range towards human re~~in.~~' The more important modi- fications of statine are described in the following sections.5.1.2.1 2-Alkylstatines. The isobutyl group448 and the benzyl group435 have been introduced into statine at C-2 to place that side-chain in the unfilled hydrophobic pocket that has been detected in the complex between Rhizopus chinensis pepsin and pepstatin. The modified Leu-Phe-NH synthon (65) was prepared enantiospecifically as indicated in Scheme 20,435 and coupled with Boc-Phe-Phe-Sta to form a N-(peptidy1)oxazol- idinone. Two subsequent steps namely hydrazinolysis and treatment with isopentyl nitrite gave the peptide amide in 47 % overall yield which is active against human kidney renin as indicated in Table 16.Another approach for incorporating the isobutyl side-chain at position 2 of statine is outlined in Scheme 21 .448 Coupling the product (67) of the reaction of the phthalimide aldehyde (66) C-terminally with Leu-Phe-NH and after deprotection N-terminally with isobutyryl-His-Pro- Phe-Phe results in a potent inhibitor of human renin [K,= 1.7 nmol dm- for the (2R,3S,4S)-isomer]. However the ad- vantage is not marked in comparison with the peptide that contains the unmodified statine residue. Interestingly inhibition of the Rhizopus chinensis pepsin is decreased strongly by 2- substitution with an alkyl group. 5.1.2.2 3-Methylstatine. The 3-methylstatine-containing ana-logues are about ten-fold less potent inhibitors than the corresponding statine-containing peptides.Surprisingly in all cases the (3R,4S)-diastereoisomer was the stronger inhibitor to porcine pepsin cathepsin D and peni~illopepsin.~~' was It proposed that 3-methylstatine-containing peptides bind in a different way to aspartic proteases than do the corresponding statine-containing inhibitors. 5.1.2.3 4-Alkylstatines. Replacement of the 4-isobutyl side-chain of statine by ben~y1,~~l 4-amino-cyclohe~ylmethyl,~~~ b~tyl,~,~ gives a modified statine building or 3-aminopr0pyl~~~ block from which the remainder of the peptide synthesis may be developed from N-acylamino-aldehydes as described in Scheme 22. If the cyclohexylmethyl group replaces isobutyl in the Sta residue of Iva-His-Pro-Phe-His-Sta-Leu-Phe-NH the product is 2.7 to 76 times more effective than the unmodified compound as an inhibitor for renins from different sources.There is no significant difference between the peptides for inhibition of pepsins. If the isobutyl group in the statine residue of a peptide 11 111 i (65) Reagents i LiNPr', THF at -60 "C then Boc-Leu anhydride ii zinc borohydride Et,O at -25 "C; iii deprotection with HCI EtOAc Scheme 20 phthaloyl phthaloyl (66) (67) Reagents i dilithio-4-methylpentanoic acid or l-benzyloxy-4-methyl-1-trimethylsilyloxypent-1-ene with Ti'" and then H, Pd/C (partial stereoselective reduction) ; ii H,NNH Scheme 21 OR2 Y NHBoc NHBoc OH NHBoc NHBoc Reagents i Bu',AIH ; ii Li EtOAc then diastereoisomers separated by chromatography; iii NaOH.(If R' = 4-aminobutyl the diastereoisomers are separated as their 3-O-CO,CH,CCI3 derivative and the 3-hydroxyl is deprotected by Cd DMF AcOH) Scheme 22 is replaced by benzyl there is no increase in the inhibition by the peptide for renin and pepsin. If an w-aminoalkyl moiety replaces isobutyl at position 4 of the statine and this modified residue is introduced in place of statine in Iva-Val-Val-Sta-OEt the inhibitory potency towards penicillopepsin is increased 10- to 100-fold. In contrast the same substitution yields exceptionally weak inhibitors for NATURAL PRODUCT REPORTS 1988 porcine pepsin. The X-ray structure of Iva-Val-Val-[4-(4-aminobuty1)lSta-OEt that is complexed with penicillopepsin indicates that the amino-group of the 4-aminobutyl side-chain binds to Asp-77 of the enzyme.449 This additional electrostatic interaction satisfactorily explains the enhanced binding energy of the inhibitor.5.1.2.4 DiJluorostatine. Fluorinated statine residues are poten- lii tial inhibitors of aspartic pr~tea~e~.~~~~~~~~~~~ The preparation of the 2,2-difluorostatine synthon (68) uses a stereospecific Reformatsky reaction as shown in Scheme 23. Boc-Phe-His- Xaa-Ile 2-methylpyridyl amide (Xaa = difluorostatine) is less potent than the corresponding statine analogue (Xaa = Sta) when tested against human renin. The inhibition of pepsin by isovaleryl-Val-Xaa-Ala isoamyl amide is however two-fold stronger for the fluorinated The ketone analogue 2,2-difluorostatone located within a suitable peptide chain shows very strong binding to porcine pepsin353 in the subnanomolar range.The higher tendency of fluoro-ketones to form a tetrahedral adduct than the corresponding unsubstituted ketones is thought to be responsible for the tight binding. Indeed the carboxypeptidase A inhibitor 2-benzyl-5,5,5-trifluoro-4-oxopentanoic acid has been shown to bind as a geminal diol to the active site of the metalloprotease.266 5.1.2.5 Aminostatine. Since ammonium ions bind to the active site of native peni~illopepsin,~~~ it was deduced that the 3-hydroxyl of statine must be replaced by NH,. N,N-Diprotected (3S,4S)-3,4-diamino-6-methylheptanoic acid was synthesized according to Scheme 24.441 In the human renin inhibitor assay all peptides that contain the (3S,4S)-3-amino- 3-deoxystatine analogue are of similar potency to their statine congeners.However an advantage may be the greater aqueous solubility of the modified peptides. In contrast to the (3S,4S)- stereoisomer (3R,4S)-aminostatine showed a 40-fold enhanced binding compared with its statine congener.420 5.1.2.6 Statone. In statine-containing peptides the 3(S)-OH group can be specifically oxidized to the appropriate ketone.444, 452 These statone-derived peptides generally have a 200-fold decrease in their effectiveness against porcine pepsin compared with the statine-containing congener. As indicated above fluorinated ketones are exceptional because of their similarity to statine after the geminal diol has been formed ; however the difluorostatone moiety does not greatly exceed the activity of its hydroxy-analogue for inhibition of rer~in.~~O Important mechanistic features of the catalysis that is mediated by aspartic proteases may be deduced from studying their interactions with statone peptides.Using Iva-Val-Sto-Ala-Iaa isotopically enriched with 13C in the keto carbonyl group Rich .~~~ et ~1observed by 13C n.m.r. that pepsin could catalyse the addition of water to yield a geminal diol when the peptide has bound to the enzyme. This observation supports a general- acid-/general-base-catalysed enzyme mechanism rather than a nucleophilic mechanism. 5.1.2.7 Phosphorus-containing statine derivatives. The structural units that are depicted in Table 12 were prepared as the fully protected compounds as described in Schemes 25 and 26.The tetrapeptide analogue Iva-Val-StaP-Ala-Iaa was made from the synthon (69) by its deprotection and then peptide coupling by the dicyclohexylcarbodi-imide method.433 Cleavage of the phosphoryl ester bond was performed by the reagent lithium thio-n-propylate with HMPA.454 The phosphonic-acid-derived tetrapeptide Iva-Val-StaP-Ala- Iaa is one of the most potent inhibitors of pepsin known (see Table 14). Possibly it perfectly mimics the tetrahedral intermediate of the hydrolytic reaction. The isomerization of the El complex (see Scheme 2) is extraordinarily slow (1; = 115 minutes for k at 37 "C). Interestingly its great advantage (sixteen-fold) compared to the statine congener arises mainly at the tetrapeptide level.In the des-Val-tripeptide the activities (68) Reagents i oxalyl chloride DMSO at -78 OC; ii CF,BrCO,Et zinc dust THF at 75 'C; iii HCI Et,O iv NaOH Scheme 23 Reagents i ethoxycarbonylmethylenetriphenylphosphorane; ii NH, EtOH ; iii N-protected by ZCI; iv chromatographic separation of diastereoisomers; v alkaline hydrolysis Scheme 24 (69) Reagents i SOCI, CH,CI, at 22 "C;ii PhSH Et,N CH2C1, at 22 "C; iii LiCH,CO,Bu' THF at -78 "C Scheme 25 Reagents i LiCH,P(O)(OMe), THF at -78 "C Scheme 26 exhibit only a 2.5-fold difference. Surprisingly Iva-Val-Val- StaP-OEt has a 70-fold weaker activity against penicillopepsin than Iva-Val-Val-Sta-OEt.Therefore elevated inhibitory pot- ency must be related to the uncharged phosphinate group.3o4 The phosphonic acid derivative (see Scheme 26) of a statine analogue gave after incorporation into an appropriate peptide sequence renin inhibitors that exhibited IC, values of 15-50 nmol dm-3.445 NATURAL PRODUCT REPORTS 1988-G. FISCHER Table 13 Peptide-bond-isosteric inhibitors Structure" R -cH-fi-NH-0 R I -CH-CHz-NH-R R' I I -CH-C-CH2-CH-C-II Id 0 R R' I I -CH-CH-CH -CH-C -I II OH 0 (a) R and R' are alkyl groups Reagents i NaCN. BH, Val-OBzl Scheme 27 BocN H Notation natural peptide unit reduced peptide bond ketomethylene dipeptide isostere hydroxyethylene dipeptide isostere Abbreviation used Ref.Xaa - n Xaa-Yaa; Xaa-$(CH,NH)-Yaa 455 K Xaa-Yaa; Xaa-~(CH,)-Yaa 456 457 OH Xaa-Yaa; Xaa-$(CHOHCH,)-Yaa 420 456 458 459 5.1.3 Peptide-bond Isosteres The cr-carbon atoms of the peptide-bond isosteres in Table 13 adopt exactly the same positions as those in the native peptide chain. This fact is responsible for the difference of the modified statine residues whose carbon number is less than a dipeptide unit. Among the structures in Table 13 the reduced peptide- bond isostere XaaLYaa can be obtained in a rather simple way (Scheme 27). Replacement of the scissile Leulo-Val" peptide bond in the minimal renin substrate human angiotensinogen- (6- 13)-octapeptide by the reduced peptide-bond isostere causes a decrease of the IC, value of about 1600-fold against human rer~in.~~' Replacing the Leu-Leu& unit of a horse angio-tensinogen-derived peptide by Leu-Leu has led to a 200-times lower value of K for human renin.Even more marked is the difference of 6700-fold in the case of canine renin to give K = 30 nmol dm-3.460 A potent inhibitor of human renin with a reduced chain length has been developed by Plattner et al.461 The enhancement has been achieved by the cyclohexylalanine"Va1 unit which is ii-iv placed near the C-terminal end (see Table 16). The syntheses of the hydroxyethylene and ketomethylene dipeptide isostere building blocks with control of stereo-chemistry at (2-2 are outlined in Schemes 28 and 29. Compared with the appropriate hydroxyethylene-isostere-substituted peptides the ketomethylene analogues are weaker inhibitors for porcine pepsin.In a series of hydroxyethylene analogues that contained -LeuwXaa- with a variety of amino acids for Xaa the best case for inhibition was equipotent with the corresponding statine-containing peptide. The assumption Reagents i chiral BrMgCH,CH(R)CH,OCH,Ph Et,O; ii Ac,O that the structural advantages of the amino acid Xaa at 4-dimethylaminopyridine; iii H, Pd/C; iv KMnO, C,H, H,O position P,. that were found for k,,,/K,, in pepsin substrates Bu",NBr for deprotection will parallel those for good inhibitors was not found. This supports arguments that these inhibitors do not act exclusively Scheme 28 as multi-substrate analogues.456 However the Leu-Val moiety is preferable to statine in the inactivation of plasma renin.,,O Ac 5.2 The Main Target Aspartic Proteases y& %% Ala -A'a-5.2.1 Pepsins and Cathepsin D Iva -Va I -N Iva-Val -N The inhibition of porcine pepsin that is achieved by the most H H active compounds is very impressive (Table 14).The size of the most active natural compound pepstatin (60) can be con- Reagents i K,CO, MeOH; ii pyridinium dichromate AcOH siderably reduced without any loss in activity. In addition some inhibitors can very effectively differentiate between fungal Scheme 29 and mammalian enzymes. For example Iva-Val-Val-[4-(4- NATURAL PRODUCT REPORTS 1988 Table 14 Inhibition of porcine pepsin Compound Slow binding K,/nmol dm-3 Ref. Iva-Val-Val-(3S,4S)-Sta-Ala-(3S,4S)-Sta + 0.046 425 462 Iva-(4R)-%aP-Ala-Iaa -900 433 Iva-Val-Val-(3S,4S)-Sta-OEt -11 438 Z-Trp-Val-Leu-H N.D." 3000 463 Iva-Val-(4R)-%aP-Ala-Iaa + <0.07 433 Iva-Val-Leue Ala-Iaa -27 456 Iva-Val- LeuEPhe- Ala-Iaa + 2.5 456 Iva-Val-LeuKPhe- Ala-Iaa -72 456 pig pepsinogen pro-part (1-12) + 100 413 <Glu-o-Phe-Pro-Phe-Phe-Val-D-Phe N. D." 260 464 Iva-Val-(70)-Ala-Iaa -0.06 353 (a) N. D. = Not determined ~~ ~~ Table 15 Comparative inhibition of some aspartic proteases Table 16 Inhibition of human kidney renin Specificity Compound KJnmol dm-3 Ref. Iva-Val-Val-(3S,4S)-Sta-Ala-(3S,4S)-Sta 13000 458 Compound I(porcine pepsin) a I(porcine pepsin) 1 Iva-His-Pro-Phe-His-(3S,4S)-(73)-Leu-Phe-NHZ 0.16 439 I(human renin) I(cathepsin D) Iva-His-Pro-Phe-His-(3S,4S)-Sta-Leu-Phe-NH2 8.8 439 n (60) 0.025,d,446 0.0016d.4'0 0.55,c.464 0,35' 410 Boc-Phe-Phe-(3S,4S)-Sta-Leu-NHbenzyl 0.026 470 (71) 2,1,d.439 3 le.439 0.13b.439 Boc-Phe-Phe-(3S,4S)-Sta-(2.S,3S,4S)-(78) 31 435 (72) 164,d.439 1756,439 1,Ob. 439 Boc-Phe-His-(S)-(79)-Val-NHCH2CHMeEt 7.8" 46 1 (74) 1,5ii 463 N. D.f (a) ICj value (75) 5 1000d~ 4s0 1000'~4s0 25'. 450 (76) 30O0Od."' O,I8C. 465 (77) N. D.f U (a) I represents values of K or IC,,,respectively; (b)rabbit liver cathepsin D; (c) bovine spleen cathepsin D; (d)plasma renin; (e)kidney renin; (f)N. D. = Not determined aminobuty1)lSta-OEt shows the following K,values penicillo-pepsin 2.1 nmol dm-3; porcine pepsin to3 nmol dmP; Rhizopus Iva-His-Pro-Phe-His -(3S 4s)-Sta-Leu-Phe-NHZ chinensis pepsin 33 nmol dm-3.438 (71) The comparative inhibition of some compounds for mam- malian aspartic protease is listed in Table 15.The derivative Iva-His-Pro-Phe-His-(3S 4S)-(73)-Leu-Phe-NHz (77)was developed by modifying the substrate of cathepsin D (72) that had the lowest value of K, and is the most potent inhibitor (K = 1.1 nmol dm-3) of this enzyme. Its low selectivity results from the similarity of the recognition part to those of substrates of pepsin and of cathepsin D respectively. The selectivity factor of 160 for Val-D-Leu-Pro-Phe-Phe-Val-D-L~u~@ was utilized to separate pepsin from gastricsin using crude human gastric juice.467 Sepharose 4B that was charged with the inhibitor gave satisfactory results even on a preparative scale.(73) 2 -Trp-Val-Leu -H 5.2.2 Renin (74) As noted above the inactivation in vivo of the renin-angiotensin system should give a successful approach to the therapy of pro-His -pro- Phe-His -Phe -Phe-Val-Tyr-Lys hypertensi~n.~~~.~~~ As prerequisites for the use of inhibitors of (75) renin as drugs the following points are important (a) high inhibition (b) sufficient proteolytic (metabolic) stability (c) Bcc -Phe- His- (70)-lle-NHCH2(2-pyridyl) rapid absorption from the gastro-intestinal tract and (d)low (76) rate of biliary excretion. It is gratifying to see that a number of compounds are in the Boc-Phe-Leu-Ala-(35,4s)-Sta-Val -Leu-OMe desired range of inhibitory efficacy (Tables 16 and 17).473.474 (77) However the complexity of the problem has been demonstrated NATURAL PRODUCT REPORTS 1988-G.FISCHER Table 17 Inhibition of human plasma renin Compound Iva-Val-Val-(3S,4S)-Sta-Ala-(3S,4S)-Sta Boc-Phe-Leu-Phe-H Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys Boc-Phe-His-(3S,4S)-(80)-Ile-NHCH2(2-pyridyl) Boc-Phe-His-(3S,4S)-Sta-Ala-(3S,4S)-Sta-OCH3 Boc-Pro-Phe-(8I)-Leu-~Val-Ile-NHCH,(2-pyridyl) Boc-(82)-Phe-His-Leu~Val-Ile-NHCH,(2-pyridyl) Boc-His-Pro-Phe-His-LeuzVal-Ile-His Iva-His-Pro-Phe-His-(3S,4S)-(73)-Leu-Phe-NHE IC,,/nmol dm-3 14000,” 6000,b 22000” 2100 9400 0.57 27 0.26 2.0 0.7 0.17 Ref. 452 471 439 463 440 450 47 1 452 472 475 439 (a) 37 “C pH 7.4 phosphate buffer; (b) 37 “C,pH 6.0 maleate buffer because the most potent inhibitor of human kidney renin lacks any remarkable activity in the human plasma renin The ten-fold difference of values of K between rhesus monkey plasma renin and rat plasma renin for inhibition by Iva-His- Pro-Phe-His-Sta-Leu-Phe-NH may also be by the postulated470 effect of the binding of plasma components to the inhibitor.In other cases apparently useful compounds are excreted rapidly in the bile when tested in vivo.4fi7~477 Short-chain peptide inhibitors479, 480 have been developed to overcome this obstacle. Methods to enhance the metabolic stability of potent parent 4 ‘Biological Functions of Proteinases’ ed. H. Holzer and H.Tschesche Springer-Verlag Berlin 1979. 5 ‘Proteinases in Mammalian Cells and Tissues’ ed. A. J. Barrett Elsevier/North Holland Amsterdam 1977. 6 ‘Proteinase Inhibitors’ ed. H. Fritz H. Tschesche L. J. Greene and E. Truscheit Springer-Verlag Berlin 1974. 7 H. Umezawa Methods Enzymol. 1976 45 678. 8 ‘Proteinase Inhibitors’ ed. A. J. Barrett and G. Salvesen Elsevier Amsterdam 1986. 9 ‘Proteinase Inhibitors Medical and Biological Aspects’ ed. N. Katunuma H. Umezawa and H. Holzer Springer-Verlag Berlin 1983. the formation of disulphide-bridged cycles,43o replacement of L-proline by D-prOhe in position P4,476and introduction of the C-terminal phenylalanyl-2-aminoadamantanemoiety.478 For example the 2-methylproline-containing inhibitor [see Table 17; (82) = 2-methylprolyl] is completely stable against various proteases and rat liver homogenate during incubation for 60 minutes.This compound causes a dose-dependent hypotensive response when given intravenously to anaesthetized ganglion- blocked hog-renin-infused rats. The administration in this rat model has to be 0.28 mg per kg of body weight to introduce a fall of 40 mmHg in mean blood pressure.472 At present there are no crystal structures available for human or mouse renin. The close relationship between the inhibitory potency of several important inhibitors of renin for that enzyme and for Endothia pepsin gives an approach to investigating the binding of inhibitors at the active site of these enzymes. The X-ray-derived structure of theH complex of Endothia pepsin with Pro-His-Pro-Phe-His-Leu-Val-Ile-His-Lys (K for Endothia pepsin is 160 nmol dm-3; K for human renin is 10 nmol dm-3) shows that the secondary amine structure of the reduced peptide bond may interact with the carboxylate groups at the active site in the transition state.490 6 References 1 ‘Proteases and Biological Control’ ed.R. Reich D. B. Rifkin and E. Shaw Cold Spring Harbor Press New York 1975. 2 N. Seiler M. J. Jung and J. Kochweser ‘Enzyme-Activated Irreversible Inhibitors’ Elsevier/North Holland New York 1978. 3 M. Sandler ‘Enzyme Inhibitors as Drugs’ University Park Press Baltimore 1980. compounds include N-methylati~n,~~~ 10 A. Warshel and S. Russell J. Am. Chem. SOC. 1986 108 6569. @-methylati~n,~~~~~~~ 11 P.Deslongschamps ‘Stereoelectronic Effects in Organic Chemis- try’ Pergamon Press Oxford 1983. 12 A. J. Kirby ‘The Anomeric Effect and Related Stereoelectronic Effects at Oxygen ’ Springer-Verlag Berlin 1983. 13 J.-M. Lehn and G. Wipff J. Am. Chem. SOC. 1980 102 1347. 14 D. G.Gorenstein and K. Taira Biophys. J. 1984 46 749. 15 S. A. Bizozzero and H. Dutler Bio-org. Chem. 1981 10 46. 16 D. W. Bolen,T. Kimura,and Y. Nitta Biochemistry 1987,26.146. 17 G. Fischer and A. Barth in ‘Dipeptidyl peptidase IV’ ed. G. Kiillertz P. Oehme and A. Barth (Beitrage zur Wirkstof-forschung Vol. 1l) Akademie der Wissenschaften der D.D.R. Berlin 1981 p. 105. 18 G. Fischer and C. Mech Biomed. Biochim. Acta in the press. 19 J. J. Sines and D.D. Hackney Biochem. J. 1987 243 159. 20 H. Neurath Science 1984 224 350. 21 F. J. Castellino Chem. Rev. 1981 81 431. 22 W. T. Troll K. Frenkel and R. Wiesner J. Natl. Cancer Inst. 1984 73 1245. 23 L. Ossowski and E. Reich Cell 1983 35 61 1. 24 U. P. Thorgeirsson L. A. Liotta and T. Kalebic J. Natl. Cancer Inst. 1982 69 1049. 25 A. Janoff and H. Carp Lung Biol. Health Dis. 1983 19 173. 26 R. A. Stockley Clin. Sci. 1983 64 119. 27 J. E. Fraki R. A. Briggman and G. S. Lazarus Science 1982 215 685. 28 C. F. Reilly D. A. Tewksbury N. M. Schechter and J. Travis J. Biol. Chem. 1982 257 8619. 29 K. Mizuno M. Kojima and H. Matsuo Biochem. Biophys. Res. Commun. 1985 128 884. 30 I. Lindberg H. Y. T. Yang and E. Costa Biochem. Biophys. Res. Commun.1982 106 186. 31 G. Kreil L. Haiml and G. Suchanek Eur. J. Biochem. 1980,111 49. 32 A. K. Bhattacharyya and L. J. D. Zaneveld ‘Biochemistry of Mammalian Reproduction’ Wiley New York 1982. 33 B. Ezquieta and C. G. Vallejo Comp. Biochem. Physiol. B 1985 82 731. 490 NATURAL PRODUCT REPORTS 1988 34 T. C. Friedman and S. Wilk J. Neurochem. 1986 46 1231. 75 F. Markwardt Ann. N. Y. Acad. Sci. 1986 485 204. 35 J. Sasaki Jpn. J. Pharmacol. 1975 25 31 1. 76 B. Ezquieta and C. G. Vallejo Biochim. Biophys. Acta 1986 883 36 T. Satoh M. Muramatu Y. Ooi H. Miyataka T. Nakajima and 380. M. Umeyama Chem. Pharm. Bull. 1985 33 647. 77 R. Kikumoto Y. Tamao T. Tezuka S. Tonomura H. Hara K. 37 M. Laskowski Jr. and I. Kato Annu. Rev. Biochem. 1980 49 Ninomiya A.Hijikata and S. Okamoto Biochemistry 1984 23 593. 85. 38 J. G. Bieth Bull. Eur. Physiopathol. Resp. 1980 16 183. 78 D. Green C. H. Tsao N. Reynolds D. Kahn and I. Cohen 39 W. Ardelt and M. Laskowski Jr. Biochemistry 1985 24 5313. Thromb. Res. 1985 37 145. 40 M. Kainosho and Y. Mitsui in ‘Protein Protease Inhibitor The 79 E. Menegatti M. Bolognesi S. Scalia F. Bortolotti M. Guarneri Case of Streptomyces Subtilisin Inhibitor’ ed. K. Hiromi K. and P. Ascenzi J. Pharm. Sci. 1986 75 1171. Akasha Y. Mitsui B. Tonomura and S. Murao Elsevier 80 G. Wagner Folia Haematol. (Leipzig) 1982 109 67. Amsterdam 1985 p. 181. 81 C. Hansch and T. E. Klein Acc. Chem. Res. 1986 19 392. 41 M. Marquart J. Walter J. Deisenhofer W. Bode and R. Huber 82 G. Naray-Szabo J. Mol.Struct. 1986 134 (THEOCHEM. Vol. Acta Crystallogr. Secr. B 1983 39 480. 27) 401. 42 R. Richarz H. Tschesche and K. Wuthrich Biochemistry 1980 83 C. F. Wong and J. A. McCammon J. Am. Chem. Soc. 1986,108 19 571 1. 3830. 43 N. Nishikata J. Biochem. (Tokyo) 1983 93 73. 84 M. Recanatini T. Klein C.-Z. Yang J. McClarin R. Langridge 44 J. T. Lane F.-M. Lo and C. Prasad Life Sci. 1980 27 451. and C. Hansch Mol. Pharmacol. 1986 29 426. 45 B. Grinde and R. Jahnsen Biochem. J. 1982 202 191. 85 D. H. Cresson W. C. Beckmann R. R. Tidwell J. D. Geratz 46 B. McRae K. Nakajima J. Travis and J. C. Powers Biochem-and G. P. Siegal Am. J. Pathol. 1986 123 46. istry 1980 19 3973. 86 S. Mori Y. Kozaki M. Kato A. Tendo Y. Kikawa H. Sekine 47 J. C. Powers in ‘Advances in Inflammation Research’ Vol.11 and M. Muramatu J. Biochem. (Tokyo) 1984 95 1617. ed. I. Otterness A. Lewis and R. Capetola Raven Press New 87 J. Sturzebecher F. Markwardt B. Voigt G. Wagner and P. York 1986 p. 145. Walsman Thromb. Res. 1983 29 635. 48 S. Terada K. Sato T. Kado and N. Izumiya FEBS Lett. 1978 88 B. Kaiser and F. Markwardt Thromb. Haemost. 1986 55 90 89. 194. 49 L. B. Sandberg and J. M. Davidson in ‘Peptide and Protein 89 H. Tschesche J. Beckmann A. Mehlich E. Schnabel E. Trus- Reviews’ Vol. 3 ed. M. T. W. Hearn Marcel Dekker New York cheit and H. R. Wenzel Biochim. Biophys. Acta 1987 913 97. 1984 p. 169. 90 R. Wolfenden and L. Frick in ‘Enzyme Mechanisms’ ed. M. I. 50 S. J. Ratcliffe G. T. Young and R. L. Stein J. Chem. Soc. Page and A. Williams Royal Society of Chemistry London 1987 Perkin Trans.1 1985 1767. p. 97. 51 J. C. Powers and J. W. Harper Res. Monogr. Cell Tissue Physiol. 91 R. L. Stein and A. M. Strimpler Biochemistry 1987 26 2611. 1986 12 55. 92 L. T. J. Delbaere and G.D. Brayer J. Mol. Biol. 1985 183 89. 52 B. M. Ashe and M. Zimmerman Biochem. Biophys. Res. Com- 93 M. N. G. James A. R. Sielecki G. D. Brayer L. T. J. Delbaere mun. 1977 75 194. and C.-A. Bauer J. Mol. Biol. 1980 144 43. 53 H. Kido N. Fukusen and N. Katunuma Arch. Biochem. Bio- 94 H. R. Williams T.-Y. Lin M. A. Navia J. P. Springer and K. phys. 1984 230 610. Hogsteen Biochem. J. 1987 242 267. 54 N. Fukusen H. Kido and N. Katunuma Arch. Biochem. Bio- 95 J. Walter and W. Bode Hoppe-Seyler’s 2. Physiol. Chem. 1983 phys. 1985 237 118.364 949. 55 E. Kasafirek P. Fric and J. Slaby Biol. Chem. Hoppe-Seyler 96 K. Tanizawa Y. Kanaoka J. D. Wos and W. B. Lawson Biol. 1985 366 333. Chem. Hoppe-Seyler 1985 366 871. 56 W. Hornbeck E. Moczar J. Szeci and L. Roberts Biochem. 97 D. 0.Shah K. Lai and D. G. Gorenstein J. Am. Chem. Sot. Pharmacol. 1985 34 3315. 1984 106 4272. 57 A. Lentini F. Farchione B. Ternai N. Kreua-Ongarjnucool and 98 N. E. Mackenzie J. P. Malthouse and A. I. Scott Science 1984 P. Tovivich Biol. Chem. Hoppe-Seyler 1987 368 369. 255 883. 58 P. Lestienne J. L. Dimicoli C. G. Wermuth and J. G. Bieth 99 I. J. Galpin A. H. Wilby G. A. Place and R. J. Beynon Int. J. Biochim. Biophys. Acta 1981 658 413. Pept. Protein Res. 1984 23 447. 59 J. L. Dimicoli H. Lam-Tanh F. Toma and S.Fermandjian 100 N. A. Roberts and A. E. Surgenor Biochem. Biophys. Res. Com- Biochemistry 1984 23 3173. mun. 1986 139 896. 60 D. L. Hughes L. C. Sieker J. Bieth and J. L. Dimicoli J. Mol. 101 C. H. Hassall W. H. Johnson A. J. Kennedy andN. A. Roberts Biol. 1982 162 645. FEBS Lett. 1985 183 201. 61 T. Teshima J. C. Griffin and J. C. Powers J. Biol. Chem. 1982 102 H. Yokosawa M. Nishikata and S. Ishii J. Biochem. (Tokyo) 257 5085. 1984 95 1819. 62 J. T. Gerig and J. D. Reinheimer J. Biol. Chem. 1985 260 103 T. Yoshimoto K. Kawahara F. Matsubara K. Kado and D. 4713. Tsuru J. Biochem. (Tokyo) 1985 98 975. 63 S. Omura H. Ohno T. Saheki M. Yoshida and A. Nakagawa 104 M. Nishikata H. Yokosawa and S. Ishii Chem. Pharm. Bull. Biochem. Biophys. Res. Commun. 1978 83 704.1986 34,2931. 64 R. W. Spencer L. J. Copp and J. R. Pfister J. Med. Chem. 1985 105 T. Someno T. Saino K. Katoh H. Miyazaki and S. Ishii J. 28 1828. Biochem. (Tokyo) 1985 97 1493. 65 L. Cook B. Ternai and P. Ghosh J. Med. Chem. 1987 30 106 T.Someno and S. Ishii Chem. Pharm. Bull. 1986 34 1748. 1017. 107 E. Schreier S. Fittkau and W. E. Hoehne Int. J. Pept. Protein 66 W. C. Groutas L. T. Huang M. A. Stanga M. J. Brubaker and Res. 1984 23 134. M. K. Moi J. Heterocycl. Chem. 1985. 22 433. 108 S. Fittkau K. Smalla and D. Pauli Biomed. Biochim. Acta 1984 67 A. Lentini B. Ternai and P. Ghosh Biochem. Int. 1985,10,221. 43 887. 68 A. S. Dutta M. B. Giles and J. C. Williams J. Chem. Soc. 109 D. Bromme and S. Fittkau Biomed. Biochim. Acta 1985 44,1089. Perkin Trans.I 1986 1655. 110 S. Fittkau and G.Jahreis J. Prakt. Chem. 1984 326 48. 69 A. S. Dutta M. B. Giles J. J. Gormley J. C. Williams and E. J. 11 1 H. Hori A. Yasutake Y. Minematsu and J. C. Powers in ‘Pep- Kusner J. Chem. Soc. Perkin Trans. I 1987 111. tides Structure and Function; Proceedings of the Ninth American 70 Y. Okada Y. Tsuda N. Teno Y. Nagamatsu U. Okarnoto and Peptide Symposium’ ed. C. M. Deber V. J. Hruby and K. D. N. Nishi Chem. Pharm. Bull. 1985 33 5301. Kopple Pierce Chem. Co. Rockford Illinois 1985 p. 819. 71 Y. Okada Y. Tsuda Y. Nagamatsu and U. Okamoto Chem. 112 B. Imperiali and R. H. Abeles Biochemistry 1986 25 3760. Pharm. Bull. 1982 30 1528. 113 E. J. Breaux and M. L. Bender FEBS Lett. 1975 56 81. 72 Y. Okada Y. Tsuda Y. Nagamatsu and U.Okamoto Int. J. 114 R. L. Stein A. M. Strimpler P. D. Edwards J. J. Lewis R. S. Peptide Protein Res. 1984 24 347. Mauger J. A. Schwartz M. M. Stein D. A. Trainor R. A. Wil- 73 Y.Okada Y. Tsuda N. Teno Y. Nagamatsu U. Okamoto and donger and M. A. Zottola Biochemistry 1987 26 2682. N. Nishi Pept. Chem. 1985 23 291. 115 R. L. Stein and D. A. Trainor Biochemistry 1986 25 5414. 74 J. Sturzebecher and F. Markwardt ‘Synthetische Inhibitoren des 116 R. P. Dunlap P. J. Stone and R. H. Abeles Biochem. Biophys. Thrombins und anderer Gerinnungsenzyme -Struktur und Res. Commun. 1987 145 509. Wirkung’ (Beitrage zur Wirkstofforschung Vol. 16) Akademie 117 D. H. Kinder and J. A. Katzenellenbogen J. Med. Chem. 1985 der Wissenschften der D.D.R. Berlin 1982. 28 1917. NATURAL PRODUCT REPORTS 1988-G.FISCHER 118 P. Amiri R. N. Lindquist D. S. Matteson and K. M. Sadhu Arch. Biochem. Biophys. 1984 234 531. 119 C. A. Kettner and A. B. Shenvi J. Biol. Chem. 1984 259 15 106. 120 A. Baici and U. Seemueller Biochem. J. 1984 218 829. 121 N. T. Soskel S. Watanabe R. Hardie A. B. Shenvi J. A. Punt and C.Kettner Am. Rev. Respir. Dis. 1986 133 635 639. 122 B. Wolf G. Fischer and A. Barth Acta Biol. Med. Ger. 1978,37 409. 123 G. Fischer and H. Bang in ‘Structure-Function Correlations in Proteases and Selected Proteins’ ed. A. Schellenberger and H.-R. Schutte Verlag der Wissenschaften Berlin 1985 p. 153. 124 R. L. Stein B. R. Viscarello and R. A. Wildonger J. Am. Chem. SOC.,1984 106 796. 125 T. Yoshimura L. N. Barker and J.C. Powers J. Biol. Chem. 1982 257 5077. 126 M. E. Ando J. T. Gerig and K. F. S. Luk Biochemistry 1986 25 4778. 127 J. C. Powers T. Tanaka J. W. Harper Y. Minematsu L. Barker D. Lincoln K. V. Crumley J. E. Fraki N. M. Schechter G. G. Lazarus K. Nakajima K. Nakashino H. Neurath and R. G. Woodbury Biochemistry 1985 24 2048. 128 J. Kraut Annu. Rev. Biochem. 1977 46 331. 129 L. A. Lambden and P. A. Bartlett Biochem. Biophys. Res. Com- mun. 1983 112 1085. 130 I. M. Kovach J. H. A. Huber and R. L. Schowen J. Am. Chem. SOC.,1988 110 590. 131 I. M. Kovach M. Larson and R. L. Schowen J. Am. Chem. Soc. 1986 108 3054 5490. 132 R. B. McWhirter V. Yevsikov and M. H. Klapper Biochemistry 1985 24 3020. 133 A. K. Mishra and M. H. Klapper Biochemistry 1986 25 7328.134 B. Tobias W. M. Westler and J. L. Markley Fed. Proc. Fed. Am. SOC.Exp. Biol. 1984 43 1775. 135 K. Tanizawa Y. Kasaba and Y. Kanaoka J. Am. Chem. Soc. 1977 99 4485. 136 M. Nozawa Y. Kasaba and Y. Kanaoka J. Biochem. (Tokyo) 1982 91 1837. 137 K. Tanizawa A. McLaren W. B. Lawson and Y. Kanaoka Chem. Pharm. Bull. 1986 34,913. 138 A. D. Turner D. M. Monroe H. R. Roberts N. A. Porter and S. V. Pizzo Biochemistry 1986 25 4929. 139 S. V. Pizzo A. D. Turner S. L. Gonias D. M. Monroe H. R. Roberts and N. A. Porter Ann. N. Y. Acad. Sci. 1986 485 199. 140 J. Sturzebecher M. Sturzebecher and F. Markwardt Toxikon 1986 24 585. 141 J. M. Kaminski L. Bauer S. R. Mack R. A. Anderson Jr. D. P. Waller and L. J. D. Zaneveld J.Med. Chem. 1986 29 514. 142 M. Geiger and B. R. Binder Biochim. Biophys. Acta 1987 912 34. 143 G. A. Digenis B. J. Agha K. Tsuji M. Kato and M. Shinogi J. Med. Chem. 1986 29 1468. 144 K. Tsuji B. J. Agha M. Shinogi and G. A. Digenis Biochem. Biophys. Res. Commun. 1984 122 571. 145 B. F. Gupton D. L. Carroll P. M. Tuhy C.-M. Kam and J. C. Powers J. Biol. Chem. 1984 259 4279. 146 J. C. Powers R. Boone D. L. Carroll B. F. Gupton C.-M. Kam N. Nishino M. Sakamoto and P. M. Tuhy J. Biol. Chem. 1984 259 4288. 147 M. Zimmerman H. Morman D. Mulvey H. Jones R. Frank- shun and B. M. Ashe J. Biol. Chem. 1980 255 9848. 148 G. Lugarella C. Gardi L. Fonzi L. Comparini N. N. Share M. Zimmerman and P. A. Martorana Exp. Lung. Res. 1986,11 35. 149 B.M. Ashe R. L. Clarke H. Jones and M. Zimmerman J. Biol. Chem. 1981 256 11 603. 150 H. Nakagawa M. Kanego K. Watanabe K. Sado and S. Tsuru-fuji J. Pharmacobio. Dyn. 1986 9 423. 151 A. R. Moorman and R. H. Abeles J. Am. Chem. SOC.,1982,104 6785. 152 M. H. Gelb and R. H. Abeles J. Med. Chem. 1986,29 585. 153 R. W. Spencer L. J. Copp B. Bonaventura T. F. Tam T. J. Liak R. J. Billedeau and A. Krantz Biochem. Biophys. Res. Commun. 1986 140 928. 154 T. Teshima J. C. Griffin and J. C. Powers J. Biol. Chem. 1982 257 5085. 155 L. Hedstrom A. R. Moorman J. Dobbs and R. H. Abeles Bio-chemistry 1984 23 1753. 156 A. Krantz R. W. Spencer T. F. Tam E. Thomas and L. J. Copp J. Med. Chem. 1987 30,589. 49I 157 D. Ringe J. M. Mottonen M. H. Gelb and R. H.Abeles Bio-chemistry 1986 25 5633. 158 R. B. Westkaemper and R. H. Abeles Biochemistry 1983 22 3256. 159 M. H. Gelb and R. H. Abeles Biochemistry 1984 23 6596. 160 W. A. Boulanger and J. A. Katzenellenbogen J. Med. Chem. 1986 29 1159. 161 J. W. Harper and J. C. Powers Biochemistry 1985 24 7200. 162 J. W. Harper K. Hemmi and J. C. Powers Biochemistry 1985 24 1831. 163 J. S. McMurray and D. F. Sykes Biochemistry 1986 25 2298. 164 C. Betzel G. P. Pal K.-D. Jany and W. Saenger FEBS Lett. 1986 197 105. 165 J. P. G. Malthouse W. U. Primrose N. E. Mackenzie and A. I. Scott Biochemistry 1985 24 3478. 166 J. P. G. Malthouse N. E. Mackenzie A. S. F. Boyd and A. I. Scott J. Am. Chem. Soc. 1983 105 1685. 167 W. U. Primrose A. I. Scott N. E. Mackenzie and J.P. G. Malt- house Biochem. J. 1985 231 677. 168 A. I. Scott N. E. Mackenzie J. P. G. Malthouse W. U. Prim- rose P. E. Fagerness A. Brisson L. Z. Qi W. Bode C. M. Carter and Y. J. Jang Tetrahedron 1986 42 3269. 169 H. Angeliker P. Wikstrom P. Rauber and E. Shaw Biochem. J. 1987 241 871. 170 P. Rauber. H. Aneeliker. B. Walker. and E. Shaw. Biochem. J.. -1986 239 633. 171 G. Tans T. Janssen-Claessen J. Rosing and J. H. Griffin Eur. J. Biochem. 1987 169 637. 172 G. D. J. Green Thromb. Res. 1986 44,175. 173 T. F. Tam R. W. Spencer E. M. Thomas L. J. Copp and A. Krantz J. Am. Chem. Soc. 1984 106 6849. 174 R. W. Spencer T. F. Tam E. M. Thomas V. J. Robinson and A. Krantz J. Am. Chem. Soc. 1986 108 5589. 175 L. J. Copp A. Krantz and R.W. Spencer Biochemistry 1987 26 169. 176 W. A. Boulanger and J. A. Katzenellenbogen J. Med. Chem. 1986 29 1483. 177 J. W. Harper and J. C. Powers J. Am. Chem. SOC.,1984 106 7618. 178 E. F. Meyer Jr. L. G.Presta and R. Radakrishnan J. Am. Chem. SOC.,1985 107 4091. 179 S. B. Daniels E. Cooney M. J. Sofia P. K. Chakravarty and J. A. Katzenellenbogen J. Biol. Chem. 1983 258 15046. 180 S. B. Daniels and J. A. Katzenellenbogen Biochemisfry 1986,25 1436. 181 S. Naruto I. Motoc G. R. Marshall S. B. Daniels M. J. Sofia and J.A. Katzenellenbogen J. Am. Chem. SOC. 1985 107 5262. 182 M. J. Sofia and J. A. Katzenellenbogen J. Med. Chem. 1986,29 230. 183 J. B. Doherty B. M. Ashe L. W. Argenbright P. L. Barker R. J. Bonney G.0.Chandler M.E. Dahlgren C. P. Dorn Jr. P. E. Finke R. A. Firestone D. Fletcher W. K. Hagmann R. Mum- ford L. O’Grady A. L. Maycock J. M. Pisano S. K. Shah K. R. Thompson and M. Zimmerman Nature (London) 1986 322 192. 184 M. A. Navia J. P. Springer T.-Y. Lin H. R. Williams R. A. Firestone J. M. Pisano J. B. Doherty P. E. Finke and K. Hoogsteen Nature (London) 1987 327 79. 185 J.-M. Ghuysen J.-M. Frere M. Leyh-Bouille 0.Dideberg J. Lamotte-Brasseur H. R. Perkins and J.-L. De Coen in ‘Topics in Molecular Pharmacology’ ed. A. S.V. Burgen and G.C. K. Roberts Elsevier/North-Holland Amsterdam 198 1 p. 63. 186 G. Fischer H. U. Demuth and A. Barth Abstracts of 12th FEBS Meeting Poster Nr. 2807 Dresden 1978. 187 G.Fischer H. U. Demuth and A. Barth Pharmazie 1983 38 249.188 H. U. Demuth R. Baumgrass 0.Schaper G. Fischer and A. Barth J. Enz. Znhib. 1988 2 129. 189 W. C. Groutas P. K. Giri J. P. Crowley J. C. Castrisos and M. J. Brubaker Biochem. Biophys. Res. Commun. 1986 141 741. 190 W. E. Brown and F. Wold. Biochemistry 1973 12 828. 191 R. E. Schofield R. P. Werner and F. Wold Biochemistry 1977 16 2492. 192 W. C. Groutas M. J. Brubaker M. E. Zandler M. A. Stanga T. L. Nuang J. C. Castrisos and J. P. Crowley Biochem. Biophys. Res. Commun. 1985 128 90. 193 W. C. Groutas M. J. Brubaker M. E. Zandler V. Mazo-Gray S. A. Rude J. P. Crowley J. C. Castrisos D. A. Dunshee and P. K. Giri J. Med. Chem. 1986 29 1302. 194 W. C. Groutas W. R. Abrams. M. C. Theodorakis A. M. Kas- per S. A. Rude R.C. Badger T. D. Ocain K. E. Miller M. K. Moi M. J. Brubaker K. S. Davis and M. E. Zandler J. Med. Chem. 1985 28 204. 195 E. H. White L. Jelinski I. R. Politzer B. R. Branchini and D. F. Roswell J. Am. Chem. Soc. 1981 103 4231. 196 S. Donadio H. M. Perks K. Tsuchiya and E. H. White Bio-chemistry 1985 24 2447. 197 ‘Pulmonary Emphysema and Proteolysis’ ed. C. Mittman Aca- demic Press New York 1972. 198 A. Janoff and R. Dearing Am. Rev. Respir. Dis. 1980 121 1025. 199 A. Janoff in ‘Granulocyte Elastase; Neutral Proteases of Human Polymorphonuclear Leucocytes’ ed. K. Havemann and A. Janoff. Urban and Schwarzenberg Munich 1978 p. 390. 200 J. Travis and G. S. Salvesen Annu. Rev. Biochem. 1983 52 655. 201 P. J. Stone J. D. Calore G. L. Snider and C.Franzblau J. Clin. Invest. 1982 69 920. 202 T. Tanaka Y. Minematsu C. F. Reilly J. Travis and J. C. Powers Biochemistry 1985 24 2040. 203 B. McRae K. Nakajima J. Travis and J. C. Powers Bio-chemistry 1980 19 3973. 204 R. L. Stein J. Am. Chem. Soc. 1985 107 5767. 205 J. C. Powers D. F. Gupton A. D. Harley N. Nashino and R. J. Whitley Biochim. Biophys. Acta 1977 485 156. 206 R. C. Thompson Biochemistry 1973 12 47. 207 G. Feinstein C. J. Malemud and A. Janoff Biochim. Biophys. Acta 1976 429 925. 208 G. L. Snider P. J. Stone E. C. Lucy R. Breuer J. D. Calore T. Seshadri A. Catanese R. Maschler and H.-P. Schnebli Am. Rev. Respir. Dis. 1985 132 1155. 209 T. Yaegashi S. Nunomura T. Okutome T. Nakayama M. Kurumi Y. Sakurai T. Aoyama and S.Fujii Chem. Pharm. Bull. 1984 32 4466. 210 J. Fareed H. L. Messmore G. Kindel and J. U. Balis Ann. N. Y. Acad. Sci. 1981 370 765. 211 K. Tanizawa A. B. McLaren W. B. Lawson and Y. Kanaoka Chem. Pharm. Bull. 1986 34,913. 212 R. R. Cook and J. C. Powers Biochem. J. 1983 215 287. 213 L. Polgar and B. Asboth J. Theor. Biol. 1986 121 323. 214 D. H. Rich Res. Monogr. Cell. Tissue Physiol. 1986 12 153. 215 H. R. B. Pelham Eur. J. Biochem. 1978 85 457. 216 B. D. Korant T. Towatari L. Ivanoff S. Petteway Jr. J. Brzin B. Lenarcic and V. Turk J. Cell. Biochem. 1986 32 91. 217 J. M. Delaisse Y. Eeckhout and G. Vaes Biochem. Biophys. Res. Commun. 1984 125 441. 218 H. Kirschke J. Langner B. Wiederanders S. Ansorge and P. Bohley Eur. J. Biochem.1977 74 293. 219 S. Wilk T. C. Friedman and T. B. Kline Biochem. Biophys. Res. Commun. 1985 130 662. 220 K. Tsuchida M. Kurachi R. Yamazaki K. Kaneko A. Higuchi K. Hosoda I. Arai Y. Isobe and S. Okuyama Yakuri To Chiryo 1986 14 747. 221 B. D. Korant Crit. Rev. Biotech. in the press. 222 I. Ohkubo K. Kurachi T. Takasawa H. Shiokawa and M. Sasaki Biochemistry 1984 23 5691. 223 J. Brzin T. Popovic V. Turk U. Borchart and W. Machleidt Biochem. Biophys. Res. Commun. 1984 118 103. 224 W. Machleidt U. Borchart H. Fritz J. Brzin A. Ritonja and V. Turk Hoppe-Seyler’s Z. Physiol. Chem. 1983 364 1481. 225 V. Turk J. Brzin M. Longer A. Ritonja M. Eropkin U. Bor- chart and W. Machleidt Hoppe-Seyler’s Z. Physiol. Chem. 1983 364 1487. 226 Y. Okada N.Teno N. Itoh and H. Okamoto Chem. Pharm. Bull. 1986 33 5149. 227 N. Teno S. Tsuboi N. Itoh H. Okamoto and Y. Okada Bio-chem. Biophys. Rex Commun. 1987 143 749. 228 N. E. McKenzie S. K. Grant A. I. Scott and J. P. G. Malthouse Biochemistry 1986 25 2293. 229 M. P. Gamcsik J. P. G.Malthouse W. U. Primrose N. E. McKenzie A. S. F. Boyd R. A. Russell and A. I. Scott J. Am. Chem. Soc. 1983 105 6324. 230 J. 0.Westerick and R. Wolfenden J. Bid. Chem. 1972 247 8195. 231 H. Umezawa Acta Biol. Med. Ger. 1977 36 1899. 232 C. A. Lewis Jr. and R. Wolfenden Biochemistry 1977 16,4886 4890. 233 S. Pontremoli and E. Melloni Annu. Rev. Biochem. 1986 55 455. NATURAL PRODUCT REPORTS 1988 234 T. C. Friedman T. B. Kline and W. Wilk Biochemistry 1985 24 3907.235 E. C. Lucas and A. Williams Biochemistry 1969 8 5125. 236 A. Williams E. C. Lucas A. R. Rimmer and H. C. Hawkins J. Chem. Soc. Perkin Trans. 2 1972 627. 237 D. Bromme 8. Bartels K. Peters H. Kirschke and S. Fittkau in ‘Proceedings of the 50th Anniversary Symposium of the Nobel Prize of A. Szent-Gyorgyi’ ed. B. Penke and D. Torok de Gruyter Berlin in the press. 238 S. A. Thompson P. P. Andrews and R. P. Hanzlik,. J. Med. Chem. 1986 29 104. 239 T.-C. Liang and R. H. Abeles Arch. Biochem. Biophys. 1987 252 626. 240 L. A. A. Sluyterman and J. Widenes Biochim. Biophys. Acta 1973 302 95. 241 J. R. Moon R. S. Coleman and R. P. Hanzlik J. Am. Chem. Soc. 1986 108 1350. 242 J.-R. Brisson P. R. Carey and A. C. Storer J. Biol. Chem. 1986 261 9087.243 C. Kettner and E. Shaw Thromb. Res. 1979 14 969. 244 V. Ranga J. Kleinerman M. P. C. Ip J. Sorensen and J. C. Powers Am. Rev. Respir. Dis. 1981 124 613. 245 E. Shaw H. Angeliker P. Rauber. B. Walker and P. Wikstrom Biomed. Biochim. Acta 1986 45 1397. 246 D. Rasnick Anal. Biochem. 1985 149 461. 247 T. Sasaki T. Kikuchi I. Fukui and T. Murachi J. Biochem. (Tokyo) 1986 99 173. 248 G. D. J. Green and E. Shaw J. Bid. Chem. 1981 256 1923. 249 K. Hanada M. Tamai M. Yamagishi S. Ohmura J. Sawada and I. Tanaka Agric. Biol. Chem. 1978 42 523. 250 M. Tamai K. Hanada T. Adachi K. Okuma K. Kashiwagi S. Ohmura and M. Ohzeki J. Biochem. (Tokyo) 1981 90 255. 251 A. J. Barrett A. A. Kembhavi M. A. Brown H. Kirschke C. G. Knight M. Tamai and K.Hanada Biochem. J. 1982 201 189. 252 A. J. Barrett A. A. Kembhavi and K. Hanada Acta Biol. Med. Ger. 1981 40 1513. 253 H. Knisatschek and K. Bauer Biochem. Biophys. Res. Commun. 1986 134 888. 254 T. C. Friedman and S. Wilk J. Neurochem. 1986 46 1231. 255 C. Parkes A. A. Kembhavi and A. J. Barrett Biochem. J. 1985 230 509. 256 T. Toyo-oka T. Kamishiro K. Hara N. Nakamura M. Kita- hara and T. Masaki Drug. Res. 1986 36 190. 257 R. P. Hanzlik and S. A. Thompson J. Med. Chem. 1984 27 711. 258 V. Shubr R. Duncan K. Hanada H. C. Cable and J. Kopecek J. Controlled Release 1986 4 63. 259 A. F. Monzingo and B. W. Matthews Biochemistry 1984 23 5724. 260 M. A. Holmes and B. W. Matthews Biochemistry 1981 20 6912. 261 M. A. Holmes D. E.Tronrud and B. W. Matthews Bio-chemistry 1983 22 236. 262 D. E. Tronrud A. F. Monzingo and B. W. Matthews Eur. J. Biochem. 1986 157 261. 263 A. F. Monzingo and B. W. Matthews Biochemistry 1982 21 3390. 264 D. W. Christianson and W. N. Lipscomb Proc. Natl. Acad. Sci. USA 1985 82 6840. 265 D. W. Christianson L. C. Kuo and W. N. Lipscomb J. Am. Chem. Soc. 1985 107 8281. 266 D. W. Christianson and W. N. Lipscomb J. Am. Chem. Soc. 1986 108 4998 545. 267 S. J. Gardell C. S. Craik D. Hilvert M. S. Urdea and W. J. Rutter Nature (London) 1985 317 551. 268 L. T. Skeggs W. H. Marsh J. R. Kahn and N. P. Shumway J. Exp. Med. 1954 99 275. 269 R. L. Soffer Annu. Rev. Biochem. 1976 45 73. 270 E. A. Bauer G. P. Stricklin H. G. Welgus J. J. Jeffrey L.J. Setzer and A. Z. Eisen in ‘Biochemistry and Physiology of Skin’ ed. W. A. Goldsmith de Gruyter Berlin 1983 p. 411. 271 J. M. Delaisse Y. Eeckhout C. Sear A. Galloway K. McCul- lagh and G. Vaes Biochem. Biophys. Res. Commun. 1985 133 483. 272 R. J. Beynon and J. S. Bond Science 1983 219 1351. 273 C. Gorenstein and S. H. Snyder L$e Sci. 1979 25 2065. 274 D. R. Lynch and S. H. Snyder Annu. Rev. Biochem. 1986 55 773. 275 E. D. Harris and S. M. Krone N. Engl. J. Med. 1974 291 557. 276 C. B. Couch and W. J. Strittmatter Cell 1983 32 257. NATURAL PRODUCT REPORTS 1988-G. FISCHER 493 277 A. Jochen and B. Berhanu Biochem. Biophys. Res. Commun. 320 W. J. Greenlee E. D. Thorsett J. P. Springer A. A. Patchett E. 1987 142 205. H. Ulm and T.C. Vassil Biochem. Biophys. Res. Commun. 1984 278 J. K. McDonald Histochem. J. 1985 17 773. 122 791. 279 H. S. Cheung and D. W. Cusman Biochim. Biophys. Acta 1973 32 1 W. H. Roark F. J. Tinney D. Cohen A. D. Essenburg and H. 293 451. R. Kaplan J. Med. Chem. 1985 28 1291. 280 M. A. Ondetti B. Rubin and D. W. Cushman Science 1977 322 N. Gruenfeld J. L. Stanton A. M. Yuan F. H. Ebetino L. G. 196 441. Browne C. Gude and C. F. Huebner J. Med. Chem. 1983 26 28 1 A. A. Patchett E. Harris E. W. Tristram M. J. Wyvratt M. T. 1277. Wu D. Taub E. R. Peterson T. J. Ikeler J. ten Broeke L. G. 323 R. F. Meyer E. D. Nicolaides F. J. Tinney E. A. Lunney A. Payne D. L. Ondeyka E. D. Thorsett W. J. Greenlee N. S. Holmes M. L. Hoefle R. D. Smith A. D. Essenburg H. R. Lohr R.D. Hoffsommer H. Joshua W. V. Ruyle J. W. Roth- Kaplan and R. G. Almquist J. Med. Chem. 1981 24 964. rock S. E. Aster A. L. Maycock F. M. Robinson R. Hirsch- 324 W. J. Greenlee P. L. Allibone D. S. Perlow A. A. Patchett E. mann C. S. Sweet E. H. Ulm D. M. Gross T. C. Vassil and H. Ulm and T. C. Vassil J. Med. Chem. 1985 28 434. C. A. Stone Nature (London) 1980 288 280. 325 I. Motoc R. A. Dammkoehler D. Mayer and J. Labanowski 282 L. D. Byers and R. Wolfenden Biochemistry 1973 12 2070. Quant. Struct. Act. Relat. 1986 5 99. 283 E. W. Petrillo Jr. and M. A. Ondetti Med. Res. Rev. 1982 2 326 P. R. Andrews J. M. Carson A. Caselli M. J. Spark and R. 1. Woods J. Med. Chem. 1985 28 393. 284 W. H. Parsons J. L. Davidson D. Taub S. D. Aster E. D. Thor- 327 M. J. Wyvratt E.W. Tristram T. J. Ikeler N. S. Lohr H. sett and A. A. Patchett Biochem. Biophys. Res. Commun. 1983 Joshua J. P. Springer B. H. Arison and A. A. Patchett J. Org. 117 108. Chem. 1984 49 2816. 285 A. J. Turner ISI Atlas of Science 1987 1 74. 328 E. D. Thorsett E. E. Harris S. D. Aster E. R. Peterson J. P. 286 C. Llorens G. Gacel J.-P. Swerts R. Perdrisot M.-C. Fournie- Snyder J. P. Springer J. Hirschfield E. W. Tristram A. A. Pat- Zaluski J.-C. Schwartz and B. P. Roques Biochem. Biophys. chett E. H. Ulm and T. C. Vassil J. Med. Chem. 1986 29 Res. Commun. 1980 96 1710. 251. 287 H. Suda T. Aoyagi T. Takeuchi and H. Umezawa J. Antibiot. 329 Y. S. Prabhakar and S. Gupta Indian J. Biochem. Biophys. 1985 1973 26 621. 22 318. 288 U. B. Goli and R. E. Galardy Biochemistry 1986 25 7136.330 K. Hayashi K. Nunami K. Sakai Y.Ozaki J. Kato K. Kinashi 289 R. Shapiro and J. F. Riordan Biochemistry 1984 23 5225. and N. Yoneda Chem. Pharm. Bull. 1985 33 2011. 290 R. Shapiro and J. F. Riordan Biochemistry 1984 23 5234. 331 M. J. Wyvratt M. H. Tischler T. J. Ikeler J. P. Springer E. W. 29 1 M. Baltas L. Cazaux L. Gorrichon-Guigon P. Marconi and Tristram and A. A. Patchett in ‘Peptides Structure and Func- P. Tisnes Tetrahedron Lett. 1985 26 4447. tion ; Proceedings of the Eighth American Peptide Symposium ’ 292 G. Grand F. Sarni and A. M. Boudet Planta 1985 163 232. ed. V. J. Hruby and D. H. Rich Pierce Chemical Co. Rockford 293 K. S. Ner C. J. Suckling A. R. Bell and R. Wrigglesworth J. Illinois 1983 p. 551. Chem. Soc. Chem. Commun.1987 480. 332 R. Ciabatti G. Padova E. Bellasio G. Tarzia A. Depaoli F. 294 C.-M. Kam N. Nishino and J. C. Powers Biochemistry 1979 Battaglia M. Cellentani D. Barone and E. Baldoli J. Med. 18 3032. Chem. 1986 29 411. 295 N. E. Jacobsen and P. A. Bartlett J. Am. Chem. Soc. 1981 103 333 J. W. H. Watthey J. L. Stanton M. Desai J. E. Babiarz and B. 654. M. Finn J. Med. Chem. 1985 28 1511. 296 P. A. Bartlett Stud. Org. Chem. (Amsterdam) 1985 20 439. 334 J. Slade J. L. Stanton B. Ben-David and G. Mazzenga J. Med. 297 P. A. Bartlett and C. K. Marlowe Biochemistry 1983 22 4618. Chem. 1985 28 1517. 298 D. Grobelny U. B. Goli and R. E. Galardy Biochem. J. 1985 335 C. H. Hassall A. Kroehn C. J. Moody and W. A. Thomas J. 232 15. Chem. Sac. Perkin Trans. I 1984 155. 299 B.Holmquist and B. L. Vallee Proc. Natl. Acad. Sci. USA 1979 336 C. H. Hassall A. Kroehn C. J. Moody and W. A. Thomas 76 6216. FEES Lett. 1982 147 175. 300 L. Poncz T. A. Gerken D. G. Dearborn D. Grobelny and R. E. 337 M. R. Attwood R. J. Francis C. H. Hassall A. Kroehn G. Galardy Biochemi.rtry 1984 23 2766. Lawton I. L. Natoff J. S. Nixon S. Reshaw and W. A. Thomas 30 1 R. E. Galardy and D. Grobelny Biochemistry 1983 22 4556. FEES Lett. 1984 165 201. 302 K. A. Mookhtiar C. A. Marlowe P. A. Bartlett and H. E. van 338 W. A. Thomas and I. W. A. Whitcombe J. Chem. Soc. Perkin Wart Biochemistry 1987 26 1962. Trans. 2 1986 747. 303 R. L. Elliott N. Marks M. J. Berg and P. S. Portoghese J. Med. 339 P. J. Gilbert and W. A. Thomas J. Chem. Soc. Perkin Trans. 2 Chem.1985 28 1208. 1985. 1077. ~ -,-304 P. A. Bartlett J. E. Hanson F. Acher and P. P. Giannousis in 340 C. J. Blankley J. S. Kaltenbronn D. E. DeJohn A. Werner L. ‘Biophosphates and their Analogues Synthesis Structure Meta- R. Bennett G. Bobowski U. Krolls D. R. Johnson W. M. Pearl- bolism and Activity’ ed. K. S. Bruzik and W. J. Stec Elsevier man M. L. Hoefle A. D. Essenburg D. M. Cohen and H. R. Amsterdam 1987 p. 429. Kaplan J. Med. Chem. 1987 30 992. 305 E. D. Thorsett E. E. Harris E. R. Peterson W. J. Greenlee A. 341 D. A. Evans D. J. Mathre and W. L. Scott J. Org. Chem. 1985 A. Patchett E. H. Ulm and T. C. Vassil Proc. Natl. Acad. Sci. 50 1830. USA 1982 79 2176. 342 M. Pozsgay C. Michaud M. Liebmann and M. Orlowski Bio-306 R. E. Galardy V. Kontoyiannidou-Oestrem and 2.P.Kortyle- chemistry 1986 25 1292. wicz Biochemistry 1983 22 1990. 343 J. T. Suh J. R. Regan J. W. Skiles J. Barton J. J. Piwinski I. 307 R. E. Galardy and D. Grobelny J. Med. Chem. 1985 28 1422. Weinryb A. Schwab A. I. Samuels W. S. Mann R. D. Smith 308 K. Yamauchi S. Ohtsuki and M. Kinoshita Biochim. Biophys. P. S. Wolf and A. Khandwala Eur. J. Med. Chem.-Chim. Ther. Acta 1985 827 275. 1985 20 563. 309 N. Nishino and J. C. Powers Biochemistry 1979 18 4340. 344 R. Escher and P. Buenning Angew. Chem. 1986 98 264. 310 R. E. Galardy and Z. P. Kortylewicz Biochem. J. 1985 226 345 J. T. Suh J. W. Skiles B. E. Williams R. D. Youssefyeh H. 447. Jones B. Loev E. S. Neiss A. Schwab W. Mann A. Khandwala 31 1 G. Fischer and K. Neubert Ger. P. 150742 (21 April 1980).P. S. Wolf and I. Weinryb J. Med. Chem. 1985 28 57. 312 D. E. Tronrud H. M. Holden and B. W. Matthews Science 346 P. R. Menard J. T. Suh H. Jones B. Loev E. S. Neiss J. Wilde 1987 235 571. A. Schwab and W. S. Mann J. Med. Chem. 1985 28 328. 313 P. A. Bartlett and C. K. Marlowe Science 1987 235 569. 347 D. S. Pickering M. V. Krishna D. C. Miller and W. W.-C. 3 I4 B. A. Bash U. C. Singh F. K. Brown R. Langridge and P. A. Chan Arch. Biochem. Biophys. 1985 239 368. Kollman Science 1987 235 574. 348 L. Frick and R.Wolfenden Biochim.Biophys. Acta 1985,829,311. 315 A. A. Patchett and E. H. Cordes Adv. Enzvmol. 1985 57 1. 349 S. Fittkau W. H. Schunck and S. Mquotsi Acta Biol. Med. Ger. 316 J. M. Wyvratt and A. A. Patchett Med. Res. Rev. 1985 5 483.1976 35 365. 317 H. G. Bull N. A. Thornberry M. H. J. Cordes A. A. Patchett 350 C. Kettner G. I. Glover and J. M. Prescott Arch. Biochem. and E. H. Cordes J. Bid. Chem. 1985 260 2952. Biophys. 1974 165 739. 318 R. Cecchi R. Ciabatti D. Favara D. Barone and E. Baldoli 351 R. E. Galardy and 2. P. Kortylewicz Biochemistry 1985 24 Farmaco Ed. Sci. 1985 40 541. 7607. 319 G. M. Kisander A. M. Yuan C. G. Diefenbacher and J. L. 352 G. Fischer M. Sieber and A. Schellenberger Bio-org. Chem. Stanton. J. Med. Chem. 1985 28 1606. 1982 11 478. 353 M. H. Gelb J. P. Svaren and R. H. Abeles Biochemistry 1985 24 1813. 354 R. E. Galardy and Z. P. Kortylewicz Biochemistry 1984 23 2083. 355 D. Grobelny U. B. Goli and R. E. Galardy Biochemistry 1985 24,7612.356 D. H. Rich B. J. Moon and S. Harbeson J. Med. Chem. 1984 27,417. 357 E. M. Gordon J. D. Godfrey J. Pluscec D. von Langen and S. Natarajan Biochem. Biophys. Res. Commun. 1985 126,419. 358 J. D. Godfrey Jr. E. M. Gordon D. von Langen J. Engebrecht and J. Pluscec J. Org. Chem. 1986 51,3073. 359 H. Umezawa Antibiot. Chemother. (Basel) 1978 24,9. 360 J. D. Godfrey Jr. E. M. Gordon and D. von Langen Tetra-hedrort Lett. 1987 28,1603. 361 D. Grobelny and R. E. Galardy Biochemistry 1986 25,1070. 362 R. G. Almquist W.-R. Chao M. E. Ellis and H. L. Johnson J. Med. Chem. 1980 23,1392. 363 E. M. Gordon J. D. Godfrey H. N. Weller S. Natarajan J. Pluscec M. B. Rom K. Niemela E. F. Sabo and D. W. Cushman Bio-org. Chem. 1986 14,148. 364 R. G. Almquist C.Jennings-White W.-R. Chao T. Steeger K. Wheeler J. Rogers and C. Mitoma J. Med. Chem. 1985 28 1062. 365 R. G. Almquist W.-R. Chao and C. Jennings-White J. Med. Chem. 1985 28 1067. 366 D. A. Wallace S. R. E. Bates B. Walker G. Kay J. White D. J. S. Guthrie N. L. Blumsom and D. T. Elmore Biochem. J. 1986 239,797. 367 D. Grobelny and R. E. Galardy Biochemistry 1985 24,6145. 368 S. Ohuchi H. Suda H. Naganawa K. Kawamura T. Aoyagi and H. Umezawa J. Antibiot. 1984 37 1741. 369 M. A. Ondetti and D. W. Cushman CRC Crit. Rev. Biochem. 1984 16,381. 370 C. S. Sweet and E. H. Blaine in ‘Handbook of Hypertension’ Vol. 3 ed. P. A. VanZwieten Elsevier Amsterdam 1984 p. 343. 371 K.G.Hofbauer and J.M. Wood in ‘Handbook of Hyper-tension’ Vol.8 ed. A. Zanchetti and R. C. Tarazi Elsevier Amsterdam 1986 p. 466. 372 K. Nakata T. Iwatani M. Horiuchi H. Kito H. Yamauchi and T. Iso Jpn. J. Pharmacol. 1986 40 367. 373 M. R. Ehlers D. L. Maeder and R. E. Kirsch Biochim. Biophys. Acta 1986 833,361. 374 M. W. Pantoliano B. Holmquist and J. F. Riordan Bio-chemistry 1984 23 1037. 375 A. S.Verdini and G. C. Viscomi J. Chem. Soc. Perkin Trans. I 1985 697. 376 D. Grobelny and R. E. Galardy Biochem. Biophys. Res. Commun. 1985 128,960. 377 P. Henklein M. Boettcher G. Heder W.-E. Siems and H. Niedrich Pharmazie 1986 41,56. 378 B. P. Roques J. Pharmacol. 1985 16,5. 379 S. Blumberg and 2. Tauber Eur. J. Biochem. 1983 136,151. 380 S.-Y. Cui M. Kajiwara K. Ishii K. Aoki J. Sakamoto T. Matsumiya and T.Oka Jpn. J. Pharmacol. 1986 42,43. 381 K. Aoki M. Kajiwara and T. Oka Jpn. J. Pharmacol. 1986 40 297. 382 T. Hiranuma and T. Oka Jpn. J. Pharmacol. 1986 40 437. 383 W. L. Scott L. G. Mendelson M. L. Cohen R. C. A. Frederick- son and D. A. Evans Life Sci.,1985 36 1307. 384 M.-C. Fournie-Zaluski A. Coulaud R. Bouboutou P. Chaillet J. Devin G. Waksman J. Costentin and B. P. Roques J. Med. Chem. 1985 28 1158. 385 G. Waksman R. Bouboutou P. Chaillet J. Devin A. Coulaud E. Hamel R. Besselievre J. Costentin M.-C. Fournie-Zaluski and B. P. Roques Neuropeptides 1985 5,529. 386 G. Waksman R. Bouboutou J. Devlin R. Besselievre M.-C. Fournie-Zaluski and B. P. Roques Biochem. Biophys. Res. Commun. 1985 131,262. 387 A. J. Turner Biochem. SOC.Trans.1986 14,399. 388 S. Bourgoin D. Lebars. F. Artaud A. M. Clot R. Bouboutou M.-C. Fournie-Zaluski B. P. Roques M. Hamon and F. Ces-selin J. Pharmacol. Exp. Ther. 1986 238,360. 389 P. Cherot M.-C. Fournie-Zaluski and J. Laval Biochemistry 1986 25,8184. 390 Y. Inaoka STakahashi and S. Sato J. Antibiot. 1986 39,1382. 391 A. B. Shenvi Biochemistry 1986 25 1286. 392 J. 0.Baker and J. M. Prescott Biochem. Biophys. Res. Commun. 1985 130,1154. NATURAL PRODUCT REPORTS. 1988 393 J. Gross E. Harper E. D. Harris P. A. McCorskey J. H. High- berger C. Corbett and A. H. Kang Biochem. Biophys. Res. Commun. 1974 61,605. 394 K. A. Mookthiar F. Wang and H. E. van Wart Arch. Biochem. Biophys. 1986 246,645. 395 C. F. Vencill D. Rasnick K. V. Crumley N.Nishino and J. C. Powers Biochemistry 1985 24,3149. 396 D. E. Clark P. Wai and N. H. Grant Life Sci. 1985 37,575. 397 A. Yiotakis and V. Dive Eur. J. Biochem. 1986 160,413. 398 R. D. Gray J. V. Edwards J. W. Harrod and A. Spatola Fed. Proc. Fed. Am. Soc. Exp. Biol. 1985 44 1423. 399 J.-M. Delaisse Y. Eeckhout C. Sear A. Galloway K. McCul- lagh and G. Vaes Biochem. Biophys. Res. Commun. 1985 133 483. 400 C. Evans and J. D. Ridella Eur. J. Biochem. 1985 133,483. 401 S. K. Mallya and H. E. van Wart Biochem. Biophys. Res. Com-mun. 1987 144,101. 402 K. E. Dombrowski J. E. Sheats and D. J. Prockop Biochemistry 1986 25,4302. 403 J. Kay Biochem. SOC.Trans. 1985 13,1027. 404 T. Hofmann R. S. Hodges and M. N. G. James Biochemistry 1984 23,635. 405 M.J. Peach J. Physiol. Rev. 1977 57,313. 406 B. J. Materson and E. D. Freis Arch. Intern. Med. 1984 144 1947. 407 R. 0.Davies J. D. Irvin D. K. Kramsch J. F. Walker and F. Mancloa Am. J. Med. 1984 77(2A) 23. 408 J. Kay Biochem. Soc. Trans. 1982 10,277. 409 R. L. Lundblad and W. H. Stein J. Bid. Chem. 1969 244,154. 410 M. Cunningham and J. Tang J. Bid. Chem. 1976 251,4528. 411 J. Tang J. Bid. Chem. 1971 246,4510. 412 J. Kay M. J. Valler and B. M. Dunn in ‘Proteinase Inhibitors; Medical and Biological Aspects’ ed. N. Katanuma H. Umezawa and H. Holzer Springer-Verlag Berlin 1983 p. 201. 413 B. M. Dunn B. Parten M. Jimenez C. E. Rolph M. J. Valler and J. Kay in ‘Aspartic Proteinases and their Inhibitors’ ed. V. Kostka de Gruyter Berlin 1985 p.221. 414 F. Cumin G. Evin J.-A. Fehrentz R. Seyer B. Castro J. Men- ard and P. Corvol J. Bid. Chem. 1985 260,9154. 415 R. J. Cody J. Burton G. Evin K. Poulsen J. A. Herd and E. Haber Biochem. Biophys. Res. Commun. 1980 97,230. 416 R. J. Cody J. Burton J. A. Herd E. Slater and E. Haber Clin. Res. 1980 20,499A. 417 H. Umezawa T. Aoyagi H. Morishima H. Matsuzaki H. Ham- ada and T. Takeuchi J. Antibiot. 1970 23,259. 418 G. R. Marshall Fed. Proc. Fed. Am. Soc. Exp. Biol. 1976 35 2494. 419 M. P. Marciniszyn J. A. Hartsuck and J. Tang J. Bid. Chem. 1976 251,7088. 420 D. H. Rich J. Med. Chem. 1985 28,263. 421 D. H. Rich E. T. 0.Sun and E. H. Ulm J. Med. Chem. 1980 23,27. 422 D. H. Rich E. Sun and J. Singh Biochem. Biophys. Res. Com-mun.1977 74,762. 423 R. Bott E. Subramanian and D. R. Davies Biochemistry 1982 21,6956. 424 M. N. G. James A. Sielecki F. G. Salituro D. H. Rich and T. Hofmann Proc. Nail. Acad. Sci. USA 1982 79,6137. 425 D. H. Rich and E. T. 0.Sun Biochem. Pharmacol. 1980 29 2205. 426 M. Blum A. Cunningham M. Bendiner and T. Hofmann Bio-chem. Soc. Trans. 1985 13,1044. 427 P. G. Schmidt M. S. Bernatowicz and D. H. Rich Biochemistry 1982 21,6710. 428 J. Kay E.-G. Afting T. Aoyagi and B. M. Dunn Biochem. J. 1982 203,795. 429 J. C. Powers A. D. Harley and D. V. Myers in ‘Acid Proteases Structure Function and Biology’ ed. J. Tang Plenum Press New York 1977 p. 141. 430 J. Boger in ‘Peptides Structure and Function Proceedings of the Eighth American Peptides Symposium’ ed.V. J. Hruby and D. H. Rich Pierce Chemical Co. Rockford Illinois 1983 p. 569. 431 I. Schechter and A. Berger Biochem. Biophys. Res. Commun. 1967 27 157. 432 M. J. Powell R. J. Haldsworth T. S. Baker R. C. Titmas C. C. Bose A. E. Phipps S. E. Rolph M. J. Valler and J. Kay in ‘Aspartic Proteinases and their Inhibitors’ ed. V. Kostka de Gruyter Berlin 1985 p. 479. 433 P. A. Bartlett and W. B. Kezer J. Am. Chem. Soc. 1984 106 4282. NATURAL PRODUCT REPORTS 1988-G. FISCHER 495 434 IUPAC-IUB Joint Commission on Biochemical Nomenclature 462 R. J. Workman and D. W. Burkitt Arch. Biochem. Biophys. ‘Nomenclature and Symbolism for Amino Acids and Peptides’ 1979 194 157. Arch. Biochem. Biophys. 1984 229 339 and Eur. J. Biochem. 463 J.-A.Fehrentz A. Heitz B. Castro C. Cazaubon and D. Nisato 1984 138 9. See Recommendations 3AA-19.7 and 3AA-22.8. FEBS Lett. 1984 167 273. 435 M. G. Bock R. M. DiPardo B. E. Evans K. E. Rittle J. S. 464 T Y. Lin and H. R. Williams J. Bid. Chem. 1979 254 11 875. Boger R. M. Freidinger and D. F. Veber J. Chem. Soc. Chem. 465 N. S. Agarwal and D. H. Rich J. Med. Chem. 1986 29 2519. Commun. 1985 109. 466 J. Pohl M. Zaoral A. Jindra Jr. and V. Kostka Anal. Biochem. 436 J. Boger in ‘Aspartic Proteinases and their Inhibitors’ ed. V. 1984 139 265. Kostka de Gruyter Berlin 1985 p. 401. 467 Z. Kucerova J. Pohl and L. Korbova J. Chromatogr. 1986,376 437 D. H. Rich M. S. Bernatowicz N. S. Agarwal M. Kawai F. G. 409. Salituro and P. G. Schmidt Biochemistry 1985 24 3165.468 M. A. Ondetti and D. W. Cushman J. Med. Chem. 1981 24 438 F. G. Salituro N. Agarwal T. Hofmann and D. H. Rich J. 355. Med. Chem. 1987 30 286. 469 K. G. Hofbauer and J. M. Wood Trends Pharmacol. Sci. 1985,6 439 J. Boger L. S. Payne D. S. Perlow N. S. Lohr M. Poe E. H. 173. Blaine E. H. Ulm T. W. Schorn B. I. LaMont T.-Y. Lin M. 470 R. E. Evans K. E. Rittle M. G. Bock C. D. Bennett R. M. Kawai D. H. Rich and D. F. Veber J. Med. Chem. 1985 28 DiPardo J Boger M. Poe E. H. Ulm B. I. LaMont E. H. 1779. Blaine G. M. Fanelli I. I. Stabilito and D. F. Veber J. Med. 440 S. Thaisrivongs D. T. Pals W. M. Kati S. R. Turner and L. Chem. 1985 28 1756. M. Thomasco J. Med. Chem. 1985 28 1553. 47 1 R. Guigan J. Diaz C. Cazaubon M. Beaumont C. Carlet J. 44 1 R. J. Arrowsmith K.Carter J. G. Dann D. E. Davies C. J. Clement H. Demarne M. Mellet J.-P. Richaud D. Segondy Harris J. A. Morton P. Lister J. A. Robinson and D. J. Wil-M. Vedel J.-P. Gagnol R. Roncucci B. Castro P. Corvol G. liams J. Chem. Soc. Chem. Commun. 1986 755. Evin and B. P. Roques J. Med. Chem. 1986 29 1152. 442 J. G. Dann D. K. Stammers C. J. Harris R. J. Arrowsmith D. 472 S. Thaisrivongs D. T. Pals J. A. Lawson S. R. Turner and D. E. Davies G. W. Hardy and J. A. Morton Biochem. Biophys. W. Harris J. Med. Chem. 1987 30 536. Res. Commun. 1986 134 71. 473 J. Boger Annu. Rep. Med. Chem. 1985 20 257. 443 J. R. Luly J. J. Plattner H. Stein N. Yi J. Soderquist P. A. 474 T. L. Blundell B. L. Sibanda A. Hemmings S. F. Foundling I. Marcotte H. D. Kleinert and T. J. Perun Biochem.Biophys. Res. J. Tickle L. H. Pearl and S. P. Wood Top. Mol. Pharmacol. Commun. 1987 143 44. 1986 3 323. 444 D. H. Rich A. S. Bopari and M. S. Bernatowicz Biochem. Bio- 475 M. Szelke D. M. Jones B. Atrash A. Hallett and B. Leckie in phys. Res. Commun. 1982 104 1127. ‘Peptides Structure and Function; Proceedings of Eighth Ameri- 445 J. F. Dellaria Jr.. and R. G. Maki Tetrahedron Lett. 1986 27 can Peptide Symposium’ ed. V. J. Hruby and D. H. Rich Pierce 2337. Chemical Co. Rockford Illinois 1983 p. 579. 446 G. J. Hanson J. S. Baran T. Lindberg G. M. Walsh S. E. 476 J. Boger C. D. Bennett L. S. Payne E. H. Ulm E. H. Blaine Papaioannou M. Babler S. E. Bittner P.-C. Yang and M. D. C. F. Homnick T. W. Schorn B. I. LaMont and D. F. Veber Corobbo Biochem. Biophys.Res. Commun. 1985 132 155. Regul. Pept. 1985 54 8. 447 S. Thaisrivongs D. T. Pals L. T. Kroll S. R. Turner and F.-S. 477 R. G. Almquist C. Jennings-White W.-R. Chao T. Steeger K. Han J. Med. Chem. 1987 30 976. Wheeler J. Rogers and C. Mitoma J. Med. Chem. 1985 28 448 D. F. Veber M. G. Bock S. F. Brady E. H. Ulm D. W. Coch- 1062. ran G. M. Smith B. I. LaMont R. M. DiPardo M. Poe R. M. 478 S. Papaioannou D. Hansen Jr. M. Babler D.-C. Yang S. Freidinger B. E. Evans and J. Boger Biochem. Soc. Trans. 1984 Bittner A. Miller and M. Clare Clin. Exp. Theor. Pract. 1985 12 956. A7 1243. 449 M. N. G. James A. Sielecki and T. Hofmann in ‘Aspartic Pro- 479 R. Matsueda Y.Yabe H. Kogen S. Higashida H. Koike Y. teinases and their Inhibitors’ ed. V. Kostka de Gruyter Berlin Iijima T.Kokubu K. Hiwada E. Murakami and Y. Imamura 1985 p. 163. Chem. Lett. 1985 1041. 450 S. Thaisrivongs D. T. Pals W. M. Kati S. R. Turner L. M. 480 T. Kokubu K. Hiwada A. Nagae E. Murakami Y. Morisawa Thomasco and W. Watt J. Med. Chem. 1986 29 2080. Y. Yabe H. Koike and Y. Iijima Hypertension 1986 8 I. 45 1 M. N. G. James and A. Sielecki Biochemistry 1985 24 3701. 48 1 T. Satoh M. Muramatu Y. Ooi H. Miyataka T. Nakajima and 452 S. Thaisrivongs D. T. Pals D. W. Harris W. M. Kati and S. R. H. Umeyama Chem Pharm. Bull. 1985 33 647. Turner J. Med. Chem. 1986 29 2088. 482 A. Morigawa K. Kitabatake Y. Fujimoto and N. Ikekawa 453 P. G. Schmidt M. W. Holladay F. G. Salituro and D. H. Rich Chem. Pharm. Bull. 1986 34,3025. Biochem. Biouhvs. Res. Commun.. 1985 129.597. 483 S. Klutchko C. J. Blankley R. W. Fleming J. M. Minkley A. E. 454 P. A. Bartletf and W. S. Johnson Tetrahedron Lett. 1970 4459. Werner I. Nordin A. Holmes M. Hoefle L. Milton D. M. 455 M. Szelke B. Leckie A. Hallett D. M. Jones J. Sueiras B. Cohen A. D. Essenburg and H. D. Kaplan J. Med. Chem. 1986 Atrash and A. F. Lever Nature (London) 1982 299 555. 29 1953. 456 M. W. Holladay F. G. Salituro and D. H. Rich J. Med. Chem. 484 K. Itoh M. Kori Y. Inada K. Nishikawa Y. Kawamatsu and 1987 30 374. H. Sugihara Chem. Pharm. Bull. 1986 34,1128. 457 M. W. Holladay F. G. Salituro P. G. Schmidt and D. H. Rich 485 W. E. Siems G. Heder K. D. Jentzsch U. Burkhardt S. Johne Biochem. SOC. Trans. 1985 13 1046. H. Kuelimstedt K. Kotte I. Wunderlich and P. Oehme Experi-458 J.Boger N. S. Lohr E. H. Ulm M. Poe E. H. Blaine G. M. entia 1986 42 141. Fanelli T.-Y. Lin L. S. Payne T. W. Schorn B. I. Lamont T. C. 486 R. A. Snyder and B. U. Wintroub Biochim. Biophys. Acta 1986 Vassil I. I. Stabilito D. F. Veber D. H. Rich and A. S. Bopari 871 1. Nature (London) 1983 303 81. 487 W. M. Moore and C. A. Spilburg Biochem. Biophys. Res. Com- .. 459 M. Tree J. J. Brown B. J. Leckie A. F. Lever P. Manhem J. J. mun. 1986 136 390. Morton J. I. S. Robertson M. Szelke and D. Webb Biochem. 488 L. Toll and R. Almquist Biochem. Biophys. Res. Commun. 1986 SOC.Trans. 1984 12 948. 135 770. 460 B. J. Leckie M. Szelke B. Atrash S. R. Beattie A. Hallett D. 489 L. H. Pearl and W. R. Taylor Nature (London) 1987 329 351. M. Jones G. D. McIntyre J.Sueiras and D. J. Webb Biochem. 490 S. I. Foundling J. Cooper F. E. Watson A. Cleasby L. H. SOC.Trans. 1985 13 1029. Pearl B. L. Sibanda A. Hemmings S. P. Wood T. L. Blundell 461 J. J. Plattner J. Greer A. K. L. Fung H. Stein H. D. Kleinert M. J. Valler C. G.Noray J. Kay J. Boger B. M. Dunn B. J. H. L. Sham J. R. Smital and T. J. Perun Biochem. Biophys. Res. Leckie D. M. Jones B. Atrash A. Hallett and M. Szelke Nature Commun. 1986 139 982. (London) 1987 327 349.

ISSN:0265-0568    

DOI:10.1039/NP9880500465

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Natural Sesquiterpenoids B. M.Fraga lnstituto de Productos Naturales Organicos CSlC La Laguna 38206-Tenerife Canary Islands Spain Reviewing the literature published during 1986 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 473) 1 Farnesane 2 Mono-and Bi-cyclofarnesanes 3 Bisabolane 4 Cuparane Laurane Herbertane and Trichothecane 5 Chamigrane 6 Carotane and Cedrane 7 Cadinane 8 Longipinane 9 Caryophyllane and Related Compounds 10 Humulane and Related Compounds 11 Germacrane 12 Elemane 13 Eudesmane Ac R2 = H 14 Vetispirane (4)R' 15 Eremophilane (5) R'=R2 =H 16 Guaiane and Related Compounds (6) R1 = H R2=Ac 17 Aromadendrane and Bicyclogerrnacrane 18 Miscellaneous Sesquiterpenoids 19 References 1 Farnesane The structures of six new nerolidol derivatives (1)-(6) isolated from Santolina oblongifolia have been determined.' Another two novel derivatives of this type (7) and (8) have been isolated from Artemisia santolinifolia.2 A new sesquiterpene 9-acetoxynerolidol (9) has been obtained from the aerial parts of Phrodus bridge~ii.~ An unusual peroxynerolidol derivative fercoperol (lo) has been found in Ferula communis subsp.communis.* Several new sesquiterpene oligoglycosides derived 4. from (I 1) and (12) and named mukurosides have been isolated from the pericarps of Sapindus mukur0ssi.j 2 Mono- and Bi-cyclofarnesanes A new sesquiterpenoid apotrisporin E (13) has been obtained from Phycomyces blakesleeanus and Blakeslea trispora these two species being members of the Mucorales.6 Feeding (+)-/OH abscisic acid to the leaves of Xanthium strumarium gave the 7'- hydroxy-derivative of the (-)-(R)-enantiomer of abscisic acid.' The 1',4-trans-diol of abscisic acid is a possible precursor of abscisic acid (14) in Botrytis cinerea.' The structures of OH (4Y drummondones A and B have been shown to be (1 5) and (16) ; these two new compounds which have a bicyclo[2.2.2]octane ring system have been isolated from the seeds of Sesbania drummondii and appear to be two catabolites of abscisic acid.8 0 (13) (14) (15) R' = C(O)Me R2 = H (16) R' = H R2 = C(0)Me 497 NATURAL PRODUCT REPORTS 1988 Ac0& (17) (18) R = p-coumaroyl (19) R = p-coumaroyl (20) R' = OH R2 H2 (21) R'= H R2 0 CO-H R (22) R' OH R2 = Me (24) R = H (26) R = H (23)R' =Me R2 = OH (25) R = CI (27) R =OH 0 -0Ang (28) (29) R3 The novel sesquiterpene (-)-3P-acetoxydrimenin (17) and the known ones safrol drimenol and polygodial have been isolated from Drimys winteri.lo Another member of this genus D.brasiliensis contains the two new drimane derivatives (18) PCHO OOH (42) R =Val' and (19)." The structures (20) and (21) of two antibiotics pereniporins A and B which have been isolated from the basidiomycete Perenniporia medullaepanis have been eluci- dated." The absolute configurations of the drimenols (22) and (23) have been determined by synthesis of their enantiomers. l3 The culture filtrates of the fungus Phoma asparagi contain the phytotoxins altiloxin A (24) and altiloxin B (25) whose absolute configurations have now been determined.'l Dictyo-ceratins A (26) and B (27) are two novel antimicrobial sesquiterpenoids that contain a hydroquinone moiety.They have been obtained from an Okinawan marine sponge of the genus Hippospongia.l5 A new sesquiterpenoid coumarin ether has been isolated from the roots of Ferula sinaica.'6 3 Bisabolane Two new bisabolene sesquiterpenes (28) and (29) have been isolated from the roots of Stevia amamb~yensis'~ and another two compounds of this type (30) and (31) have been obtained from Gochnatia po/ymorpha.'* The structure of a bisabolene derivative (32) isolated from Artemisia stelleriana has been NATURAL PRODUCT REPORTS 1988-B.M. FRAGA 0Lo0 0 499 RO 15 RO 15 0 0 (48) R = Val’ (43) R =Val’ (45) R = Tig (49) R = Val’; 7,lO-epi (44) R =Tig (46) R =Val’ (50) R = Tig; 7,lO-epi (47) R = Vai’; 10d-H Scheme 1 (51) (52) (53) *.,* NC (54) R = NH2 (58)R NH2 (61) (55)R =NH3CI (59)R = -NCO (56) R =NHC(O)NHR (60)R = -NC (57) R -NCS R R (62) (63) elucidated.l9 The Argentinian species Senecio pampeanus contains twelve new bisabolane sesquiterpenes [(33)-(44)] and six compounds with a novel carbon skeleton [(45)-(50)] probably derived from (43) or (44) (see Scheme 1).20 The endoperoxide (51) has been obtained from an Egyptian member of the Compositae Senecio desfontainei.21 The structure of perezone (52) has been confirmed by X-ray analy- skZ2 The absolute configuration of (+)-hernandulcin (53) which is a sesquiterpene with an intensely sweet taste has been determined by synthesis of the four possible isomers starting from the enantiomers of limonene.Only the stereoisomers corresponding to the naturally occurring compound show sweet proper tie^.^^ The nitrogenous bisabolane sesquiterpenes [(54)-(57)] have been isolated from a species of marine sponge of the genus Halichondria that was collected in the Marshall Islands.24 Three other compounds of this type but epimeric at the nitrogen-bearing carbon C-7 [(58)-(60)] have been OH (66) R =OH (64)R (65)R = OAC (67)R = OAC obtained from a sponge of the genus Ciocalypta; this species was previously believed to belong to Hymeniacidon.” The sesquiterpene (61) was found in a species of nudibranch of the genus Phyllidia.2s 4 Cuparane Laurane Herbertane and Trichothecane The full paper of the structure of isoaplysin (62) (a brominated sesquiterpene that has been obtained from the red alga Laurencia okamurai) has been published.26 Five new sesquiter- penes derived from cuparene and named cyclolaurene (63) cyclolaurenol (64) cyclolaurenol acetate (65).cupalaurenol (66) and cupalaurenol acetate (67) have been isolated from the sea hare Aplysia dactylomela.2’ A comparison of the sesquiterpenes from the seaweed Laurencia pacijica and its epiphyte Erythrocystis saccata has been carried out.28 The NATURAL PRODUCT REPORTS 1988 R yy5? HO OH (68) R = Me (70) (69) R = CHO HH (73) R’ = H R2 = a-OH (74) R’ OAc R2 a-OH (75)R’ = H R2 E 0-OH (76)R’ = OAc R2 O-OH (84)R’ (85)R’ (80)9,10 2’,3‘-tetradehydro; R = OH H (81) 9,lO-didehydro; 2’ 3’-epoxy; R =OH,H (82) 90 100-epoxy; 2’ 3’-epoxy; R =O (83) 9,lO-didehydro; 2‘ 3’-epoxy; R =o (87) (88) structures of several ent-herbertane sesquiterpenes (68)-(72) which display antifungal properties and which have been isolated from the liverwort Herberta adunca have been determined.29 Cane et have studied the biosynthesis of trichodiene and the stereochemistry of the enzymatic cyclization of 2-trans,6-trans-farnesyldiphosphate ; they used a prepara- tion of trichodiene synthetase that had been obtained from the fungus Trichothecium roseum.The seven new mycotoxins myrotoxins A B C and D [(73)+76)] and mytoxins A,B and C [(77)-(79)] have been isolated from a liquid culture of Myrothecium rorid~m.~’ Another four new macrocyclic tricho- thecenes roritoxins A-D [(80)-(83)] have been obtained (71) (72) A (86) = Ac R2 =H R3 = OH = R3 = H R2 = Val’ H voI ‘0*‘ (89) (90) from this The structure of the trichothecene (84) which was isolated from Fusarium roseum has been confirmed by X-ray-crystallographic analysis,33 and the minor metabolites of strain ATCC-28114of this fungus have also been ~tudied.~’ Two new trichothecene sesquiterpenes sporotrichiol (85) and sporol (86),have been obtained from Fusarium sporotrichi- oide~.~~ Three other novel mycotoxins (87)-(89) have also been isolated from this fungus,36 while desepoxy-diacetoxyscirpenol (90)has been obtained from a culture of Fusarium graminearum that had grown on a solid rice sub~trate.~’ The acid-catalysed rearrangement of 12,13-epoxytrichothec-9-enes has been NATURAL PRODUCT REPORTS 1988-B.M. FRAGA 501 0 "CI t+ R' (91) R1=H R2= Br (93) R = H Br (96) R =Br (92) R' = Br R2=H (94)R = OAc (95) (97) R =H (98) R = Ang (101) (1021 (99)R = AC (100)R = p-C(0)C6H40Me HO& dR2 (103) R' :R2 =Ang R3 =OAc (107) (108)R = Ang (104) R' Ac R2 = Ang R3 =OAng (105) R' = Ang R2= p-C(O)C,H,OH R3= H (106) R' = R2 IAng R3= H 5 Chamigrane The structures and absolute configurations of four new halogenated chamigranes [(9 1)-(94)] from the sea hare Aplysia dactylomela have been determined.3Q Attached-proton- test spectra that had been acquired with residual coupling (RECAPT) have been used in the assignment of the 13C n.m.r.signals of the chamigrane epoxide (95).40The chami- grane sesquiterpenes (96) and (97) their enantiomers and their racemates have been synthesized by cyclization of the corres- ponding stereoisomers of y-bisabolane derivative^.^^ 6 Carotane and Cedrane Some time ago the carotane sesquiterpene vaginatin was isolated from Selinum vaginat~rn~~ and assigned the structure (98) without the stereochemistry ;later a similar structure but with a trans-junction of the bicyclic system was assigned to a compound that was isolated from Inula crithmoide~.~~ More recently a similar erroneous structure was assigned to an acetate that had been obtained from Sium latij~gum,~~ and finally American and Italian authors have separately proposed the correct stereostructure of vaginatin and that of an acetyl derivative as (98) and (99) respe~tively.~~.~~ The structure of the latter sesquiterpene was previously reported correctly as a component of Sium latifoli~rn.~~ Members of the Italian group46 have isolated vaginatin from the ripe fruits of Laserpitium halleri subsp.halleri. Two new carotane derivatives fercolide (100) and fercomin (IOl) have been isolated from Ferula communis subsp. cornrnuni~.~~ Four new carotane esters (109) R Epang H0& (112) R' H ~2= Val' (115) (113) R' ::OH R2 = Val' (114) R' =OH R2 = Ang [(102)+105)] have been obtained from the roots of Ferula tingita~za.~'The structure and stereochemistry of pallinin (a sesquiterpene that has been obtained from Ferula pallida) have been shown to be (106).49Ferula linkii is an endemic species of the Canary Islands and it is very rich in carotane sesquiterpenes.Nine new compounds of this type [(107)+115)] have now been NATURAL PRODUCT REPORTS 1988 R' ,-.. o Od HI H H A (116) (118) R = Ang (121) R' =Me R2 =O (119) R = Mebu (122) R' = COZH R2= H2 (120) R = C(0)Prl ,OAc dH \ ;rl A (1 2 5) II H! .q .' \ 0 (128) (129) isolated from this plant.jO,jl Renecraviotonic acid (1 16) which is a derivative of a-cedrene was found in the aerial parts of Isocoma coronopijolia.j2 The assigment of the 13Cn.m.r.spectra of several cedrene derivatives has been carried 7 Cadinane The aerial parts of Chromolaena arnottiana contain the cadinane sesquiterpene (1 17).j4 Another five compounds of this type (1 18)-( 122) have been isolated from specimens of Heterotheca grandiJora that had been collected in Hawaii ; there are phytochemical differences between these plants and specimens of the same species from Arizona.55 The structures of three new cadinane sesquiterpenes obtained from Australian soft corals of the genus Xenia have been shown to be (123)-(125).j6 The structure and the absolute configuration of (-)-isozingiberene have been defined by an X-ray analysis of its dihydrochloride (126).57 Several derivatives of the cadinanolide (127) have been obtained from Vern~niajalcana.~~ Another derivative of (127) vernojalconalide 8-O-methacrylate has been isolated from Vernonia morelana ; this compound was also obtained when glaucolide A was passed through silica gel indicating that the cadinanolide sesquiterpene lactones are artefacts rather than natural products.jg Arteannuin C (128) is a new sesquiterpene lactone that has been found in the aerial parts of Artemisia annua.60 Artemisinin has been produced in tissue cultures of Artemisia annua,61 and the possible role of quinghao acid in the biosynthesis of artemisinin has been studied.62 Curzeone (1 29) is a novel furanocadinane sesquiterpene which has been isolated from the crude drug zedoary (the dried rhizomes of Curcuma (126) (127)R =various q [Mebu = &] HO (131) zedo~ria).~~ Chilled radicles of cotton (Gossypium arboreum) biosynthesized gossypol from 2-cis,6-trans-farnesyl diphos-phate (or an equivalent such as nerolidyl diphosphate) and not from 2-cis,6-cis-farnesyl diphosphate as had previously been Three minor nitrogenous sesquiterpenes (1 30) have been obtained from the marine sponge Axinella cannabina and their structures determined from spectral data.65 A cubebol derivative related to one that had been obtained from Osteospermum auriculatum (see Nut.Prod. Rep. 1985 2 150) has been found in Aster tanacetijolius.66 8 Longipinane The conformation and the absolute configuration of naturally occurring longipinene derivatives that have been found in species of Stevia Critonia Polypteris and Artemisia have been shown to be the same as those of (+)-l~ngipinene.~~ The longipinane sesquiterpene (1 3 1) has been isolated from Stevia achalensis.68 NATURAL PRODUCT REPORTS 1988-B.M. FRAGA (;”. ”.;;)(c ,-C0,H 0 (132) (133)R = CH3 (135) (136) (134)R = CH20H l&$) 9H02CgH Ho2c.H H02C@H OH OH I 0’ R I (137) (138) R = d-OH (140) (141) (142) R =O %-OH H (139)R = O-OH (143) R (145)R’=H R2= O-OH (144) (146) R’ H R2 LX-OH (147) R’ = OH R2 = =-OH OH R’ 0 UOMe HO (148)R = CHO (150) R = H (152) R’ = O-H R2 = H (149)R = CH20H (151) R = CI (153) RT = OH R2 H 9 Caryophyllane and Related Compounds A caryophyllenic acid (132) has been isolated from Austro-brickellia patens.69 The structures of naematolin (133) and naematolin B (134) which are two sesquiterpenes with a (1S,9s) ring-fused caryophyllane skeleton have been deter- mined by spectroscopic methods ; these two compounds have been isolated from the fungus Naernatolorna fasciculare and both are the first case of a 1-epi-caryophyllane skeleton in Nature.’O Four caryophyllane derivatives have been identified in the high-boiling constituents of clove oil (from Eugenia caryophyllata) and hop oil (from Hurnulus lupulus).” A new isocomene derivative (135) has been obtained from Helichrysum nudifoliurn var.nudifoliurn (a species from South Africa).’* The absolute configuration of terrecyclic acid has been determined from the circular dichroism spectrum of the derivative (1 36).73 The biosynthesis of quadrone and terrecyclic acid in cultures of Aspergillus ferreus has been ~tudied.’~ Punctatins D (137) E (138) and F (1 39) are three antibiotics that have been obtained from Poronia punctata (a fungus isolated from horse dung) ;75 these compounds must be renamed punctaporonins D E and F (see Nat. Prod. Rep. 1986,3,278). Cantabradienic acid (140) (154) R’ = OH R2 I CI epoxycantabronic acid (141) cantabranonic acid (142) and cantabrenolic acid (143) are four new sesquiterpenes with a silphiperfolane skeleton which have been isolated from Artemisia cantabrica; this member of the Compositae is endemic to northern Spain.76 10 Humulane and Related Compounds The crystal and the molecular structure of the humulane sesquiterpene fexerol (144) have been determined by X-ray analysis; this compound was isolated some time ago from Ferula ts~hatkalensis.’~ Leptographiol (145) isoleptographiol (146) and isoafricanol (147) are three novel sesquiterpenes with the africanane skeleton that have been isolated from Leptographiurn lundbergii.’8 The four new sesquiterpene esters melledonal (148) melledonol (149) armillyl everninate (1 50) and arnamiol(15 1) have been obtained by Donnelly et al.from the culture broth of Arrnillaria rnellea ; this basidiomycete is known to produce chemical defensive metabolites that possess antibacterial acti~ity.’~.*~ Another three novel compounds [(l52)-( 154)] with the same protoilludane skeleton have been NATURAL PRODUCT REPORTS 1988 R- I I - H I OAng R (158) R =Ang (160) (155) (156) R = H (159) R = H (157) R = OH OAc OH (161) R’ O-OH H; R2 = OAng (162)R’=0; R2=OAng (167) (163) R’ = O-OAc H; R2 = OAng (164)R’ = O-OAc H; R2= H R‘.. m R 3 Montafrusin B (173) Deocetylargentiolide B (174) (168) R’ R2 =H R3 = 0 (169) R’ =OH R2=H R3=OC(0)Pr1 (170) R’ = H R2 = OAC R3 = 0 %O Ac HO (171) R’ = R3=H R2 =OGlc (172) R’ = H R2 = OH R3 = 0 AcO obtained by an Italian group from the same species.81 The sesquiterpene protoillud-6-ene (1 55) was the major volatile metabolite that could be obtained from the ascomycete Ceratocystis piceae.82 The structure of capnell-9( 12)-ene- 8cr,lOP-diol (156) has been determined by X-ray analysis; this compound has been isolated from a soft coral that was collected in the South China Sea.83 A new tricyclic sesquiterpene alcohol (1 57) with a capnellene skeleton has been found in the Chinese soft coral Capnella imbricata.84 11 Germacrane Three new germacrane esters i.e.the tovarol derivatives (158) and (1 59) and the shiromodiol derivative (160) have been isolated from Thapsia villosa var. minor.a5The structures of shiromodiol 8-O-angelate (161) and the corresponding 6-ketone (162) have been determined by X-ray analysis.86 The compound (161) and its acetate (163) have been obtained from Laserpitium halleri subsp.halleri.40A new germacrane sesquiter- pene (164) has been isolated from Sideritis varoi subsp. cuatrecasasii and subjected to several biomimetic cyclizations which led to ~is-guaianes.~’ The sesquiterpene 13-hydroxy- Q0 ‘0 (175) R = CH,OGlc Epitulipinolide derivative (176) R = CO,H (177) R%o; 0 Epitulipinolide derivatives (178)R = H or Ac; A4 (’) (179)R = H; A3(4) germacrone has been obtained from Curcuma ~edoaria.~~ Versicolactone B is a new sesquiterpene lactone that has been isolated from Aristolochia versicolor.88 The structure of acetyl- versicolactone (165) (also isolated from this species) has been determined by X-ray analy~is.~’ The molecular structure of tschimganidin has also been resolved by X-ray analysis.a0 Two sesquiterpene glycosides derived from the alcohol (l66) have been isolated from Machaeranthera pulverulata.66 Helmintho-germacrene (1 67) is a major component in the defensive secretion of the termite Amitermes ~heeleri.~~ Many new germacrane lactones have been obtained from natural sources during 1986.The structures (168)-(190) and NATURAL PRODUCT REPORTS 1988-B. M. FRAGA 505 Table 1 Sources of germacrane lactones Source Germacranolides Source Germacranolides Anvillea garcini" Artemisia argenteas3 Artemisia fragrans" Austroliabum candidumg5 Bartlettina karwinskianas6 (192) (193) (174) (183)(24 I)-(244) (177)-( 179) Vernoniu cinerea"" Vernonia cotoneaster" Vernonia erdverbengii"' Vernonia jalcanasR Vernonia murginatd2' Bejaranoa balansae" Blainvillea latifolia9R Calea jamaicensiss9 Vernonia patensSR Vernonia poskenna'" Vicoa indicdY3 Calea leptocephulaLoq Viguiera deltoideu'" Centaurea coronopifolia"' Centratherum punctatum'u2 Source Cotula cineredU3 Cr it oniopsis hua ir cajana '" Bejaranoa balansaeg' Calea leptocephaln'Ou Decachaeta ovaiifolia'06 Calea jamaicen,sisRs Elephantopus carolianus"'6 Eupatorium altissimum'O' Calea rupicola"g Chaenactis douglasii'3" Eupatorium fortunei'" Gochnatia ,foliosa var.foli~sa'~~~~'~ Gochnaiia h?;poleuca" Helianthus argophyllus"' Eupatorium alti.rsimuml'" Heliunthus heterophyllus131 Helogyne hutchisonii"3 lsocarpu oppositifolia var. uchvran thes "" Helianthus niveus subsp.Tanaceturn santolinoides'"3 Helianthus resinosus"' Helogyne huichisonii"3 Lactuca sativa'14 canescens'l' Viguiera deltoidea' " Viguiera gillie.yii'3' Source Laser ~rilohum"~ Montanoa .frutescens116 Montanoa leucantha subsp. Neohintonia n~onaniha"s Onopordon carmanicum"B leucantha"7 Acanthospermum hispidurn lS6 Lactuca laciniata'"' Lactuca sativa' Stevia urnambayensis" Urospermum dulechanipii"G Picris hieracioides var. Source japonica12u Pseudoelephantopus spicatuss8 Stevia amambayen,sis'' Acanthospermum hispidum'36 Stevia amambayensis1' (180) R = 0-0 iL (182) R = =-Me 0 Shonachalin C (183)R = 0 -Me (184) R' = C OH ,R =H (181) R = a-OMeacr (1851R' = Mebu R2 =OH R' (186) R'=H R2 = various (187) R'=OH R2 = Epang 506 NATURAL PRODUCT REPORTS.1988 k-q= OH HO-J’QypoH 0 0 (191) R = &-OH (192) R = -OH (1931 Argophyllin C (194) Onopordopicrin derivative (195) qoR qoR2 0 I 0 (196) R = H (198) R’ = Tig R2 = H (200) R =Tig (202) (197) R AC (199) R’ = R2 =Ac (201) R =Meacr AcOmoH @oAc 0 0 (203) (204)R’=R2= H (206) R =H (208) Leucanthanolide (205)R’ =OH R2 =OC(O)Pr’ (207) R :Ac 0 0 qoAc 0 ‘0 qoAc 0 (209) (210) (211) R = Ac (212) R = Ang (2.13) R C(0)Prl (214) R = C 0 &+OR [Meacr = +] POA 0 c (215) R = Meacr (217) (216) R = Ang NATURAL PRODUCT REPORTS 1988-B. M. FRAGA I '0 (220) o%o 2 4 (226)R' :Ac R =Ang R3 0-Me R =H (227) R' = Ac R2 Ang R3 = a-Me R4=OH (228)R'=H,R2=Ac R3= O-Me,R4=OH (229)R'=Ac,R2 z various R3=a-Me R4=0H (230) R' = Ac R2 = various R3= 0-Me R4 = OH 0 (232) R = H or Ac 0 (235) R = various (192)-(246) represent the new germacranolides whilst the structures (248)-(268) have been assigned to the heliangolides (270)-(274) to the melampolides and (275) and (276) to the cis cis-germacranolides [see Table I].There are several points to note in relation to these lactones. The full paper with the structure of 8-deacetyl-laserolide (236) has been published ;l15 0 AcO. (221) (224) R = Ang (225) R = Meacr Me02C OH Poskeanolide (231) (233) W O A n g 0 (236) this compound was isolated from Laser trilobum (see Nut. Prod. Rep. 1986 3 285). The structures of Iaserolide'*j (see Nut.Prod. Rep. 1986 3 284) spiciformin acetate and tatridin B dibenzoatelz6 have been determined by X-ray diffraction analysis. The conformations of germacra-1(10),4-dien-6,12-olides and 412-olides have been studied and the crystal 508 NATURAL PRODUCT REPORTS 1988 woHOm0Wob0 I OH OR’ I OH I 6H \ OH (237) R =Meacr (240)R’:Ac. R2=Ang (238) R =Tig (or reverse) (239) R = C(O)Pr OEpang \ AcOl‘ R OH OH (243)R = CH2 (245) Vicolide 0 (246) (244)R = =-Me H fR1 ‘”:?-0 R”-b\ -.. 0 (247) H0mR 0 \ 0 Douglasine (258) (259)R1=H R2=Mebu (262) R = Mebu or Tig (260)R’=H R2= Tig (26l)R’=OH. R2 = Mebu 0 0 (263) R’ =OH R2 OH (266) (264) R’ =H. R2=OH (265) R’ =OH R2 = H NATURAL PRODUCT REPORTS 1988-B.M. FRAGA CHO A R3 R' U 0 (270)R = H or Glc (OH (OH CHO 0 >-?- HO 0 OAc (274) (275) (276) 0 (277) (278)R =CH2 or a-Me H (279) structure of (245) has been determined by X-ray analysis.127 The molecular structure of the diacetate of crispolide has also been resolved by this diffraction technique;lZ8 crispolide (247) which is a 4,14-cyclogermacranolide was isolated from Tanacetum vulgare (see Nut. Prod. Rep. 1984 1 146 and 148). The myrtenyl-substituted sesquiterpene lactone (269) has been obtained from Calea rupi~ola.'~~ The lactone 17,18-dihy-drobudlein A which was isolated from Helianthus debilis var. cucumerifolius showed antimicrobial insecticidal and plant- growth-inhibiting activity.The chemotaxonomy of the genus Helianthus is also discussed in these The molecular structure of montafrusin A has been confirmed by X-ray analysis."' The configuration at C-4 in some germacrane lactones has been re-investigated. Nuclear Overhauser effect difference spectroscopy showed that the configuration must be revised to 4/3-methy110z in compounds which were isolated from Alcantara ekmani~na,~~~ Eremanthus bicolor,'40 E. croton-oides,141 E. glomeratus,141*142 P. lepto- Piptolepis eric~ides,'~~ spermoides,la4 Lychnophora crispa,14b and L.blanchetii.145More-over the configuration at C-4 of the 4 5-dihydrofuro- heliangolides from Trichogoniopsis species has also been revised to 4/3-methyl. It may be that in these compounds the configuration at this centre is always the same.97 The formula of a lactone which was obtained from Matricaria suffr~ticosa'~~ and initially thought to be the acetate of (192) has had to be revised to the acetate of (191) (5a-a~etoxyparthenolide).~~ The n.m.r.data showed that in the lactones (224) and (225) the configuration of the 5-6 double-bond was E.js This requires a change in the configuration that had been assigned to this double-bond is some lactones which were isolated previously from Vernonia compacti~4ora.'~' The structure of (227) has been determined by X-ray analysis and as a result of this work CQY OAc (280) (281) the authorsbs have proposed a revision of the configuration of several lactones that had been reported previously as components of species of the genera Stilpnopappu~,'~~ Ver-n~nia,'~~, 14Q,1b0 Chresta,151 Stokesia,'j2 and Pipt~carpha."~ 12 Elemane The aerial parts of Onopordon carmanicum contain the elemane sesquiterpene elemacarmanin (277).lg9 The two novel elemanol- ides (278) and its 11,13-dihydro-derivative have been obtained from Stevia achalensis.68 Another new lactone (279) has been isolated from Centratherum punctatum.102 The full paper in which the revised structure of isolaserolide is described (see Nut.Prod. Rep. 1986 3 284) has been published.125 13 Eudesmane The eudesmane sesquiterpene (280) has been found in the roots of Senecio bracteolatus,20 while the alcohol (28 1) has been obtained from Sideritis varoi subsp. oriensis.lS4 The liverwort Lepidozia reptans contains the new sesquiterpene eudesm-3- NATURAL PRODUCT REPORTS 1988 q& c^fcx/ OH R3 HO'* HO-0 H 0 & R4ByOH (284)R' = OH R2 = R3= H (287) R =H (289) (285)R' = R3 =H R2 =OH (288) R =OH (286) R' = R~ =H R~ = OH p..f 0 0 (2901 (291) (292) wo I (293) (294) (295) (296) R =H (297) R =OAc Qh OH I HO' (298) (300) (301) (299)3,4-didehydro Ho..Q OH OH Ac OH (302)R' = Ac; R2= I3 -OAc H; R3 E a-OAc,H (307) R =H (303)R' = H; R2 = 0-OH H; R3 = d-OAc H (308) R =OH (304)R' = Ac; R2= 0; R3 = a-OAc H (305)R' Ac; R2 = 13-OH H; R3 a-OAc H (306)R' = H;R2 = O-C(O)Ph H; R3 0-OAc,H NATURAL PRODUCT REPORTS 1988-B.M. FRAGA 51 1 AcO 0 Q--0 00 H 0 q 0* 0 (310) Artegallin (311) (312) OH p+ q; 0 0 (313)R' H2; R2 = OAC (319) R = Meacr (322) (314)R' = =-OH H; R2 :OAc (320)R = C(0)Pr' (315)R' d-OH,H; R2 =Meacr (321)R = AC (316)R' = a-OH H; Rz =C(O)Pf' (317)R' = 0; R2 = Meacr (318)R' = 0;R2 = C(0)Pri OH 3:I;?b *.10 ' 0 lxerin W (323) (326)R =CHZ (327) R = 0 -Me H ene-6P,7n-diol (282).lb5 (+)-Coralloidin A (283) is a novel diene that has been isolated from the Mediterranean alcyon- Table 2 Sources of eudesmanolides acean Alcyonium coralloides.'b6 The P-cyperone derivatives Source (284)-(286) have been obtained from Haplopappus free- Eudesmanolides rnontii.'ji The compounds 4-epi-cryptomeridiol (287) and Artemisia caerulescens var.cretacea' (341) selina-3P 4a 11-trio1 (288) have been isolated from Amanoa Artemisia caerulescens subsp. gallica'7a (311) ~blongijolia,'~~ while 4-epi-plucheinol (289) has been obtained Artemisia iwayomogi* (3 30)-(340) from Pluchea arg~ta.'~'The structure of vachanic acid has been Artemisia j~daica'~~ (3 12) confirmed by X-ray studies.lGO The sesquiterpene peroxides Bartlettina karwinskianag6 (322) Chamaemelum fuscatum''5 (315)-( 320) (290) and (291) have been found in the aerial parts of Zsocoma Decachaeta ~vatifolia'"~ (324) (325) coronopifoliab2 and Artemisia douglasiana,'61respectively. The Ixeris dentaia'76 (323) norsesquiterpene lactone (292) has been isolated from the roots Laser trilobum115 (329) of Senecio gilliesianus."j' The three eudesmane derivatives Mikania gu~co'~~ (313 (3141 (321) (293)-(295) have been obtained from the fruits of Smyrnium Sphaeranthus indic~s"~ (326)-(328) galati~um.'~~ The structures of tubipofuran and 15-acetoxy- Stevia achalensise8 (345)-(347) tubipofuran which have been found in the stolonifer Tanacetum partheni~m'~' (310) (342)-(344) Tubipora musica have been shown to be (296) and (297) Wedelia pinetorum180 respecti~ely.'~~ These compounds showed ichthyotoxicity to- wards the killifish Oryzias latipes and (297) showed cyto- toxicity against B-16 melanoma cells in vitro.The new sesquiterpenes baimuxinol (298) and dehydro- structure of ever-1 (309) has been resolved by X-ray analysis.'68 baimuxinol (299) have been isolated from the volatile oil of The novel sesquiterpene alkaloids canthothamine horridine Aquilaria sinensis.16j The polyhydroxyagarofuran derivatives and mayteine have been obtained from Acanthothamnus aphyl- (300) and (301) have been obtained from Mortonia hidalgen- Ius,'~' Maytenus horrida,liO and Maytenus guianensis,Ii1 respec- while the compounds (302)-(306) of the same type have tively.The structures of the three novel macrolide sesquiterpene S~S,'~~ been found in Rzedowskia tolant~nguensis.'~' These species alkaloids cathedulin-K19 cathedulin-K17 and cathedulin-belong to two Mexican genera of the Celastraceae. Seven new K20 which were obtained in very low yield from the aerial sesquiterpene esters have been isolated from Euonymus verru-parts of Catha edulis have been determined by spectroscopic cosus the compounds named ever-1 -4 -8 and -10 being method^."^ derivatives of 3,4-dideoxymaytol (307) and ever-2 -6 and -7 New eudesmanolides have been isolated from different species being derivatives of 3,4,12-trideoxyeuonyminol (308) ; the (see Table 2) and their structures shown to be (310)-(347).The NATURAL PRODUCT REPORTS 1988 ?H I! r 0 (328) (329) (330) (331)R'=OH R2=U-H (332)R' = H R2 = a-OH (333)R' =OH R2 CY -OH (334)R' =OH Rz= O -OH R (338)R = u-OH (339)R = 0-OH OH 0 HO" Po Ac0 OR' (340) (341) (342)R' = Tig; R2 =CH2 (345) (3431R' =Tig; R2 =@-Me H (344)R' Ang; R2 = IX-Me H I 0 0wo (346) (347) (348) R structure of 7a-hydroxycostunolide has been confirmed by X-ray analysis.lo5 The full paper with the structure of isolasolide (329) has been pub1ished;"j this compound was obtained from Laser trilobum (see Nut.Prod. Rep. 1986 3 286). Rudbecki- olide (348) is a new dimeric sesquiterpene lactone which has been obtained in low yield from Rudbeckiu laciniatu.'*' The chemical and microbiological transformation of (-)-n-san-tonin into 8-epi-artemisin has been carried out.'** The 'H and n.m.r. spectra of vulgarin and 4-epi-vulgarin have been (351) unambiguously assigned. The compounds barrelin and judaicin (349)R =OH (350) R =H were proved to be identical with vulgarin; this lactone was obtained from Artemisia rehan.ls3 that in the potato this compound is one of the intermediates between solavetivone (350) and lubimin (351) in the route to 14 Vetispirane rishitin.lB4 This last compound labelled with deuterium has Oxysolavetivone (349) is a new metabolite which has been been biosynthetically transformed in healthy potato tuber isolated from aged potato.Biosynthetic studies have shown tissue into rishitin M-2.ls5 NATURAL PRODUCT REPORTS 1988-B. M. FRAGA (353)R’ =H; R2 =O-OH H (3 5 6) (357) (358)R =Sen (354) R’ = H; R2 0 (359)R = Ang (360) (361) (362)R’ =various R2 = H (36L) R’ OAng R2 = H or OH R3= H2 (363)R’ and R2 Ivarious (365) R1= H R2 = various R3 =O pJ-& HOfJpo HOfJ& ..o 1 \ 0 \ OTig OR OR OR (366) (367) R = Ac or C(O)Pr’ (368)R =various (369)R = various b0 wo R2 (370) R1 = O-OH; R2 =O (375) R’ = O-OH R2=OAc R3 = o(-OH (371) R’ = cf-H; R2 = 0 (376) R’ = cf-OAng R2 = H R3 O -H O-H; R2 0 (372) R’ (373) R’ N-H; RZ = d-OAng H (374) R’ O-OH; R2 d-OAng H O..’H R2 CHO R2 \o OAc OR‘ R3 1 OR’ (381)R = cc -OH (383) R’ =various (377) R’ = Ac R2 = a-epoxide R3 d-Me (380) (382)R = 0 -OH R2 =a-orO-OH (378) R’ =Ac R2 O-epoxide R3 O-Me (379) R’ H R2 = a-epoxide R3 a-Me 15 Eremophilane The new eremophilane sesquiterpenes (352)-(354) have been isolated from Stevia achalensis.68A fungitoxic sesquiterpene CinnO cyclodebneyol(355) has been obtained from Nicotiana debneyi which had been inoculated with tobacco necrosis virus.ls6 Bohlmann et a/.*’ have investigated ten Argentinian species of (384) Senecio and have isolated the compounds (356)+36 I) the eremophilanes (362)-(367) the eremophilanolides (368)- (379) the diepoxide (380) the secoeremophilanolides (381)- (383) and the two rearranged eremophilanolides (384) and 20 NPR 5 514 NATURAL PRODUCT REPORTS 1988 OR ,@0 ,R2 RO' R1O* "P (385) (386)R =various (387)R = various (388) R' = various ~2 = H or OH OMe OMe Ang 0 R' OAc (389) (390) (391)R' =OH RZ =H R3 =CHO (392)R' = H R2= 0-various R3 =Me 0 0 R0' OR OR (393)R = various (394)R = Sen or Meacr (395)R = various 0 (396)R = !A''gHll R2R'-wo (397) R' =OH; R2 = H2 (398) R1 =H; R2= O-OH,H (399) R' :H; R2 = 0 HO OR (4011 (402) R =H or Ac (385).The acetate and tiglate esters at C-6 derived from (362) are identical with two esters previously isolated from Senecio jlaginoides for which a 6a-orientation was proposed (see Nut.Prod. Rep. 1985,2 156). Members of the same German school have investigated another twenty-three Senecio species ; they isolated the new eremophilane sesquiterpenes (386)-(396).'*' The lactones (397)-(399) have been obtained from Srevia a~halensis,~~ while (400) has been found in Senecio rosmarinus which grows in Chile.'** 16 Guaiane and Related Compounds The sesquiterpene (401) has been obtained from a marine sponge of the genus Halich~ndria.~~ The cycloshiromodiol derivative (402) has been found in Laserpitium halleri subsp. h~lleri~~ and the furoguaiane zedoarol (403) has been obtained from Curcuma zed~aria.'~ Pechueloic acid (404) and its 11,13- dihydro-derivative are two new guaiane sesquiterpenes which (400) (4031 (404) ($+ A H HO'.Oa OH (406)R = H OH (407)R = OH (405) (408)R = OAC have been found in Decachaeta ~cabrella.'~~ The biotrans- formation of the synthetic guaiane-6,12-diol (405) into the corresponding guaianolide has been studied. Although this diol promoted the formation of adventitious roots in cuttings of these plants it is probable that the true agent that promotes root formation is the guaianolide which was formed.lgO Three new guaiane derivatives (406)-(408) have been obtained from NATURAL PRODUCT REPORTS 1988-B. M. FRAGA Table 3 Sources of guaianolides Source Guaianolides Source Guaianolides '4egopordon ber~rioides'~~ Gaillurdia megapotamica var.scabiosoides (451) Artemisia douglusiana161 Helenium donianun~'~~ (4541 (455) Artemisia gmelinii2 Lactuca laciniata13' (4161 (4321 (433) Artemisia leu code^'^^ Laser iribolum1'5 (444)-(447) Artemisia rutijoliu'g Laserpitiurn g~rganicum'~~ (443) Artemisia x~nthochroa~~ Mikunia vitifolia"' (414) Bejarnnoa balansaeg7 Montanou imbricatu"Q (4481 (449) Calea jamaicensis Pieris hieracioides var. japonical" (415) Calea lepiocephala'uu Stevia hreviaristata2u1 (422) Ceniaurea in~ana'~~ Stevia mercendensis6a (4121 (413) Centuurea unifloru subsp. nervo.~a~~~ Thqsia gargunicaZu' (450) [see the text] Cotula cineredo3 Vernonia jalcana5' (436) Decachaeta ovatifoliu'O" Vernonia marginaia'22 (4341 (435) Decachaeta scabrell~'~~ Vernonia puiens" (436) Eupatorium altissimumlO' 14 Table 4 Novel guaian-6cr 12-olides 0 Position of Name Structure double-bond(s) Substituents' References Rupicolin A derivative 34 9-10 11-13 la-OH (or OOH); 8a-OAc 2 Rupicolin B derivative 34 10-14 11-13 la-OH (or OOH); 8a-OAc 2 Pre-eupatundin derivative 34 1614 11-13 2P-OH ; 8P-OR4 107 Ligustrin derivative 34 10-14 11-13 8P-OR4 68 Leucodin derivative 34 10-1 11-13 8P-OR4 68 Leucodin derivative 34 1C-I 11-13 2-0x0 ; 3-Cl; 8P-OR' 177 Picriside A 34 10-1 11-13 2-0x0 ; &-OH ; 15-OGlc 120 Lactupicriside C 34 l&l 11-13 2-0x0 ; 8a-OC(0)C6H,0H; 15-OGlc 137 Artelin 34 ILL1 2-0x0; 3-OH; 8a-OH; lla 194 Pre-euparotin derivative 34 10-14 11-13 2P-OH; 5a-OH; XP-OTig; 9P-OH 97 Euparotin derivative 34 11-13 2P-OH; 5a-OH; 8P-OTig; 9P-OH; IOn,l4-epoxy 97 Euparotin derivative 34 11-13 2P-OH; 8P-OH; 91-OTig; IOa-OH; 14-OH 97 Balansolide 34 11-13 2P,9P-epoxy; 8P-OTig; IOa,l4-epoxy 97 Breviarolide 34 11-13 8a-OR3; lop; 14-OH 20 1 Dehydroleucodin derivative 34 11-13 2-0x0; 5P-OH; IOa-OH 19 Artecanhydrate 11-13 la,2a-epoxy ; 3a-OH ; 4P-OH ; IOa-OH 19 Jamaicolide A 34 10-14 11-13 Ia-OH; 4P-OH; 8P-OR' 99 Jamaicolide B 11-13 la,2a-epoxy; 3a,4a-epoxy; 8p-0R2; 10a-OH 99 Leptocephalide 11-13 2P-OH; 4P; 8a-OAng; IOP,lp-epoxy 100 Cynaropicrin derivative 10-14 11-13 3-0x0 ; 4a-OH ; &-OR; 15-CI 193 Repdiolide trio1 1C-14 11-13 4a-OH ; 8a-OSen ; 15-OH 195 Dehydrocostuslactone IC-14 11-13 2a-OH ; 3P-OH ; 4a,l5-epoxy; 8a-OTig 196 Deoxyzaluzanin C 10-14 11-13 41; 7a-OH; 105 Zaluzanin C derivative 415 1&14 11-13 3P-OH; 9a-OH 137 Zaluzanin C derivative 415 1&14 3P-OH; 9a-OH; 1la 137 Jalcaguaianolide derivative 7-11 10-14 4a-OH; 8a-OTig; 1 I-OAc 122 Jalcaguaianolide derivative 7-1 1 4a,SP-epoxy; 8a-Tig 1Oa-OH; 1I-OAc 122 Jalcaguaianolide derivative 7-1 1 4a,5a-epoxy; 8a-OR4; 1Oa-OH; 1l-OR4 58 Dehydrocumambrin B derivative 34 8a-OR4; 10a-OH; Ila 161 Dihydrokauriolide derivative 34,1&1 8a-OAc; 11% 161 Dihydrokauriolide derivative 10-1 3a,4a-epoxy; 8a-OR4; 112 161 Viscidulin C derivative 1G-14 3a,4a-epoxy; 8a-OR4; 1la 161 Tanaparthin derivative 2-3 11-13 la,4a-epidioxy; &-OR4; 10a-OH 161 Dihydrotanaparthin derivative 2-3 la,4a-epidioxy ; 8a-OR4; IOa-OH ; 1la 161 NATURAL PRODUCT REPORTS 1988 0 0 (448)R H.(450) R =various (449) R = 0 H\ \ o*o 0$+ Q0 Ac0 0 (452) 0 0 (456) I I 9 0 (459) (460) Dolichlasium laga~cae.'~'A study of the structural relationship of the sesquiterpenes that have been isolated from Alpinia japonica (hanalpinol alpiniol hanamiol etc.) has been des-cribed.lg2 New guaianolides have been obtained from different plants (see Table 3). Table 4 shows the novel guaian-6a,l2-olides which have been isolated whilst other lactones of this series are depicted by the structures (443)-(455). The structure of a lactone that was isolated from a species of Lasiolaena (see Nut. Prod. Rep. 1984 2 257; ref. 344) has been revised; the hydroxyl group was also at C-14 [as in (414)] and not at C-15."' German authorszo2have obtained the sesquiterpene lactone (450) from Thapsia garganica but in accordance with the absolute structures of thapsigargin and trilobolide (see Nat.Prod. Rep. 1987 4 491) I think that the stereochemistry of this compound at C-1 C-2 C-3 C-8 and C-10 is erroneous. Nine new guaianolides cebellins A-I have been isolated from Centaurea bella. Cebellins F G,and I were also obtained from OH (453) (454) (455)A (lo) 0 (458) Qj-0 RRll (461)R' CI R2 =OH (462)R' R2 =O Centaurea adjari~a.~~~ An esterified slovanolide is the precursor for the 1,4-dimethylazulene in the essential oil of Thapsia garganica that was extracted by steam distillation of the The configurations of some 10,14-epoxyguaianol-ideszo5have been revised to Several dimeric guaian-olides related to one that had been isolated previously from Gochnatia paniculata (see Nat.Prod. Rep. 1986 2 157) have been obtained from Gochnatia polymorpha and Gochnatia hypoleuca.i8 A paper in which the natural guaianolides with an oxetane ring are reviewed has been published.206The seco-guaianolides isosecotanapartholide (456) and bis-secotanapar-tholide (457) have been isolated from Artemisia xanthochroa and Artemisia rutijolia respectively ;the latter compound is the result of a retro-aldol reaction of secotanapartholide A (458) which has been isolated from Artemisia la~iniata.'~The stereochemistry at C-7 that was given earlierzo7for (458) has now been revi~ed.'~ The structure of the pseudoguaianolide confertiflorin has NATURAL PRODUCT REPORTS 1988-B.M.FRAGA AcO 0 (463) (465) HOq-OR R1 (46 6 1 (467)R'=OH R2=H (468) R1 = various R2 = H 2 (469)R1 = H R =various R1 AcO-& q ROAc OR (472) (473) (474) R' = 0;R2 = H; R3 = Sen (476) R = various (475) R1 = 0 -OAc H; R2 = various; R3 = various R2a0 w dH CHO Ac (477) R1 = R2 = HI R3= various (478) R' = R3= H R2= OAng (480) (479) R' = OSen R2 R3 = H been confirmed by X-ray analysis.208 Artesovin (459) has been found in Artemisia szo~itsiana,~~~ whilst the compounds of the same type [(460)-(462)] have been isolated from Gaillardia Two novel glycosides pittosporanosides A and A, which are megapotarnica var.scabiosoide~.'~~ Parthoxethine (463) and derived from the alcohol (472) have been isolated from the isochiapine (464) are another two new pseudoguaianolides that leaves of Pittosporum tobira. These two compounds are active have been obtained from Parthenium fruticosum.210 The new against the blue mussel (Mytilus ed~lis).~'~ The new bicyclo- lactone 1la,l3-dihydroconfertin has been isolated from Dit-germacrane sesquiterpene (-)-coralloidin B (473) has been trichia viscosa.160 The secoambrosanolide altamisic acid (465) obtained from Alcyonium coralloides.156 has been found in Ambrosia tenuijolia.211 A sesquiterpene with a new skeleton derived from guaiane and named cyclokessyl acetate (466) has been isolated from the roots of Valerianu 18 Miscellaneous Sesquiterpenoids fauriei.'12 The valerenane sesquiterpenes (467)-(469) have The sesquiterpene (-)-pacifigorgiol has been obtained from been found in the roots of Valeriana ofJicinalis.213 Valerianu ofJicinalis;216 the optical antipode of this alcohol has been isolated from Pacifigorgia adamsii (see Nut.Prod. Rep. 1984 2 163). Several 'a-isocedrene ' derivatives [(474)-(476)] 17 Aromadendrane and Bicyclogermacrane have been isolated from Proustia c~neifolia.'~~ The thapsane The guayule plant (Parthenium argentatum) contains two new sesquiterpenes (477)-(483) have been obtained from Thupsia aromendrane sesquiterpenes guayulins C (470) and D (47 1).'14 villosa var. rnin~r.~'~,'~~ The structure of herbacin has been NATURAL PRODUCT REPORTS.1988 I I (484) (485 1 (488) R = Ti g (489)R = H (490) R = Tig shown to be (484); this furanosesquiterpene has been found in the marine sponge Dysidea herbacea.21s The basidiomycete Collybia peronata contains the sesquiterpene deox ycollybolidol (485)."O The structure of the furodysinin derivative (486) has been determined by X-ray analysis. This compound and (487) are two new metabolites of the nudibranch Chromodoris funerea.221Several sesquiterpene lactones [(488)-(491)] with a new skeleton named vernomargolides and probably being derived from the glaucolides have been obtained from Vernonia marginata.122A tricyclic sesquiterpene oblongifolidiol (492) has been isolated from Santolina oblongijolia.' 19 References 1 J.de Pascual Teresa I. S. Bellido M. S. Gonzalez and S. Vicente Phytochemistry 1986 25 185. 2 H. Greger C. Zdero and F. Bohlmann Phytochemistry 1986,25 891. 3 V. Gambaro M. Piovano and J. A. Garbarino Phytochemistry 1986 25 739. 4 M. Miski T. J. Mabry and F. Bohlmann J. Nut. Prod. 1986,49 916. 5 R. Kasai H. Fujino T. Kuzuki W. H. Wong C. Goto N. Yata 0.Tanaka F. Yasuhara and S. Yamaguchi Phytochemistry 1986 25 871. 6 R. P. Sutter Exp. Mycol. 1986 10 256. 7 G. L. Boyer and J. A. D. Zeevaart Phytochemistry 1986 25 1103. 8 N. Harai M. Okamoto and K. Koshimizu Phytochemistry 1986 25 1865. 9 R. G. Powell D. Weisleder C. R. Smith and F. E. Boettner J. Org. Chem. 1986 51 1074. 10 J. R. Sierra J. T. Lopez and M. J. Cortes Phyfochemistry 1986 25 253.11 W. Vichnewski P. Kulanthaivel and W. Herz Phytochemistry 1986 25 1476. 12 T. Kida H. Shibai and H. Seto J. Antibiot. 1986 39 613. 13 M. A. F. Leite M. H. Sarragiotto P. M. Imamura and A. J. Marsaioli J. Org. Chem. 1986 51 5409. 14 A. Ichihara Y. Kawakami and S. Sakamura Tetrahedron Lett. 1986 27 61. 15 H. Nakamura S. Deng J. Kobayashi Y. Ohizumi and Y. Hirata Tetrahedron 1986 42 4197. 16 H. M. G. Al-Hazimi Phyfochemistry 1986 25 2417. 17 G. Schmeda-Hirschmann C. Zdero and F. Bohlmann Phyto-chemistry 1986 25 1755. 18 F. Bohlmann C. Zdero G. Schmeda-Hirschmann J. Jakupovic X. A. Dominguez R. M. King and H. Robinson Phytochem-istry 1986 25 1175. 19 S. Huneck C. Zdero and F. Bohlmann Phytochemistry 1986 25 883.(486)R 0 (487)R = O-0OH.H (4911 (492) 20 F. Bohlmann J. Jakupovic U. Warning M. Grenz T. V. Chau- Thi R. M. King and H. Robinson Bull. SOC. Chim. Belg. 1986 95 707. 21 M. A. Metwally and A. A. Dawidar Pharmazie 1986 41 522. 22 M. Soriano-Garcia R. A. Toscano E. Flores-Valverde F. Mon-tolla-Vega and I. Lopez-Celis Acta Crystallogr. Sect. C. 1986 42 327. 23 K. Mori and M. Kato Tetrahedron Left. 1986 27 981. 24 B. W. Sullivan D. J. Faulkner K. T. Okamoto M. H. M. Chen and J. Clardy J. Org. Chem. 1986 51 5134. 25 N. K. Gulavita E. D. de Silva M. R. Hagadone P. Karuso P. J. Scheuer G. D. van Duyne and J. Clardy J. Org. Chem. 1986,51 5136. 26 M. Suzuki K. Kurata and E. Kurosawa Bull. Chem. SOC.Jpn. 1986 59 3981. 27 T.Ichiba and T. Higa J. Org. Chem. 1986 51 3364. 28 P. Crews and S. J. Selover Phytochemistry 1986 25 1847. 29 A. Matsuo S. Yuki and M. Nakayama J. Chem. Soc. Perkin Trans. I 1986 701. 30 D. E. Cane H.-J. Ha C. Pargellis F. Waldmeier S. Swanson and P. P. N. Murthy Bioorg. Chem. 1985 13 246. 31 B. B. Jarvis F. T. Comezoglu Y.-W. Lee J. L. Flippen-Ander-son R. D. Gilardi and C. F. George Bull. SOC. Chim. Belg. 1986 95 68 1. 32 B. B. Jarvis and C. S. Yatawara J. Org. Chem. 1986 51 2906. 33 A. W. Hanson Acta Crystallogr. Sect. C 1986 42 503. 34 R. Greenhalgh R. M. Meier B. A. Blackwell J. D. Miller A. Taylor and J. W. ApSimon J. Agric. Food Chem. 1986 34,115. 35 D. G. Corley G.E. Rottinghaus and M. S. Tempesta Tetra-hedron Lett. 1986 27 427. 36 D.G. Corley G. E. Rottinghaus J. K. Tracy and M. S. Tem-pesta Tetrahedron Lett. 1986 27 4133. 37 K. Chatterjee R. J. Pawlosky C. J. Mirocha and T. X. Zhu Appl. Environ. Microbiol. 1986 52 311. 38 J. F. Grove J. Chem. SOC., Perkin Trans. I 1986 647. 39 R. Sakai T. Higa C. W. Jefford and G. Bernardinelli. Helv. Chim. Acta 1986 69 91. 40 P. Crews S. Naylor B. L. Myers J. Loo and L. V. Manes Magn. Reson. Chem. 1985 23 684. 41 J. D. Martin C. Perez and J. L. Ravelo J. Am. Chem. Soc. 1986 108 7801. 42 K. Rajendran S. K. Paknikar G. K. Trivedi and S. C. Bhatta- charyya Indian J. Chem. Sect. B 1978 16 4. 43 Z. F. Mahmoud N. A. Abdel Salam T. M. Sarg and F. Bohl-mann Phytochemistry 1981 20 735. 44 K. Pandita S. G. Agarwal R. K. Thappa and K. L. Dhar Indian J.Chem. Sect. B 1984 23 956. 45 M. Miski and T. J. Mabry Phytochemistry 1986 25 1673. 46 G. Appendino M. G. Valle and P. Gariboldi J. Chem. Soc. Perkin Trans. I 1986 1363. 47 C. G. Casinovi S. Cerrini 0.Motl G. Fardelle W. Fedeli E. Gavuzzo and D. Lamba Collect. Czech. Chem. Commun. 1983 48 2411. NATURAL PRODUCT REPORTS 1988-B. M. FRAGA 48 M. Miski and T. J. Mabry J. Nat. Prod. 1986 49 657. 49 A. Yu. Kushmuradov A. I. Saidkhodzhaev and V. M. Malikov Khim. Prir. Soedin. 1983 53. 50 J. G. Diaz B. M. Fraga A. G. Gonzalez M. G. Hernandez and A. Perales Phytochemistry 1986 25 1161. 51 B. M. Fraga M. G. Hernandez J. G. Diaz A. G. Gonzalez and P. Gonzalez Phytochemistry 1986 25 2883. 52 X. A. Dominguez J. Verde S. N. E.Guerra R. E. Ellenmaurer and J. Jakupovic Phytochemistry 1986 25 2893. 53 P. Joseph-Nathan A. Gutierrez J. D. Hernandez L. U. Roman and R. L. Santillan J. Nat. Prod. 1986 49 79. 54 R. Boeker F. Bohlmann and R. M. King Rev. Latinoam. Quim. 1986 17 47. 55 S. El-Dahmy T. Sarg N. M. Farrag A. M. Ateya J. Jakupovic F. Bohlmann and R. M. King Phytochemistry 1986 25 1474. 56 B. F. Bowden J. C. Coll and R. H. Willis Aust. J. Chem. 1986 39 1717. 57 M. D. Soffer and L. A. Burk Tetrahedron Lett. 1985 26 3543. 58 J. Jakupovic G. Schmeda-Hirschmann A. Schuster C. Zdero F. Bohlmann. R. M. King H. Robinson and J. Pickardt Phyfo-chemistry 1986 25 145. 59 M. Martinez V. A. Sanchez F. G. Lopez B. and P. Joseph- Nathan Z. Naturforsch. Sect. C 1986 41 1119. 60 L.N. Misra Phytochemistry 1986 25 2892. 61 M. S. R. Nair N. Acton D. L. Klayman K. Kendrick. D. V. Basile and S. Mante J. Nut. Prod. 1986 49 504. 62 F. S. El-Feraly I. A. Al-Meshal M. A. Al-Yahya and M. S. Hifnawy Phytochemistry 1986 25 2777. 63 Y. Shiobara Y. Asakawa M. Kodama and T. Takemoto Phyto-chemistry 1986 25. 1351. 64 R. D. Stipanovic A. Stoessl J. B. Stothers D. W. Altman A. A. Bell and P. Heinstein J. Chem. Soc. Chem. Commun. 1986 100. 65 P. Ciminiello E. Fattorusso S. Magno and L. Mayol Experi-entia 1986 42 625. 66 X. A. Dominguez J. Jakupovic V. P. Pathak H. Sanchez. R. M. King and H. Robinson Rev. Latinoam. Quim. 1986 17 207. 67 P. Joseph-Nathan C. M. Cerda R. E. del Rio L. U. Roman and J. D. Hernandez J. Nat. Prod. 1986 49 1053.68 F. Bohlmann. C. Zdero R. M. King and H. Robinson Liebigs Ann. Chem. 1986. 799. 69 J. Jakuuovic. E. Ellmauerer F. Bohlmann R. M. Kine and H. -Robinsin Phytochemistry 1986 25 1927. 70 K. Doi T. Shibata M. Nara S. Tsuboyama T. Sakurai. and K. Tsuboyama Chem. Lett. 1986 653. 71 T. Uchida. Y. Matsubdra and A. Adachi Agric. Biol. Chem. 1986 50 1903. 72 J. Jakuuovic. J. Kuhnke. A. Schuster M. A. Metwally and F. Bohlmann Phytochemistry 1986 25 1133. 73 A. Hirote M. Nakagawa H. Hirota T. Takahashi and A. Isogai J. Antibiot. 1986 39 149. 74 D. E. Cane Y. G. Whittle and T. C. Liang Bioorg. Chem. 1986 14 417. 75 J. P. Poyser R. L. Edwards J. R. Anderson M. B. Hursthouse N. P. C. Walker G. M. Sheldrick and A. J. S. Whalley. J. Anti-biot.1986 39 167. 76 A. San Feliciano J. M. Miguel del Corral E. Caballero A. Alvarez and M. Medarde J. Nut. Prod. 1986 49 845. 77 M. K. Makhmudov B. Tashkhodzhaev G. V. Sagitdinova A. I. Saidkhodzhaev. M. R. Yagudaev and V. M. Malikov Khim. Prir. Soedin. 1986 42. 78 W. R. Abraham L. Ernst L. Witte H. P. Hanssen and E. Sprecher Tetrahedron 1986 42 4475. 79 D. M. X. Donnelly D. J. Coveney and J. Polonsky Tetrahedron Lett. 1985 26 5343. 80 D. M. X. Donnelly D. J. Coveney N. Fukuda and J. Polonsky J. Nut. Prod. 1986 49 111. 81 A. Arnone R. Cardillo and G. Nasini Phytochemistry 1986,25 471. 82 H.-P. Hanssen E. Sprecher and W.-R. Abraham Phytochem-istry 1986 25 1979. 83 T. C. W. Mak K.-L. Shi R.-S. Li and K.-H. Long Zhongshan Daxue Xuebao Ziran Kexueban 1985 No.4 p. 22. 84 R.-S. Li K.-H. Long Z.-S. Fang H.-W. Zhao and M.-Y. Zhang Zhongshan Daxue Xuebao Ziran Kexueban 1985 No. 4 p. 17 (Chem. Abstr. 1987 105 187928). 85 J. de Pascual Teresa J. R. Moran J. M. Hernandez and M. Grande Phytochemistry 1986 25 1167. 86 G. Appendino M. Calleri and G. Chiari J. Chern. Soc. Perkin Trans. 2 1986 205. 87 A. Garcia-Granados A. Molina and E. Cabrera Tetrahedron 1986 42 81. 88 J. Zhang and L.-X. He Yaozue Xuebao 1986 21 273 (Chem. Abstr. 1987 105 149709). 89 J. Zheng G.-P. Li Z.-G. Chen Y.-Q.Tang X.-C. Wei and L.-X. He Huaxue Xuebao 1986 44 551 (Chem. Abstr.. 1987 105 112030). 90 M. K. Makhmudov. B. Tashkhodzhaev. A. I. Saidkhodzhaev. M. R. Yagudaev and V. M. Malikov Khim. Prir. Soedin.1986 436. 91 R. H. Scheffrahn J. J. Sims R. K. Lee and M. K. Rust J. Nat. Prod. 1986 49 699. 92 A. Rustaiyan M. Dabiri and J. Jakupovic Phytochemistry 1986 25 1229. 93 N. A. El-Emary M. A. Makboul and M. Hamed Phytochem-istry 1986 25 314. 94 S. V. Serkerov and A. N. Aleskerova Khim. Prir. Soedin. 1985 787. 95 J. Jakupovic R. N. Baruah F. Bohlmann R. M. King and H. Robinson Planta Med. 1986 204. 96 F. Gao M. Miski and T. J. Mabry Phytochemistry 1986 25 1231. 97 G. Schmeda-Hirschmann J. Jakupovic V. P. Pathak and F. Bohlmann Phytochemistry 1986 25 2167. 98 S. R. Rojatkar. N. N. Dhaneswar V. G. Puranik S. S. Tavale T. N. Gururow and B. A. Nagasampagi J. Chem. Res. (9,1986 272. 99 A. G. Ober N. H. Fischer and F. Parodi Phytochemistry 1986 25 877.100 A. G. Ober L. E. Urbatsch and N. H. Fischer Phytochemistry 1986 25 467. 101 S. Oksuz and H. Ayyildiz Phytochemistry 1986 25 535. 102 S. Banerjee G. Schmeda-Hirschmann V. Castro A. Schuster J. Jakupovic and F. Bohlmann Planta Med. 1986 29. 103 M. A. Metwally S. El-Dahmy J. Jakupovic F. Bohlmann A. M. Dawidar and S. A. Metwally Phytochemistry 1986 25 255. 104 J. Jakupovic S. Banerjee V. Castro F. Bohlmann A. Schuster J. D. Msonthi and S. Keeley Phytochemistry 1986 25 1359. 105 D. H. de Luengo M. Miski D. A. Gage and T. J. Mabry Phy?o-chemistry 1986 25 1917. 106 D. Zhang M. Huruna A. T. McPhail and K. H. Lee Phyto-chemistry 1986 25 899. 107 R. Boeker J. Jakupovic F. Bohlmann R. M. King and H. Robinson Phytochemistry 1986 25 1669.108 M. Haruna. Y. Sakakibara and K. Ito Chem. Pharm. BUN.,1986 34 5157. 109 M. Galvez M. Hoeneisen M. Silva and W. H. Watson Bol. Soc. Chi/. Quim. 1986 31 3. 110 M. Hoeneisen and H. Becker J. Nat. Prod. 1986 49 359. 11 1 K. Watanabe N. Ohno and T. J. Mabry Phytochemistry 1986 25 141. I12 J. Pearce J. Gershenzon and T. J. Mabry Phytochemistry 1986 25 159. 113 J. Jakupovic V. P. Pathak F. Bohlmann D. Gage and M. 0. Dillon Phytochemistry 1986 25 2563. 114 Z. F. Mahmoud F. F. Kassem N. A. Abdel-Salam and C. Zdero Phytochemistry 1986 25 747. 115 Z. Smitalova M. Budesinsky D. Saman and M. Holub Collect. Czech. Chem. Commun. 1986 51 1323. 116 L. Quijano J. S. Calderon F. Gomez-Garibay S. Bautista T. Rios and F. R. Fronczek Phytochemistry 1986 25 695.117 Y. Oshima S. M. Wong C. Konno G. A. Cordell D. P. Waller D. D. Soejarto and H. H. S. Fong J. Nat. Prod. 1986 49 313. 118 N.-B. Fang D. H. de Luengo and T. J. Mabry Phytochemistry 1986 25 2665. 119 A. Rustaiyan B. Ahmadi J. Jakupovic and F. Bohlmann Phyto-chemistry 1986 25 1659. 120 K. Nishimura T. Miyase A. Ueno T. Noro M. Kuroyanagi and S. Fukushima Chem. Pharm. BUN.,1986 34 2518. 121 X. A. Dominguez G. Cano H. Sanchez G. Velazquez E. Ell- mauerer and J. Jakupovic J. Nat. Prod. 1986 49 704. 122 J. Jakupovic D. A. Gage F. Bohlmann and T. J. Mabry Phyto-chemistry 1986 25 1179. 123 K. K. Purushothaman and S. Vasanth Indian J. Chem. Sect. B 1986 25 417. 124 F. Gao and T. J. Mabry Phytochemistry 1986 25 137. 125 M.Holub M. Budesinsky Z. Smitalova D. Saman and U. Rychlewska Collect. Czech. Chem. Cornmun. 1985 50 1878. 126 G. Appendino G. M. Nano M. Calleri and G. Chiari Gazz. Chim. Ital. 1986 116 57. 127 W. H. Watson and R. P. Kashyap J. Org. Chem. 1986 51 252 1. 128 G. Chiari G. Appendino and G. M. Nano J. Chem. Soc. Perkin Trans. 2 1986 263. 129 G. Schmeda-Hirschmann R. Boeker J. Jakupovic and F. Bohl-mann Phytochemistry 1986 25 1753. 130 D. B. Stierle Phytochemistry 1986 25 743. 131 W. Herz and M. Bruno Phytochemistry 1986 25 1913. 132 A. L. Perez L. Naya and A. Romo de Vivar Phyiochemisiry 1986 25 745. 133 N. A. El-Sebakhy M. G. El-Ghazouly A. A. S. El-Din and C. Zdero Pharmazie 1986 41 525. 134 E. Guerreiro Phyiochemistry 1986 25 748.135 0.Spring V. Klemt K. Albert and A. Hager Z. Naturforsch. Sect. C 1986 41 695. 136 J. Jakupovic R. N. Baruah F. Bohlmann and J. D. Msonthi Planta Med. 1986 154. 137 K. Nishimura T. Miyase A. Ueno T. Noro M. Kuroyanagi and S. Fukushima Phyiochemistry 1986 25 2375. 138 U. Rychlewska D. J. Hodgson H. Grabarczyk B. Drozdz W. M. Daniewski W. Kroszczynski M. Budesinsky and M. Holub Collect. Czech. Chem. Commun. 1986 51 1698. 139 F. Bohlmann P. Singh R. M. King and H. Robinson Phyio-chemistry 1982 21 456. 140 F. Bohlmann C. Zdero R. M. King and H. Robinson Phyio-chemistry 1986 25 2663. 141 F. Bohlmann P. Singh C. Zdero A. Ruhe R. M. King and H. Robinson Phyiochemisiry 1982 21 1669. 142 F. Bohlmann R. K. Gupta J. Jakupovic R. M. King and H.Robinson Phyiochemisiry 1981 20 1609. 143 F. Bohlmann C. Zdero H. Robinson and R. M. King Phyto-chemistry 1981 20 731. 144 F. Bohlmann M. Wallmeyer R. M. King and H. Robinson Phytochemistry 1982 21 1439. 145 F. Bohlmann C. Zdero H. Robinson and R. M. King Phyio-chemisiry 1982 21 1087. 146 F. Bohlmann and C. Zdero Chem. Ber. 1975 108,437. 147 F. Bohlmann C. Zdero R. M. King and H. Robinson Phyto-chemistry 1982 21 695. 148 F. Bohlmann C. Zdero R. M. King and H. Robinson Phyio-chemistry 1982 21 1045. 149 F. Bohlmann G. Brindopeke and R. C. Rastogi Phyiochemistry 1978 17 475. 150 F. Bohlmann L. Muller R. K. Gupta R. M. King and H. Robinson Phytochemisiry 1981 20 2233. 151 F. Bohlmann C. Zdero R. M. King and H. Robinson Phyio-chemistry 1981 20 518.152 F. Bohlmann C. Zdero R. M. King and H. Robinson Phyio-chemistry 1979 18 987. 153 W. Herz and P. Kulanthaivel Phytochemistry 1983 22 1286. 154 A. Garcia-Granados A. Martinez A. Molina and M. E. Onor-ato Phyiochemisiry 1986 25 2171. 155 J. D. Connolly L. J. Harrison S. Huneck and D. S. Rycroft Phyiochemisiry 1986 25 1745. 156 A. Guerriero B. Dematte M. D’Ambrosio and F. Pietra J. Nai. Prod. 1986 49 608. 157 J. Jakupovic R. Boeker and R. M. King Planta Med. 1986,411. 158 N. P. D. Namayakkara A. D. Kinghorn and N. R. Farnsworth J. Chem. Res. (S),1986 454. 159 V. U. Ahmad and K. Fizza Phytochemisiry 1986 25 949. 160 W. M. Daniewski W. Kroszczynski E. Bloszyk B. Drozdz J. Nawrot U. Rychlewska M. Budesinsky and M. Holub Collect.Czech. Chem. Commun. 1986 51 1710. 161 J. Jakupovic T. V. Chau-Thi U. Warning F. Bohlmann and H. Greg Phytochemisiry 1986 25 1663. 162 F. H. Guidugli M. J. Pestchanker M. S. A. de Salmeron and 0.S. Giordano Phytochemistry 1986 25 1923. 163 A. Ulubelen and N. Goren J. Nat. Prod. 1986 49 1104. 164 K. Iguchi K. Mori M. Suzuki H. Takahashi and Y. Yamada Chem. Lett. 1986 1789. 165 J.6. Yang and Y.-W. Chen Yaoxue Xuebao 1986,21,516 (Chem. Abstr. 1986 105 187604). 166 L. Rodriguez-Hahn L. Antunez M. Martinez A. A. Sanchez B. Esquivel M. Soriano-Garcia and A. Toscano Phyiochemistry 1986 25 1655. 167 A. G. Gonzalez I. Bazzocchi A. G. Ravelo J. G. Luis and X. A. Dominguez Heierocycles 1986 24 3379. 168 M. J. Begley L. Crombie R. A. Fleming D.A. Whiting Z. Rozsa M. Kelenyi J. Hohmann and K. Szendrei J. Chem. Soc. Perkin Trans. I 1986 535. NATURAL PRODUCT REPORTS 1988 169 A. A. Sanchez J. Cardenas M. Soriano-Garcia R. Toscano and L. Rodriguez-Hahn Phyiochemistry 1986 25 2647. 170 A. G. Gonzalez E. E. Ferro and A. G. Ravelo Heterocycles 1986 24 1295. 171 J. R. de Sousa J. A. Pinheiro E. F. Ribeiro E. de Souza and J. G.S. Maia Phyiochemistry 1986 25 1776. 172 L. Crombie D. Toplis D. A. Whiting Z. Rozsa J. Hohmann and K. Szendrei J. Chem. Soc. Perkin Trans. 1 1986 531. 173 A. San Feliciano M. Medarde M. T. Poza and J. M. Miguel del Corral Phyiochemisiry 1986 25 1757. 174 F. A. Eid Pharmazie 1986 41 674. 175 J. de Pascual Teresa E. Caballero J. Anaya C. Caballero and M. S. Gonzalez Phyiochemisiry 1986 25 1365.176 M. Seto T. Miyase and S. Fukushima Chem. Pharm. Bull. 1986 34,4170. 177 V. Castro J. Jakupovic and F. Bohlmann Phytochemisiry 1986 25 1750. 178 M. G. Gogte L. Ananthasubramanian K. S. Nargund and S. C. Bhattacharyya Indian J. Chem. Sect. B. 1986 25 233. 179 M. Stefanovic S. Mladenovic M. Dermanovic and N. Ristic J. Serb. Chem. Soc. 1985 50 435. 180 W. Herz and V. E. Sosa Phytochemisiry 1986 25 1481. 181 J. Jakupovic Y.-Y. Jia R. M. King and F. Bohlmann Liebigs Ann. Chem. 1986 1474. 182 K. Yamakawa K. Nishitani M. Iida and A. Mikami Chem. Pharm. Bull. 1986 34,1319. 183 B. Abegaz F. Camps J. Coll M. Feliz U. Jacobson C. Mira- vitlles E. Molins and J. Torramilans Tetrahedron 1986,42,6003. 184 A. Murai Y.Yoshizawa N. Katsui S. Sato and T. Masamune Chem. Lett. 1986 771. 185 A. Murai Y. Yoshizawa M. Ikura N. Katsui and T. Masamune J. Chem. Soc. Chem. Commun. 1986 891. 186 R. S. Burden R. S. T. Loeffler P. M. Rowell J. A. Bailey and M. S. Kemp Phyiochemisiry 1986 25 1607. 187 F. Bohlmann C. Zdero J. Jakupovic L. N. Misra S. Banerjee P. Singh R. N. Baruah M. A. Metwally G. Schmeda-Hirsch- mann L. P. D. Vincent R. M. King and H. Robinson Phyio-chemistry 1985 24 1249. 188 G. Morales J. Borquez A. Mancilla and S. Pedreros Phyto-chemistry 1986 25 2412. 189 M. Miski D. H. de Luengo and T. J. Mabry Phytochemistry 1987 26 199. 190 K. K. Talwar and P. S. Kalsi Phyiochemisiry 1986 25 262. 191 C. Zdero F. Bohlmann R. M. King and H. Robinson Phyio-chemistry 1986 25 2873.192 H. Itokawa H. Morita K. Osawa T. Kobayashi H. Kubota K. Watanabe and Y. Iitaka Tennen Yuki Kagobuisu Toronkai Koen Yoshishu 27ih 1985 458 (Chem. Abstr. 1986 105 75863). 193 M. Izaddoost M. Dabiri Z. Sharif and A. Rustaiyan Fito-ierapia 1985 56 275. 194 I. M. Saitbaeva N. D. Abdullaev A. Mallabaev G. P. Sidyakin and M. R. Yagudaev Khim. Prir. Soedin. 1986 115. 195 G. Massiot A.-M. Morfaux L. Le Men-Olivier J. Bouquant A. Madaci A. Mahamoud M. Chopova and P. Aclinou Phyto-chemistry 1986 25 258. 196 G. Appendino P. Gariboldi and F. Belliardo Phytochemisiry 1986 25 2163. 197 J. Jakupovic V. P. Pathak F. Bohlmann R. M. King and H. Robinson Planta Med. 1986 331. 198 C. Zdero F. Bohlmann R. M. King and H. Robinson Plania Med.1986 22. 199 G. Appendino M. G. Valle R. Caniato and E. M. Cappelletti Phyiochemistry 1986 25 1747. 200 F. C. Seaman N. H. Fischer and T. J. Mabry Phytochemistry 1986 25 2663. 201 J. C. Oberti R. R. Gil V. E. Sosa and W. Herz Phytochemisiry 1986 25 1479. 202 G. Falsone H. Haddad and D. Wendisch Arch. Pharm. (Wein- heim Ger.) 1986 319 372. 203 G. Nowak B. Drozdz M. Holub M. Budesinsky and D. Saman Acta Soc. Boi. Pol. 1986 55 227. 204 U. W. Smitt P. Moldt and S. B. Christensen Acta Chem. Scand. Ser. B. 1986 40,711. 205 F. Bohlmann A. Suwita H. Robinson and R. M. King Phyto-chemistry 1981 20 1887. 206 I. Gonzalez-Collado F. A. Macias G. M. Massanet and F. Rodriguez-Luis Rev. Latinoam. Quim. 1986 16 128. 207 F. Bohlmann and C.Zdero Phyiochemistry 1982 21 2543. 208 D. Vargas F. R. Fronczek N. H. Fischer and K. Hostettmann J. Nat. Prod. 1986 49 133. NATURAL PRODUCT REPORTS. 1988-B. M. FRAGA 209 S.V. Serkerov and A. N. Aleskerova Khim. Prir. Soedin.. 1986.645. 210 A. Ortega and F. Maldonado Phj,tochemistry 1986 25 699. 211 J. C. Oberti G. L. Silva V. E. Sosa P. Kulanthaivel and W. Herz Phytochemistry 1986 25 1355. 212 Y. Oshima Y. Hikino and H. Hikino Tetrahedron Left. 1986 27 1829. 213 R. Bos H. Hendriks A. P. Bruins J. Kloosterman and G. Sipma Phytochemistry 1986 25 133. 214 M. Martinez G. Flores A. Romo de Vivar G. Reynolds and E. Rodriguez J. Nut. Prod. 1986 49 1102. 215 D. Takaoka H. Kawahara S. Ochi M. Hiroi H. Nozaki M. Nakayama K. Ishizaki K.Sakata and K. ha Chem. Lett. 1986 1121. 521 216 R. Bos H. Hendriks J. Kloosterman and G. Sipma Phyto-chemistry 1986 25 1234. 217 J. de Pascual Teresa J. R. Moran A. Fernandez and M. Grande Phytochemistry 1986 25 703. 21 8 J. de Pascual Teresa J. R. Moran A. Fernandez and M. Grande Phytochemistry 1986 25 117I. 219 N. S. Sarma M. Rambabu A. S. R. Anjaneyulu C. B. S. Rao and I. Saito Indian J. Chem. Sect. B. 1986 25 1001. 220 M. Fogedal and T. Norberg Phytochemistry 1986 25 2661. 221 B. Carte M. R. Kernan E. B. Barrabee D. J. Faulkner G. K. Matsumoto and J. Clardy J. Org. Chem. 1986 51 3528.

ISSN:0265-0568    

DOI:10.1039/NP9880500497

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites R. B. Herbert Department of Organic Chemistry University of Leeds Leeds LS2 9JT Reviewing the literature published between July 1986 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1987 Vol. 4 p. 423) 1 Pyrrolidine and Piperidine Alkaloids 1.1 Pyrrolidine Alkaloids 1.2 Piperidine and Pyridine Alkaloids 1.3 Pyrrolizidine Alkaloids 1.4 Quinolizidine Alkaloids 1.5 Cyclizidine 2 Benzylisoquinoline Alkaloids 3 Metabolites Derived from Tryptophan 3.1 Terpenoid Indole Alkaloids 3.2 Streptonigrin 3.3 Miscellaneous Metabolites 4 Other Metabolites of the Shikimate Pathway 4.1 Naphthyridinomycin 4.2 Ansamycins and Mitomycins 4.3 Tuberin and Xanthocillins 4.4 Benzodiazepines 4.5 Actinomycin 4.6 Capsaicin 5 /3-Lactams 5.1 Penicillins and Cephalosporins 5.2 Clavulanic Acid Thienamycin and Tabtoxin 6 Miscellaneous Metabolites 7 References Following custom appropriate reference is made in the following discussion to earlier reviews'-' which provide back- ground information.1 Pyrrolidine and Piperidine Alkaloids 1.1 Pyrrolidine Alkaloids In work on the biosynthesis of cocaine (4) in Erythroxylum coca (cf. ref. 3 p. 163; ref. 2 p. 181) it has been shown that the ester (1) is an intact precursor for the alkaloid (4). A possible biosynthetic intermediate beyond (1) was considereds to be 2,3- didehydrococaine [as (2)].When this compound labelled as shown (0 = 14C 13C) was fed to E. coca the cocaine isolated was specifically labelled in the same way as the precursor but the 3H/14C ratio was quite different. This indicates that hydrolysis of (2) had occurred to give labelled (l) followed by reduction to (3) and then esterification with benzoic acid (some of which bore tritium from the precursor fed) leading to doubly labelled cocaine (the change in ratio is a reflection of the different pool sizes of the two halves). In these experiments (conducted over 3 and 15 days) 2,3- didehydrococaine was re-isolated (in the 3-day experiment). It was found to have the same specific activity as the material which was fed if it were an intermediate some dilution of label would have been expected.Radioactive 2-carbomethoxytropin- 3-one (1) was also isolated. It was essentially antipodal with respect to natural cocaine. Thus it was concluded that the racemic (2) which was fed underwent hydrolysis but only the ( +)-enantiomer was subsequently reduced to ecgonine methyl ester (3) en route to cocaine (4). The evidence then points clearly to (3) but not 2,3-didehydrococaine [as (2)] being an intermediate in the biosynthesis of cocaine (4). C02Me / " (2) 0-C-Ph II 0 NMe T I c=o I Ph*H CYOH (5 1 A H ,CO2H 0 Ph H NH2 Ph OH H The (5')-tropic acid moiety (8) found in some tropane alkaloids e.g. hyoscyamine (9 originates in phenylalanine (7).The formation of tropic acid involves an intramolecular 1,2- migration of the carboxyl group of phenylalanine from C-cc to C-/3 and a 1,2-shift of hydrogen from C-/3 to C-a (cf. ref. 4 p. 186). Further results have come from the incorporation of L-(PR)-and ~-(PS)-[carboxyl-~~C /3-3H]phenylalanine into hyo- scyamine (5) and scopolamine (6) in Datura innoxia.@The results are that the P(pro-PS)-proton in phenylalanine (7) is the one that migrates but it is not yet apparent whether this migration is intramolecular or intermolecular. From the stereochemistry of natural (5')-tropic acid it follows that migration of the carboxyl group results in retention of configuration at what was C-/3 of phenylalanine (7).Analogy for the migration seen here was found in the vitamin-B,,-mediated conversion of (2R)- 523 5 24 NATURAL PRODUCT REPORTS 1988 (9) methylmalonyl-coenzyme A (9) into succinyl-coenzyme A (10) in which the thioester undergoes intramolecular migration with retention of configuration ; the displaced hydrogen migrates in the opposite direction in an intermolecular fashion.However the evidence for the presence in higher plants of vitamin B,, which would be required in this analogy for the biosynthesis of tropic acid is tenuous and contro~ersial.~ Different results have been obtained by other workers for the biosynthesis of tropic acid also using phenylalanine that was chirally tritiated at C-P." The results may however be simply explained as arising from ready racemization of the tropic acid moieties in the alkaloids during the course of the experi- ment~.~ If this is so both sets of results are in agreement.The production of tropane alkaloids in root and callus cultures of seven species of Hyoscyamus has been studied." An inverse relationship between growth in the root cultures and the production of alkaloids was noted. Auxins stimulated the growth of root cultures but the production of alkaloids was inhibited as the auxin concentration increased. There is a group of alkaloids based on nicotine in which the nitrogen atom of the pyrrolidine ring bears an acyl rather than a methyl group. Experiments with 14C-labelled nicotine and nornicotine in leaves of Nicotiana stocktonii show that both precursors give rise to the N-acylated products indicating that the sequence is nicotine +nornicotine (which was also obtained as a product from radioactive nicotine in vivo) + N-acylated products.12 1.2 Piperidine and Pyridine Alkaloids The biosynthesis of pipecolic acid from lysine (cf.ref. 1 Vol. 12 p. 6; Vol. 7 p. 4; Vol. 3 p. 25; and refs. 6 and 7)and of 4- hydroxypipecolic acid from pipecolic acid13 has been con-firmed in experiments with leaves of Acacia mellfera subsp. detinens.l4 Securinine and allosecurinine are major alkaloids produced by callus cultures induced from Securinega suffr~ticosa.'~ The effects of various factors on the growth of the cultures and the production of alkaloids have been examined in detail. A scheme for the biosynthesis of the alkaloids was presented (for experimental work on biosynthesis see refs.6 and 7). Sesbanine (11) is a unique alkaloid found in seeds of Sesbania drummondii. [carb~xyl-'~C]Nicotinic acid a predicted precursor was incorporated at a low level and with relatively poor specificity.16 However tryptophan which is a known precursor for nicotinic acid in animals and some micro-organisms was a notably better precursor for (11). Radio- activity from ~-[5-~H]tryptophan was incorporated both into (11) and into nicotinic acid; label was incorporated specifically into C-5 of sesbanine (11) as predicted if utilization was via nicotinic acid. The remaining carbon atoms in (1 1) (C-9 through C-14) have been shown to derive from shikimic acid via p-hydroxybenzoic acid with the loss of one carbon atom from the ring (L- phenylalanine and L-tyrosine were poorly utilized).Label from [7-14C]shikimic acid appeared specifically at C-9 of (1 1) while the pattern of incorporation of p-hydr~xy[U-~~C]ber~zoic acid into fragments which were obtained by degradation of (1 1) was entirely consistent with an origin of C-9 through C-14 being in this compound.16 Further results are awaited with considerable interest. Results of experiments with deuteriated pyridine-2,6-dicarboxylic acid in Pseudomonas putida show that the bio- synthesis of pyridine-2,6-di(carbothioic acid) (12) involves the sequence C(0)OH +C(O)SOH +C(O)SH." This is the first time such a reaction sequence has been found.NH (12) HO OH 1.3 Pyrrolizidine Alkaloids Root cultures of Senecio vulgaris have been obtained.ls Notably the cultures were able to synthesize pyrrolizidine alkaloids which accumulated in the form of their N-oxides. Very high incorporations into the alkaloids were observed of the usual precursors (such as arginine isoleucine putrescine and spermidine) with the exception of spermine which was an ineffective precursor. The primary product of biosynthesis was senecionine which was formed exclusively as its N-oxide. In root cultures of S. vulgaris it appears that alkaloid synthesis is closely related to polyamine metabolism and depends on conditions of active growth. It appears further that the alkaloidal N-oxides which can be taken up and stored in the vacuoles are much safer forms of the alkaloids for translocation and storage.The course of biosynthesis which leads to retronecine (13) (the base portion of retrorsine) has been mapped in intricate detail (cf. ref. 5 p. 424; ref. 4 p. 186; ref. 3 p. 163; and ref. 2 p. 182). Results relating to the incorporation of (2R)- and (259- [2-2H]putrescine into (I 3) previously published in preliminary form19 (cf ref. 5 p. 424) are now available with experimental detaiLZ0 Trachelanthamidine (14) is a good precursor for retronecine (13). By contrast (racemic) isoretronecanol (15) is a much better precursor for rosmarinecine (16) [the base portion of rosmarinine (17)] than is trachelantharnidinez1 (cf ref. 5 p. 424). Because of these differences the pathway to rosmarinine has been subjected to close scrutiny using whole plants of Senecio pleistocephalus." Results from experiments with [l-T]- [2,3-13C,]- and [I-% l-amin~-~~N]-putrescine showed that like retronecine (13) rosmarinecine (16) is formed from two molecules of putrescine via an intermediate with C, symmetry.Again as with retronecine this intermediate was shown to be homospermidine (18) by the incorporation of 1,9-'3C,-labelled material. NATURAL PRODUCT REPORTS 1988-R. B. HERBERT DW '\ DR I; 0 (21) R = D (22) R = OH D (23) (24) (25) .1 (p Nl I op-H Scheme 1 1.4 Quinolizidine Alkaloids Results relating to the incorporation of (1 I?)-and (1 S)-[l-zH,]-cadaverine into sparteine (20) lupanine (21) and angustifoline (23) which had previously been published in a preliminary comm~nication~~ have now appeared in a full paperz4 (cf.ref. 4,p. 186). Additional results relating to lupinine were exactly similar to those obtained by othersz5 (cf. ref. 5 p. 425 and ref. 3 p. 164). The course of biosynthesis of quinolizidine alkaloids has been probed further with deuteriated samples of cadaverine. [3,3-2Hz]Cadaverine (19) has been incorporated into (+)-lupanine (21) and (+)-13a-hydroxylupanine (22) in Lupinus polyphyllus2Band Lupinus ang~stifolius,~~ into ( +)-angustifoline (23) in L. polyphyllus and into (-)-lupinhe (24) and (-)-sparteine (20) in Lupinus luteus.*' The labelling patterns illustrated on structures (20>-(24) were determined by *H n.m.r.spectroscopy.z'~ z7 It follows from the results that during the biosynthesis of quinolizidine alkaloids from cadaverine C- 3 of cadaverine remains unaffected by biochemical events; in the case of 13a-hydroxylupanine the retention of deuterium at C-13 indicates that the introduction of oxygen at this site does not involve keto or enol intermediates. The labelling of (2-13 in angustifoline (23) by deuterium demonstrates that the allylic moiety derives from cadaverine. Nearly half of more than 60 plant species examined for quinolizidine alkaloids were found to produce ammodendrine A (28) -CH,CHz CO2Na CD C H ,C02Na Scheme 2 (26).28 Cadaverine a precursor for quinolizidine alkaloids has been found also to be a precursor for ammodendrine (26) in leaves of Lupinus polyphyllus; both rings of (26) derive from this precursor as demonstrated by the incorporation of [l-zH]-cadaverine.It is reasonable to conclude that ammodendrine is formed by the dimerization of A'-piperideine which is in turn derived from cadaverine by the action of a diamine oxidase. This is supported by further evidence. Cell-free preparations of Lupinus arboreus and of Pisum sativum (which is known to contain an active diamine oxidase) were prepared.28 Incubation with cadaverine gave smipine (27) tetrahydroanabasine and tripiperideine ; in the presence of pyruvate ammodendrine was also produced. It is likely that tetrahydroanabasine (25) is the precursor for both (27) and (26) (Scheme 1).Low-molecular-weight compounds such as ATP and coenzyme A were absent from the preparation as used and it was speculated that S-acetyl-dihydrolipamide formed through the action of the pyruvate dehydrogenase complex on pyruvate provides the acetyl group in (26). It is to be noted that neither smipine nor ammodendrine could be detected in extracts of seeds or leaves of P. sativum. Cultured shoots of Heimia salicifolia accumulate quino- lizidine alkaloids but no callus cultures or cell suspension cultures were found to do The levels of lysine decarboxylase in cell and organ cultures have been examined. In chloro- phyllous cell cultures enzyme activity correlated positively with chlorophyll ; in shoot cultures the activity also paralleled alkaloid produ~tion.~~ It was concluded that the control of alkaloid production in H.salicifolia is not mediated by lysine decarboxylase. 1.5 Cyclizidine Cyclizidine (28) is one of only two indolizidine bases elaborated by Streptomyces species. Of particular note in the structure is the unique cyclopropyl group at the terminus of the chain. The labelling of C-2 C-5 C-7 and C-12 by [I-13C]acetate established that biosynthesis of (28) was likely to be by a polyketide route.31 The acetate units were then firmly located by the results of an experiment with [l3C,]acetate and the remaining atoms could be defined as arising from propionate by the results of an experiment with [l-13C]propionate (Scheme 2). Important confirmation that all three carbon atoms of the cyclopropyl residue originate in propionate was obtained with [3,3,3-2H3]- propionate (Scheme 2).Further results particularly in relation to the ring-forming reactions associated with the biosynthesis of cyclizidine (28) are awaited with interest. Of additional interest here is the NATURAL PRODUCT REPORTS 1988 6)-Reticuline (29) i' Shikimate metabolism \ (30) R1 = H R2 =Me (31) R' =Me R2 =H co2H HO \ Ho CF (34) 6)-Norlaudanosoline (32) R OH (s)-Norcoclaurine (33) R = H HOmCozH NH2 7 (35) co2 (37 1 4t CHo (5')-Norcoclaurine (33) HO mCozH i \ T \ (38) COZ (39) \ L-Dopa (34) -+Dopamine (37) \(See ref. 36) 4 Enzymes i a decarboxylase [L-dopa (34) > L-tyrosine (35)]; ii a decarboxylase; iii a phenol oxidase [I.-tyrosine (35) z tyramine (36) zp-hydroxyphenylacetaldehyde (39)]; iv an amine oxidase [tyramine (36) > dopamine (37)]; v a transaminase [L-tyrosine (35) 2 L-dopa (34)] Scheme 3 alternating acetate-propionate pattern which is found similarly in the polyethers and macrolides that are produced much more widely by species of Streptomyces where butyrate is also often involved.2 Benzylisoqui no1ine Alkaloids It has been very well established that the benzylisoquinoline skeleton seen in simple form in e.g. reticuline (29) and in more complex form in e.g. jatrorrhizine (30) is formed from two molecules of tyrosine (35).6,7 On the other hand dopa (34) provides via dopamine (37 only the upper or isoquinoline part of benzylisoquinoline alkaloids [see (30)13* (cf.ref. 1 Vol. 11 p. 12). In well-detailed work it has been shown that there is a key biosynthetic enzyme called (5')-norlaudanosoline syntha~e~~ 34 (cf. ref. 3 p. 166) which catalyses the condensation of dopamine (37) with 3,4-dihydroxyphenylacetaldehyde(41) to give (5')-norlaudanosoline (32). The enzyme will accept p-hydroxyphenylacetaldehyde as an alternative substrate in which case the product is (5')-norcoclaurine (33) (cf. ref. 3 p. 166). There are known enzymes which will convert (5')-norlaudanosoline (32) into (9-reticuline (29) by a sequence of methyl at ion^.^^ The puzzling question if 3,4-dihydroxybenz- aldehyde does not arise from dopa where does it come from has been largely answered in two recent paper^.^^,^^ The incorporation into jatrorrhizine (30) of early precursors has been checked using vigorously growing callus tissue of Berberis canadensi~.~~ Very high incorporations were recorded (25-35 YO)and degradation allowed the relative distribution of activity between the two 'halves ' [see (30)] to be established.The precursors that were used with their distribution between the upper and lower portions shown in brackets were L-tyrosine (54 YO,46 YO),L-dopa (97 YO,3 Oh) tyramine (75 % and dopamine (85 YO,15YO). 25 YO) The last result is at variance with previous findings (that there was no incorporation into the lower half) but the first two are those expected from previous work.6,'The incorporation of dopamine and tyramine into the lower portion of (30) demonstrates that an amine oxidase must be active in the tissue to furnish the corresponding phenyl- acetaldehydes.This enzyme and others involved in tyrosine metabolism were investigated using Berberis cell cultures that produced large amounts of protoberberines. Following earlier work which demonstrated the presence of an aromatic-L-amino-acid decarboxylase a transaminase and a phenol oxidase in opium- NATURAL PRODUCT REPORTS 1988-R. B. HERBERT Me0 / p Me0 \ 0.0.@NMe@NMe /NMe 0 i X-LO (43) (44) ' - Tyrosine B O H j (S)-Coclaurine (45) (46 Scheme 4 v- (47) R1 =R2=Me (49) R' Rz =Me (48) R' R2 CH2 (50) R' R2 = containing Papaver species a decarboxvlase (considerably more active with dopa than with tyrosine) a transaminase (with similar activity towards the two amino acids) and a phenol oxidase (showing similar activity with tyrosine tyr-amine and p-hydroxyphenylacetaldehyde)were found in the Berberis cultures.35 An amine oxidase that acts mainly on tyramine and less on dopamine was also found as was a decarboxylase acting on p-hydroxyphenylpyruvate (also poss-ibly on 3,4-dihydroxyphenylpyruvate).Phenylacetaldehydes are the products in each case from these two enzymes.The routes which the enzymic and labelling results open up for the metabolism of tyrosinelp-hydroxyphenylpyruvatefrom shiki-mate metabolism to the benzylisoquinoline alkaloids are summarized in Scheme 3 (re-interpreted particularly in the light of ref.36). Further definition of the metabolic pathways must await future results; other do however circumscribe what may actually be going on. The fact that L-dopa (34) does not enter the lower portion of benzylisoquinoline alkaloids such as jatrorrhizine (30) (see discussion above) raises the possibility that norcoclaurine (33) [which is derived from (39)] rather than norlaudanosoline (32) [which is derived from (41)] is the true biosynthetic intermediate (cf Scheme 3). This has been the subject of careful examin-CH2 tissue leading to dilution of label passing through to the upper portion of the alkaloids. Since radioactive norlaudanosoline and norcoclaurine led to browning of the leaves if they were fed to plants (8-[0-methyl-''C]coclaurine [as (45)] was examined as a precursor.It was found to be an efficient (2.6 %) and specific precursor for (8-reticuline (29) in Annona reticulata [the (R)-isomer of coclaurine was not incorporated]. The (S)-coclaurine was also an efficient precursor in calli of Fumaria capreoluta for reticuline and all benzylisoquinolines in the culture. Similar results were obtained for other alkaloids based on the reticuline skeleton namely (i) the bisbenzylisoquinoline alkaloid berbamunine (42) and the protoberberines jatrorrhizine (30) and columbamine (31) in calli of Berberis stolonifera; (ii) the benzophenanthridine alkaloid macarpine (43) in cell cultures of Eschscholtziu californica ; and (iii) the morphinandienone alkaloid thebaine (44) in seedlings of Papaver somniferum (5.7 % incorporation which was shown to be specific).The (R)-enantiomer of labelled coclaurine showed absolutely no incorporation into these alkaloids except for (42) where it was efficiently and predominantly incorporated into the (R)-half of the molecule. It follows from the above evidence that the biosynthesis of (9-reticuline (29) and the alkaloids derived from it is by way of (S)-norcoclaurine (33) and (5')-coclaurine (45) (Scheme 4). This is a very important conclusion. It remains for the enzyme which carries out the 3'-hydroxylation of (45) to be isolated. As previous reviews in this series attest much is now known regarding the biosynthesis of tetrahydroprotoberberines and of the protopine and benzophenanthridine alkaloids e.g.san-guinarine (51) which are derived from them. N-Methyltetra-hydroprotoberberines are involved as intermediates and it is only the cis-N-methyl derivatives which are active3' (cf. ref. 2 p. 184). An important methyltransferase S-adenosyl-L-methionine :(S)-7,8,13,14-tetrahydroberberine cis-N-methyl-transferase has been identified38in cell cultures of a number of alkaloid-producing plant species using canadine (47) as substrate. The enzyme from Corydalis vaginans was isolated ati~n.~~ It was shown first that a mixture of ~-[2,6-~H]tyrosine and ~-[U-'~C]tyrosine was incorporated into (S)-reticuline (29) and (5')-coclaurine (45) in leaves of Annona reticulata. Both alkaloids had similar 3H/14Cratios which were close to the theoretical value (which shows that L-tyrosine was incorporated in the expected way and without degradation).Further it was found that in A. reticulata ~-[ring-U-'~C]tyrosine was used similarly for the two halves of coclaurine (45) and reticuline (29); the ratios were respectively 1:4.9 and 1:4.7. Thus the two alkaloids must have one and the same biosynthetic origin. Unusually (see for example above) L-tyrosine was found to label the lower (benzylic) portion of the alkaloids more heavily than the upper portion. This may be explained as the consequence of the large pool of dopamine found in the leaf NATURAL PRODUCT REPORTS 1988 d-," N (52) 153) 2.Methylation 1. Hydroxylation (,04 1.Hydroxylaiim c-____, 2.Methylation Me0 \ Me0 \ H Me CO Me CO,Me CO2Me Scheme 5 (56) purified and characterized. It is specific to (9-canadine (47) [lo0 %] and ($)-stylopine (48)[77%] that is to say it acts only on tetrahydroprotoberberinesof (5')-configuration that contain a methylenedioxy-group at C-2 and C-3 (which is reflected in the structures of the vast majority of protopine and benzo- phenanthridine alkaloids). The N-methylstylopine was trans- formed into protopine and sanguinarine (51) in cell cultures of Fumaria capreolata and may thus be assigned as the cis-compound (50). Further details (cf. ref. 5 p. 425) have been published39 on S-adenosyl-L-methionine :columbamine O-methyltransferase. It is a compartmentalized enzyme.An immobilized cell-culture system using calcium alginate beads has been successfully developed for the production of berberine by Thalictrum minus.40 A bioassay (antibacterial activity against Bacillus cereus) for screening the production of berberine in T. minus cells has been reported.41 The relationship between the production of berberine in T. minus plants and cell cultures has been An elicitor has been isolated from bakers' yeast which enhances the biosynthesis (up to four-fold) of berberine in cells of Thalictrum rugo~um.*~ Radioimmunoassay procedures have been developed for opium alkaloids and have been used for screening in Papaver species and for examining the time course of the appearance of alkaloids in germinating poppy Callus cultures of 34 Berberis cell lines have been screened for alkaloid^.^^ Jatrorrhizine (30) was always a major con- stituent; two lines of Berberis stolonifera were richest in bisbenzylisoquinoline alkaloids.The alkaloids of B. stolonifera V29 were isolated and identified. The time course of bisbenzyl- isoquinoline production in this cell line was studied. 3 Metabolites Derived from Tryptophan 3.1 Terpenoid Indole Alkaloids Aspects of research with tissue cultures of Catharanthus roseus have been reviewed by K~tney.~~ This research is mainly concerned with the propagation of stable cell lines for the production of the alkaloids catharanthine vinblastine and vincristine and also the biosynthesis and biotransformation of 3',4'-anhydrovinblastine.An enzyme (cinchoninone :NADPH oxidoreductase) has been isolated from cells of Cinchona ledgeriana which catalyses the reduction of cinchoninone (52) to an unequal mixture of cinchonine (53) and cinchonidine (54);in the latter case there is an epimerization of C-8of (52) to cinchonidinone prior to red~ction.~' The enzyme is present in two isoenzymic forms both of which are cytosolic act reversibly and have an absolute requirement for NADPH. Isoenzyme I acts specifically on cinchoninone in the forward direction and on cinchonidine cinchonine cupreine and cupreidine in the reverse direction whereas isoenzyme I1 has a broad specificity acting on all of the quinoline alkaloids of Cinchona species. Quinoline alkaloids such as quinine and cinchonine (53) are elaborated along a pathway involving intermediates which also yield more obviously terpenoid indole alkaloids such as ajmalicine and ajmaline (59).6,7.48 A key early intermediate is strictosidine.The activities of strictosidine synthase and tryptophan decarboxylase have been compared with the production of quinoline alkaloids in suspension cultures of C. ledgeriana which had been transformed with Agrobacterium tumefacien~.~~ Enzyme activities and production of alkaloids were both substantially greater in dark-grown cultures than in light-grown cultures. Activities of the enzymes were measured in relation to the age of the cultures. The effects of plant growth regulators on the growth and the production of alkaloids in callus cultures and suspension cultures of C.ledgeriana have been reported,50 as has the effect of age and growth regulators in leaf-shoot organ cultures of C. ledgeriana on alkaloid production.j' The toxicity of quinoline alkaloids towards cell cultures of C. ledgeriana has been noted.52 The stimulation by vanadyl sulphate of the production of ajmalicine and catharanthine in cultures of some cell lines of Catharanthus roseus has been 0bser~ed.j~ Multiple shoot cultures of C. roseus have been obtained and the alkaloid content has been measured.j4 Work on cells of C. roseus entrapped in calcium alginate has been reported,55 as has work on the effect of temperature on the production of alkaloids in cell cultures of C. rose~s.~~ Growth of seedlings of C.roseus in the dark leads to the accumulation of tabersonine (55) as a major alkaloid; enhanced accumulation of vindoline (56) resulted when the seedlings were NATURAL PRODUCT REPORTS 1988-R. B. HERBERT (64) R =H (65) transferred to the light.5' The pattern of alkaloid production suggested that the biosynthetic conversion of tabersonine (55) into vindoline (56) is as shown in Scheme 5. Other results suggested that the enzymes for tabersonine biosynthesis occur in all parts of the plant whereas the last five steps in the biosynthesis of vindoline are restricted to aerial parts and the whole pathway is developmentally regulated. The effect of drought and wounding stress on the production of terpenoid indole alkaloids in C.roseus plants has been noted.5s The results of work at the enzyme level have provided a clear picture of the late stages of the biosynthesis of ajmaline (61) and related alkaloids (cf. ref. 5 p. 427; ref. 3 p. 169; ref. 2 p. 185). A novel enzyme [named 2P(R)-17-0-acetyl- ajmalan :acetylesterase by the authors of ref. 591 has been isolated from suspension cultures of Rauwo@a serpentina and has been partially It converts 17-0-acetylated alkaloids of the type (62) into the corresponding deacetylated compounds e.g. ajmaline (61). This esterase shows high substrate specificity and accepts only acetylated ajmaline derivatives with the natural 2p (R) configuration ; structural differences tolerated were associated with ring D and the indolic nitrogen atom.Other properties of the enzyme which is seen to have a specific biosynthetic function were recorded. Earlier evidence which is supported by that reported here had shown that ajmaline (61) arises from the sarpagan skeleton through vinorine (57) vomilenine (58) acetylnorajmaline (60) and norajmaline (59) (cf. ref. 3 p. 169). Although the esterase is most active with 17-0-acetylnorajmaline (60) (K =22 pmol dm-3) 17-0-acetylajmaline (62) is also an excellent substrate (K =27 pmol dmd3) from which it may be concluded that an alternative pathway via (62) may also normally be operating. Overall it can be seen that the role of the esterase is finally to remove an U-acetyl protecting group that has been introduced 0 OMe (66) in order to stabilize the vinorine skeleton which would otherwise open to regenerate the sarpagan ring system.The highest enzyme activities were observed in the leaves and in cell suspension cultures of members of the Tribe Rauwolfieae which are known to synthesize ajmaline and its congeners. 3.2 Streptonigrin Investigation of the biosynthesis of streptonigrin (66) in Streptomyces flocculus has turned up most interesting results as a just reward for some elegant experiments (cf. ref. 5 p. 428 and ref. 3 p. 172). The focus of the current investigations is on the origins of rings A and B. Results of labelling experiments with [13C/14C]erythr~~e and [U-13]glucose show that ring A originates in the shikimate pathway with carbon atoms 4 3,2 and 6' being formed from an intact erythrose unit (cf.ref. 3 p. 172). The oxygen atom at C-5 was labelled by 1802 but not the oxygen atom at C-8 which suggested that this latter oxygen atom derived from a shikimate intermediate and that a later aromatic intermediate was 4-amino-3-hydroxyanthranilicacid (63).60 However this quinone oxygen is subject to ready exchange in water so any labelling by lsO2 may have disappeared by the time the streptonigrin was analysed. The origin of this oxygen atom is currently uncertain and therefore the status also of (63) as a biosynthetic intermediate.e1 However it has been shown61 that [4-15N]-4-aminoanthranilic acid [as (64)] is specifically incorporated into streptonigrin (66) with exclusive labelling of the 7-amino function.Further [4-2H]-7- aminoquinoline-2-carboxylicacid [as (65)] was well incor- porated with exclusive labelling of the hydrogen atom at C-4 in (66). These results indicate a pathway for the biosynthesis of streptonigrin (66) which involves (64) and (65). This represents a most interesting new metabolic diversion from the shikimate pathway (cf. ref. 5 p. 430; ref. 4 p. 193; ref. 3 p. 174; and ref. NATURAL PRODUCT REPORTS 1988 HO CHO Ery throse (63) 4-phosphate (R = CHO or COpH) Scheme 6 * - N / H O NH (67) Tryptophan (68) R =H (72) (69) R =OH (70) R = OMe OH - I I 0 Me COzH Me COZ H Me 0 (73) (74) (75) Scheme 7 (76) 2 p. 188). The formation of (65) is suggested to be as shown in Scheme 6 by analogy with the formation of tryptophan from anthranilic acid and ribose diphosphate.3.3 Miscellaneous Metabolites lac-labelled tryptophan (tryptamine was not incorporated) in which the specific activity of the alkaloids that were produced was noted.64 These results together with those obtained by incorporation of various alkaloids into others which were produced by the culture allowed a pathway to alkaloids such as (70) to be proposed. Canthin-6-one (68) is a key intermediate. phan in cultures of Chromobacterium violaceum reveal that violacein (67) is assembled from two molecules of tryptophan in the manner shown.62 A notable and unprecedented 1,2-migration of an indole unit during the biosynthesis of (67) is apparent. The incorporation of ~-[P-'*C]tryptophan into canthin-6-one (68) 1-hydroxycanthin-6-one (69) and 1-methoxycanthin-6- one (70) in cell suspension cultures of Ailanthus altissima has been reported.63 More extensive work has been carried out with Results of experiments with L-[P-'~C]- and ~~-[a-'~C]-trypto- It is formed from tryptophan via (71) and (72).By steps of hydroxylation 0-methylation and N-oxidation it is converted into alkaloids that have been found in the cultures of A. altissima. Other Of the Shikimate Pathway The biosynthesis of asukamycin acarbose reductiomycin actinorhodin and granaticin has been reviewed.65 NATURAL PRODUCT REPORTS 1988-R. B. HERBERT 531 C02H C02H HO" J// AH (78) (77) OH U H2Nx OZH Me H D -A lanine Scheme 8 4.1 Naphthyridinomycin demonstrates that the failure of radioactive shikimic acid to The origins of naphthyridinomycin (76) with the exception of label the C,N unit in (81) is not the result of a permeability C-9 and C-9' have been established66 (cf.ref.2 p. 187; ref. 4 problem. The cyclohexanecarboxylic acid unit in (8 1) derives p. 190). Tyrosine (73) is a precursor [labelling results shown on from shikimic acid (77) with retention of the carboxyl group (76)] but not dopa. This suggested that methylation of the ring (incorporation of [G-14C]shikimate).69 has been obtained on the biosynthesis might precede hydroxylation. This has been confirmed in Further informati~n~~ feeding experiments in Streptomyces lusitanus with 3-methyl[a- of the cyclohexylcarboxylic acid residue which corroborates 13C]tyrosine [as (74)] and 5-methyl[a-13C]dopa [as (75)].Both the results with shikimic acid. [c~rboxyl-~~C]Cyclohexane-precursors were efficiently and specifically incorporated in the carboxylic acid [as (79)] 1,4-dihydro[~arboxyl-'~C]benzoic acid appropriate manner. It was concluded that the biosynthesis of acid [as (80)] and 2,5-dihydro[carbo~yl-'~C]benzoic naphthyridinomycin (76) proceeds as shown in Scheme 7 [as (78)] were found to be efficient precursors but not [car- through (74) and (75) which were previously unknown natural b~xyl-'~C]benzoic acid or 2,5-dihydro-~~-[P-l~C]phenyl-alanine. Compounds (78) and (80) cannot both be directly on the normal biosynthetic pathway. However the detection of a minor metabolite in S.collinus with a cyclohex-1-ene 4.2 Ansamycins and Mitomycins ring favours 2,5-dihydro-compound (78) over the 1,Cdihydro-Ansatrienin A ( = mycotrienin I) (81) is one of a small number compound (80). of novel ansamycins. A notable feature of (81) is the cyclohexyl Several analogues of the mitomycins have been obtained residue that exists also in e.g. asukamycin (cf. ref. 4 p. 198). following the addition of amines to cultures of Streptomyces The results have a bearing on the biosynthesis of Results6* of experiments with [l-WIacetate and [ 1-13C]-caespito~us.~~ propionate have established part of the origins of (81) as these antibiotics but no clear conclusions can yet be reached illustrated in Scheme 8. As for other ansamycins (cf. ref. 4,p.(for the biosynthesis of the mitomycins see refs. 6 and 7 and 193 and refs. cited therein) the C unit originates in 3-amino- ref. 1 Vol. 12 p. 21). 5-hydroxybenzoic acid [very efficient and specific incorporation of 13C-labelled material (82)] in Streptomyces collin~s.~~ indicates 4.3 Tuberin and Xanthocillins Incorporation of label from ~-[methyl-'~C]rnethionine that the 0-methyl group originates from this source (no Some results relating to the biosynthesis of tuberin (87) in degradation to establish the labelling site). Results of experi- Streptomyces amakusaensis which were previously published in ments with 15N-labelled samples show that the D-alanine preliminary form71.72 (cf. ref. 4 p. 190) are now available in a moiety in (81) is derived directly from D-alanine rather than full paper.73 The results are concerned with the incorporation from L-alanine.Cyclohexylcarbonyl-D- and -L-alanine were of tyrosine threo-3-hydroxytyrosine,and glycine (83). C-2 of only utilized after hydrolysis which indicates that the side- glycine was incorporated into the 0-methyl and the N-formyl chain is formed by the addition of one component at a time.6g group of (87). These C units are reasonably the products of As in other cases radioactive shikimic acid (77) failed to tetrahydrofolate metabolism in which C-2 of glycine becomes label the C,N unit in (81) but served as an efficient precursor for linked to tetrahydrofolic acid through metabolism involving the cyclohexanecarboxylic acid residue. This result incidentally the glycine cleavage system.NATURAL PRODUCT REPORTS 1988 a HR.*? CO2H . u. R R Glycine (83) 3 0 OH Serine (86) f Scheme 9 From the results of experiments with glycine (83) chirally labelled with deuterium at C-2 it was deducedi3 that in the transformation of the amino acid through methylenetetra- hydrofolate (84) into methenyltetrahydrofolate (85) and thence into the N-formyl group of tuberin (87) the 2@ro-2S)-proton was retained with (partial) stereospecificity. From results in liver it is known that the conversion of (84) into (85) results in loss of the 1I@ro-l1R)-proton of (84).74 Thus the 2bro-29- proton in glycine becomes the ll@ro-llS)-proton in (84) as shown in Scheme 9. C-3 of serine (86) may also act as a source of C units via tetrahydrofolate metabolism; [3-14C]serine labels both the 0-methyl and the N-formyl group of (87).73 Investigation of the stereochemistry of the transformations of (86)+(84) +(85) + (87) shows that the 3@ro-3S)-proton of serine is preferentially retained in the N-formyl group of (87) and it follows that the 3(pro-3R)-proton in serine becomes the 1l(pro-1 1R)-proton in (84).75 This conclusion agrees with earlier resultsi4 from experi- ments in which an enzyme (serine hydroxymethyltransferase) was used which had been isolated from liver.As before only partial stereochemical control was observed in this process which contrasts with results for glycine where a higher degree of stereochemical identity was preserved. These results73 75 are in further accord with others obtained using a different system.76 The biosynthesis of the isocyanide functions which are found in a few natural products has been the subject of some attention and some success7' (cf.ref. 4 p. 190; ref. 2 p. 188; and ref. 5 p. 437). The origin of the isocyanide groups in the xanthocillins e.g. xanthocillin monomethyl ether (88) remains unknown.7s The origin lies not in C,-tetrahydrofolate metabolism nor apparently in other C sources potassium [14C]cyanate [14C]- carbamyl phosphate and [~reido-'~C]citrulline were incor-porated into (88) in Dichotomomyces cejpii to an insignificant extent." Potassium ["C 14C l5N]cyanide and [14C 13C 15N]-2- hydroxy-4-methylvaleronitrile(seen either as a 'protected' form of cyanide for safe delivery to the site of biosynthesis or as a representative of amino-acid metabolism found in plants which affords cyanogenic glycosides) were both satisfactory precursors for (88) but only the 0-methyl group was labelled in each case.Methionine may be metabolized to ethylene and hydrogen C- C- cyanide the latter being derived from C-2 of the amino acid. However [2-14C]methionine failed to label the isocyanide groups of (88). The conclusion is that cyanide is not a source of the isocyanide functions in (88) which contrasts with marine isocyanides (cf. ref. 5 p. 437). This is supported by other results. Careful comparison78 of the incorporation of DL-['~N]-tyrosine [15N]ammonium sulphate and ~-[amido-'~N]-glutamine shows that tyrosine is clearly the preferred source for the nitrogen atoms in (88).Since the skeleton derives largely from this amino acid it was concluded that the isocyanide functions in (88) are biosynthesized by attachment of an as yet unknown carbon atom to tyrosine or a derivative; in view of the evidence discussed above it would appear that this atom must on reaction be initially part of a unit larger than just a single carbon atom. What this is remains a mystery. NATURAL PRODUCT REPORTS 1988-R. B. HERBERT C02H (90) (93) COz H 4.4 Benzodiazepines Of several labelled amino acids which were tested as precursors for auranthine (89) in Penicillium auranteogriseum L-[U-'~C]-glutamine and [~arboxy-'~C]anthranilicacid gave positive incorporations of radioactivity.'? This information was used as aid in determining the structure of the metabolite.4.5 Actinornycin Two enzymes have been isolated from the actinomycin-synthesizing bacterium Streptomyces chrysomallus and purified. They were identified as peptide synthases involved in the biosynthesis of the peptidic part of actinomycin.80 For other studies on the biosynthesis of actinomycin particularly the phenoxazinone moiety see refs. 6 and 7 ref. 5 p. 429 and ref. 4 p. 190. Results of a study with a mutant of Streptomyces antibioticus provide information at the genetic level on the induction of phenoxazinone synthase (PHS) a key enzyme in the biosyn- thesis of actinomycin. The findings were suggested to be of general significance in the induction of enzymes involved in secondary metabolism.81 The gene for the 88000 Da subunit of PHS in Streptomyces antibioticus has been cloned and has been used to study the regulation of the enzyme in S.antibioticus.s2 Two other fragments of the S. antibioticus genome have also been cloned. These fragments appear to function by activating a normally silent PHS gene in the cloning host Streptomyces lividans (cJ ref. 4,p. 190). 4.6 Capsaicin Capsaicin is biosynthesized in part from phenylalanine via cinnamic acid.6 The incorporation of ~-[U-'~C]phenylalanine and [3-14C]cinnamic acid into this alkaloid in cultured cells of Capsicum frutescens has been studieds3 in relation to their growth. With immobilized cells generally higher levels of radioactivity were incorporated than with free cells in sus-pension culture.The accumulation of radioactive and total capsaicin was reduced in culture conditions which promote cell division. This suggests that protein and cell-wall metabolism are potential sinks for capsaicin precursors. 5 p-Lactams 5.1 Penicillins and Cephalosporins Work on the biosynthesis of these important antibiotics continues apace ; the area has been the subject of an authoritative reviews4 (for earlier reviews in this annual series see ref. 2 p. 190; ref. 3 p. 174; ref. 4 p. 193; and ref. 5 p. 432). An enzyme &(L-a-aminoadipyl)-L-cysteinyl-D-valine syn-thetase has been identified in cell-free preparations of Cephalosporium acremonium.86 It transforms L-a-aminoadipate plus L-cysteine plus L-valine into the tripeptide L,L,D-ACV (90) in the presence of Mg2+ and ATP.It is a multifunctional enzyme similar to those involved in the biosynthesis of some other peptide antibiotics; the conversion is not as suggested earlier a two-step process involving two enzymes with L-U-aminoadipyl-L-cysteine as an intermediate. The enzyme was found to accept some other amino acids as substrates. It is apparent that the L +D inversion of valine occurs during the formation of the tripeptide (90) since D-valine is not a substrate for the enzyme. The next step in the biosynthesis of penicillins and cephalosporins after the formation of (90) involves the cyclization of this tripeptide by isopenicillin-N synthase (IPNS) to give isopenicillin N (91).Isopenicillin-N synthase has been isolated from Streptomyces clavuligerus (a prokaryote) and purified." Its properties were found to be similar to those reported for IPNS from C. acremonium (a eukaryote). It has been founds7 that glucose represses the formation of (90) and represses IPNS in Penicillium chrysogenum but has no effect on the acyltransferase which catalyses the exchange of the acyl side-chain in (9 1). In Streptomyces lactarndurans glucose exerted a concentration-dependent negative regulation of the biosynthesis of cephamycin C (92).88 Excess glucose led to a decrease in the formation of (90). The ring-expanding enzyme deacetoxycephalosporin-C synthase was strongly repressed but IPNS and isopenicillin-N epimerase were not repressed.The IPNS genes from C. acremoniumsg and P. chrysogenumgo have been cloned in Escherichia coli. The protein-coding regions of the two genes were greater than 74% homologous and the predicted amino-acid sequences of the encoded proteins were about 73 % homologous. The extensive homology hampers attempts to draw conclusions about important regions in the two enzymes. Both proteins however contain two cysteine residues in exactly analogous regions. These cysteine residues may be involved in catalysis and/or binding of iron since it is known that sulphydryl-reactive reagents inactivate IPNS protein^.^' The cysteine residues in each protein have a histidine residue 5 to 10 amino-acid residues downstream.One or both of these residues may be involved in the binding of iron.go The cloned IPNS from C. acremonium has been purified.92 The value of K for the conversion of ACV into isopenicillin N was found to be identical with that for the fungal IPNS even though the N-terminus of the cloned enzyme has an additional glycine residue (processing of the proenzyme in C. acremonium removes a methionine and a glycine residue whereas in E. coli only the methionine residue is removed). The incubation of the ACV analogue (93) with recombinant IPNS gave the same penam and cepham products and in the same ratio as with the NATURAL PRODUCT REPORTS 1988 H [-4H] [-2H.+lo1 A H H AA-N AA-Ny4 + 0 I H COz H CO H (95) epimers (96) epimers (97) H AA-N H 0U& COZH (100) COzH ( 99) AA-N 0D Y C! h O H Scheme 10 fungal enzyme.Further the tripeptide (94) gave the same six products (95)-(98) with both enzymes (cf. ref. 93 and ref. 4 p. 194). In the examination of analogues of the natural tripeptide (90) as substrates for IPNS it has been found generally that the formation of bicyclic products involves desaturation but when unsaturation is present [as in (94) and (99)] two paths are followed simultaneously i.e. desaturation ( -4H) and hydrox- ylation (-2H; + 10)pathways (Scheme 10) (cf ref. 4 p. 194 and ref. 5 p. 433). It has now been shown using 1802 that the origin of the hydroxyl groups in (97) (98) and (101) is in molecular o~ygen.~' The other products as expected did not contain lSO.The competing hydroxylation and desaturation pathways indicate that the cyclization site on IPNS contains a reactive species which can abstract hydrogen or donate oxygen concomitant with formation of the C-S bond to give the sulphur-containing rings of the products. It has been hypoth- esized that this is an iron-oxo species and this has been used to rationalize the products observed.94 The enzymic conversion of phenylacetyl-L-cysteinyl-D-vahe into benzylpenicillin and of phenoxyacetyl-L-cysteinyl-D-vahe into penicillin V has been reported (cf. ref. 5 p. 433). Cell-free preparations of Streptomyces clavuligerus have been found to effect the former but not the latter transformation. No cephalosporin products were obtained.g5 The conversion of D,L,D-ACV into deacetoxycephalosporin C by a partially purified extract of Cephalosporium acremonium (cf.ref. 4 p. 194) has been examined Penicillin N is formed as an intermediate in the conversion as has been reported by others (cf. ref. 4 p. 194). The cyclization of both L,L,D-ACV (90) and D,L,D-ACV is inhibited by penicillin N. Only in the presence of 2-oxoglutarate does the reaction with D,L,D-ACV proceed rapidly. This is due to the rapid removal of CO H (103) penicillin N in the expandase reaction which yields deace- toxycephalosporin C. For analogues of ACV (90) to be effective substrates for IPNS they need to have a six-carbon or equivalent side-chain terminating in a carboxyl function (cf ref.4 p. 194). Those with phenylacetyl or phenoxyacetyl side-chains are converted slowly into p-lactam products (see above; cf. ref. 5 p. 433). It has now been demonstrated that rn-carboxyphenylacety1-L-cysteinyl-D-valine (102) where the side-chain may be seen to be analogous to that in (90) is an efficient substrate for IPNS from C. acremonium with similar Michaelis constants and maximum velocity parameters to the natural substrate (90).97 The results were interpreted as implying that once bound the m-carboxyl function in (102) helps to orientate the peptide into an optimal conformation for ring-closure at the catalytic site of the enzyme. The product of the enzymic transformation was (103) which showed 75 YOof the antibacterial activity of penicillin G against Staphylococcus aureus.NATURAL PRODUCT REPORTS 1988-R. B. HERBERT H .nu.,. I COZ H (104) R = CH,CO (105) R F3C2 N=N HH uu AA-N AA-N4-SH 0hY-R do2H CQH (106) R = CH=C=CH2 (108) R' = H R2 CH=C=CHZ (107) R = CH,CH=C=CH (109) R' =CH=C=CH2,RZ = H I do H C02H (110) (111) R' = H R2= CH=C=CH (112) R' =CH=C=CH2,q2 H HO ".OH; HO COZH HS c5 I (118) The biosynthesis of cephalosporins involves the ring-expansion of penicillin N (1 14) to deacetoxycephalosporin C (115); penicillin N (114) is derived by epimerization of isopenicillin N (91). The ring-expansion activity from C. acremonium has been purified and a number of analogues of (1 14) have been examined as substrates for the enzyme.lo0 For reasonable ring-expansion of penam into cephem derivatives a six-carbon N-acyl side-chain was found to be necessary.This is broadly similar to the requirements of IPNS with the exception of the inability of the ring-expansion enzyme to process (AA isopenicillin N (91) (with L-configuration in the side-chain). C02H In both the formation of the crucial C-S bond in the uHH CO H (115) The m-and p-acetyl analogues of both phenoxyacetyl- and phenylacetyl-L-cysteinyl-D-valinehave been found to act as substrates for IPNS.98 The meta-substituted analogue (104) was converted into products most efficiently. Following this finding and as a preliminary to probing the action of IPNS by photo- affinity labelling the analogue (105) has been found to be converted into a p-lactam product.Following the interesting outcome of the reaction of the unsaturated tripeptides (94) and (99) with IPNS (Scheme lo) the allenic compounds (106) and (107) have been examined as substrates for homogeneous IPNS from C. acremoni~m.~~ In each case only the products of desaturative ring-closure i.e. (108) (109) and (110) from (106) and (lll) (112) and (113) from (107) were obtained. biosynthesis of isopenicillin N (9 1) and the ring-expansion of (1 14) to (1 15) a free radical or its equivalent i.e. a very weak ironxarbon bond derived from an iron-oxo species may be implicated. The chemical feasibility of a free-radical process has been successfully modelled.101 Evaluation by bioassay of the enzyme phenylacetyl-CoA :6-aminopenicillanic acid acyltransferase of Penicillium chryso- genum has been reported as have the optimal catalytic conditions for the enzyme.lo2 5.2 Clavulanic Acid Thienamycin and Tabtoxin Clavulanic acid (1 18) is biosynthesized from a C and a C unit as illustrated.D-Glycerate [as (1 17)] has been identified as a late intermediate for the C moiety and glycerol (1 16) can also serve as a precursor for it (cf ref. 4 p. 197). It has now been shown using (1 R,2R)- and (1 S,2R)-[ 1,3-14C 1-3Hl]glycerol [as (1 16)] as a labelled probe that the l(pro-lS,2R)-proton in glycerol is largely lost in clavulanic acid (1 18) whereas the l(pro-lR,2R)- proton is largely retained. lo3 The (pro-2R)-hydroxymethylene of (1 16) becomes C-5 in (1 18) so the ring-closure which yields the p-lactam ring proceeds with retention of stereochemistry.It is notable that the formation of the /?-lactam ring during biosynthesis of penicillin also occurs with retention of stereo- chemistry. Both carbon atoms of the hydroxyethyl side-chain of thienamycin (1 19) originate from the methyl group of meth- ionine (cf. ref. 5 p. 436). The observation that all of the hydrogens in the side-chain are carried over from methionine was confirmed in an experiment with [methyl-T methyl-2H3]- methionine in cultures of Streptomyces cattleya.lo4 The stereochemical fate of the methyl group of methionine when it is incorporated into (1 19) has been explored with L- 536 A [MeIMethionine m = L -Threonine 0 * = L -Aspartate = C2 unit from glycerol * (120) " IOH Scheme 11 (methyl-R)- and L-(methyf-S)-[methyl-zHl, methyl-3Hl]meth-ionine.lo4 Degradation of (119) yielded chiral acetic acid of opposite chirality from each precursor and analysis revealed that the former was of (R)chirality and the latter of (5') chirality i.e.methylation of C-8 in (1 19) proceeds with overall retention of configuration. Methylation was suggested to occur through transfer of the methyl group (without loss of hydrogen at any stage; see above) by two steps each involving an inversion; a corrin is possibly involved (cf. ref. 105). Tabtoxin (120) is an exotoxin of the phytopathogenic bacterium Pseudomonas tabaci which induces the disease wildfire (a leaf spot disease) on tobacco plants.Following initial experiments with l4C-labe1led precursors experiments with 13C-labelled methionine aspartate glycerol and acetate were carried out. As expected L-threonine is the direct precursor of the threonine moiety of (120). The building blocks for the remainder of the skeleton of (120) are L-aspartate the methyl group of methionine and a C unit derived from the C pool ([13C,]acetate did not label this C unit) (Scheme 1l).lo6 Many intriguing questions remain concerning the biosynthesis of tabtoxin (120) notably that concerned with the mechanism of formation of the p-lactam ring where at some stage the methyl group derived from methionine has undergone extensive oxidation. 6 Miscellaneous Metabolites Valine and alanine stimulate the production of valanimycin (121) in cultures of Streptomyces viridifaciens.Results of experiments with labelled samples of valine and alanine indicate that the isobutyl moiety of (121) derives from the former amino acid whilst the acrylate moiety is formed from alanine (efficient incorporations were observed ; radioactivity from labelled alanine was also incorporated into the isobutyl fragment).'" The biosynthesis of acivicin (126) and 4-hydroxyacivicin (127) in Streptomyces sviceus has been shownlos to be from an intact molecule of ornithine ~~-[2-'~C]ornithine [as (122)] was efficiently incorporated into the two metabolites and DL-[~-'~ C,5-'4C,5-'5N]ornithine (122) was incorporated intact (analysis by 13C n.m.r.; J, = 2.7 Hz; upfield isotope shift of 1.4 Hz for both).Neither DL-[ l-'4C]glutamic acid [as (123)] nor L-[U-'~C]- glutamine [as (124)] yielded radioactive (126) and (127). This is a curious contrast with the results for ornithine because C-5 in these compounds is of the same oxidation level as C-5 in the metabolites. NATURAL PRODUCT REPORTS 1988 I - I (122) R = '3?H2'5:H2 (125) (123) R = C02H (124) R = CONHz 8N"qC02H'0 '\ H NH2 (126) R = H (127) R =OH A t Ii Me0A N H2 HOCH,CH-' 'CO,Hx' (128) L -Serine #&&$DH2 * A CHj-COzH _it D CD2H The subsequent metabolism of ornithine was probedlos with HOA [2,3,3-zH,]ornithine deuterium was only incorporated into 0' CN "0-C-CDHz II 0' C-3.The absence of deuterium at C-2 correlates with a similar (129) R = AC finding for the biosynthesis of streptothricin F which also Y = ''0 frorn'802 (130)R H involves a P-hydroxylation (in this case of arginine; cf. ref. 3 p. = l80 from acetate \' OH 1 A 176). In both cases the loss of hydrogen from C-2 may be associated with hydroxylation at C-3. The compound (125) may be an intermediate in the biosynthesis of (126) and (127). 0 The biosynthetic origins of rhizoxin (128) in Rhizopus chinensis have been mapped with precursors that bear stable isotopic labels [see (128)].'09 Preliminary experiments with radioactive precursors showed that acetate and methionine but not propionate were involved. ['3C,]Glycine was examined as a precursor and was found to label the units derived from serine and methionine.A clear picture has emerged from the incorporation of (132) (133) R = H (134) R = OH labelled acetate (['3Cc,]- [1-'3C,2H3]- and [1-'3C,'80,]-acetate) Scheme 12 NATURAL PRODUCT REPORTS 1988-R. B. HERBERT Am CH C-CO;,H 3-~ I 0 0 \ =-"in;. (135) R H o=r 7 (137) 1' HOZ C 0 (136) R =OH CH3-CO; H 0 r---- and lSO,,of the origins and course of biosynthesis of kinamycins C (129) and D (130) in Streptomyces murayamaensis."O The results are summarized in Scheme 12. The skeleton is derived entirely from acetate and the involvement of two polyketide chains is apparent as is the requirement that neither of the polyketide molecules passes through a symmetrical inter- mediate ; (1 32) (1 33)/( 134) and (1 3 1) are reasonable inter- mediates in the biosynthesis of the kinamycins.The putative intermediate (1 34) is juglone which interestingly derives in other systems from shikimate and glutamate. The absence of deuterium labelling at C-1' and (2-3' of (129)/ (130) is notable. The latter may be associated with (131) as an intermediate and the former with C-1' being at some point part of an aromatic ring with the hydroxyl group present. The oxygen at C-3' was not labelled by either lS0-containing precursor so it must derive from water which indicates that there is an intermediate epoxide bridging C-2' and C-3' which is opened by the addition of water at C-3'.The origin of the cyano-group remains to be established. The coronofacic acid moiety (136) of the phytotoxin coronatine (135) has been shown to derive in Pseudomonas syringae pv. glycinea from five molecules of acetate [see (137)] with pyruvate strikingly serving as the starter unit for one of the polyketide chains."' The aminocyclopropane moiety of H Y HO OH (138) Ade = adenin -9-yl (1 35) has been clearly demonstrated to originate in isoleucine a mixture of DL-[ I-13C]isoleucine and DL-[ 1-13C]alloisoleucine led to labelling of C-1' (for earlier reports see ref. 4 p. 198 and ref. 5 p. 436). The streptothricin-resistance gene of Streptomyces lavendulae has been cloned in Streptomyces lividans; the gene product was streptothricin acetyltransferase112 (for the biosynthesis of streptothricin see ref.3 p. 176). Prodigiosin-condensing enzyme which is responsible for the last step in the biosynthesis of prodigiosin has been identified in wild Serratia marcescens and in several mutants113 (for biosynthetic studies see refs. 6 and 7). Using cell-free extracts of Streptomyces incarnatus it has been shown that the immediate biosynthetic precursors for sinefungin (1 38) are L-arginine and ATP.l14 A pyridoxal-linked arginine adduct was proposed as the activated intermediate for condensation with ATP. The unusual oxazole ring in virginiamycin M (139) is biosynthesized by way of an acylserine intermediate (cf. ref. 3 p. 177 and ref. 4 p. 199). Samples of L-(~R)-[~-~H,]- and L-(~S)- [3-3H,]-serine as well as labelled L-and DL-serine have been used to probe the conversion of the amino acid into the oxazole moiety of (139) in Streptomyces virginiae.'15 The L-serine was a better precursor than racemic material ;the 3(pro-3R)-hydrogen was retained whilst the 3(pro-3S)-hydrogen was lost.Possible routes were discussed for the conversion from an intermediate (140) which is formed from L-serine. Generally so far as is known for secondary metabolites dehydrogenations proceed with syn stereochemistry which argues against such a pathway here. Virginiamycin S (141) contains an L-phenylglycine fragment. Its derivation from phenylalanine has been explored in an experiment with DL-[3-l3C 15N]phenylalanine in S. virginiae.l16 A specific incorporation of 13Clabel was observed but not of "N label indicating that the conversion of phenylalanine into phenylglycine involves a nitrogen-free intermediate.A useful check that loss of 15N label was not via simple competing transamination was provided by demonstrating that a signifi- cant amount of double label was incorporated into the N-methylphenylalanine moiety of (141) [for related work on the NATURAL PRODUCT REPORTS 1988 biosynthesis of nocardicins which are formed in part from L-@-hydroxyphenyl)glycine see ref. 4 p. 197 and refs. cited therein]. Deox ystreptamine i'-Neosamine B Scheme 13 0 1.oxidation at C-4 or C-5 OH 2. Tautomerism (143) HO W O O H -0 OH C.OH OH I 2-Deoxystreptamine in (142) Scheme 14 (OH A 0-7 0*o 0 0 o -[~-'~~lg\ucose D -[6-13~ ]glucose A o -[1-'3C]mannosem Inducing factors for the production of virginiamycin anti- biotics have been isolated from S.virginine."' It has been shown that the neosamine C ring in neomycin B (142) is formed from D-ghCOSe (143) vin D-ghcosamine by a route in which C-6 of glucose becomes C-6 of the neosamine C residue in (142) and the incorporation of the amino-group probably occurs as shown in Scheme 13 (cf. ref. 2 p. 192). Further examination of the biosynthesis of the neosamine B ring in (142) shows that C-6 in this unit is derived similarly (Scheme l3)."* Tritium-labelling experiments showed that the hydrogen atom at C-4 of D-glucose was retained when the neosamine B residue in (142) was formed whilst that at C-5 in (143) was largely lost.The results show that the inversion of configuration at C-5 which occurs in the conversion of (143) into the neosamine B residue of (142) occurs by way of an enolization reaction that involves a carbonyl at C-6 (but not one at C-4) i.e. the one involved in the amination reaction (Scheme 13). The partial retention of tritium at C-5 has been interpreted as arising from partial return of a labelled proton from the basic catalytic site(s) in the epimerase."* The 2-deoxystreptamine ring of (142) is also formed from D-glucose (143) C-6 of this precursor provides C-2 of the deoxy- streptamine and without loss of the 6-proton~"*,"~ (cf. ref. 2 p. 192). Further results120 show that the proton at C-3 of (143) is retained whilst that at C-4 is lost during bio- synthesis of 2-deoxystreptamine.The mechanism for ring- closure indicated by these results is illustrated in Scheme 14. The valienamine (144) and validamine (145) moieties of the validamycins resemble the C,N units found in for example geldanamycin and pactamycin. The units in these latter antibiotics are constructed from C +C units derived from glucose a pattern which is the same as in the biosynthesis of metabolites of the shikimate pathway (cf. ref. 1 Vol. 13 p. 22 and Vol. 12 p. 24). Poor incorporations of glycolate and glycerate into (144) and (145) in Streptomyces hygroscopicus var. limoneus cast doubt on such a manner of construction for (144) and (I45),lz1 since both precursors were well incorporated into geldanamycin.A very low incorporation of methionine excluded a C plus C pathway. The pattern of incorporation of ~-[U-'~C]glucose however revealed that the valienamine unit (144) in validamycin A is made up of a new combination of C +C +C,. Incorporation of other labelled precursors (Scheme 15) also demonstrated a labelling pattern different from that of a shikimate-related pathway. It appeared that glucose mannose and ribose underwent cleavage between C-2 and C-3 (non-oxidative pentose phosphate pathway) and that the C fragment was derived from D-glyceraldehyde 3-phosphate by way of the glycolytic pathway. Sedoheptulose 7-phosphate or ~-ido-heptulose 7-phosphate were considered to be likely late intermediates.Similar conclusions have been briefly reported for the valienamine moiety of acarbo~e.~~ 0-[l-'3Clribose 0 0-[2-"C]ribose A Scheme 15 NATURAL PRODUCT REPORTS 1988-R. B. HERBERT I HN 7jC0,H H (146) It has been established that ~-azetidine-2-carboxylicacid (146) is biosynthesized (in Convallaria majalis) from methionine and several closely related compounds. lZ2It was concluded that (146) was probably biosynthesized by direct cyclization of S-adenosyl-L-methionine. Alternative routes have been explored in a set of experiments with DL-[I-’T lSN]rnethionine (RS)-[ 1-W 2J5N]- and (RS)-[ I-l4C 4-1SN]-2,4-diaminobutanoic acid and [l-13C ~arboxyl-’~C lSN]-1-aminocyclopropane-1-carboxylic The labelled methionine was the most efficient precursor and ‘jN and ‘T label were similarly well incorporated; a direct and intact incorporation of the precursor is thus indicated.The aminocyclopropanecarboxylic acid was not incorporated and the results with the diaminobutanoic acid samples were interpreted as showing that it is incorporated by way of methionine. Loss of the 2-proton (tritium) in methionine which was reported earlier,lZ2 was rationalized as being through deproto- nation-re-protonation of a pyridoxal-linked intermediate formed at an earlier stage of biosynthesis from methionine.lZ3 7 References 1 R. B. Herbert in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Chemical Society/The Royal Society of Chemistry London 1978-1983 Vols.8-13. 2 R. B. Herbert Nut. Prod. Rep. 1984 1 181. 3 R. B. Herbert Nut. Prod. Rep. 1985 2 163. 4 R. B. Herbert Nut. Prod. Rep. 1986 3 185. 5 R. B. Herbert Nut. Prod. Rep. 1987 4 423. 6 R. B. Herbert in “Rodd’s Chemistry of Carbon Compounds” ed. S. Coffey Elsevier Amsterdam 1980 2nd edn. Vol. IV Part L p. 291. 7 R. B. Herbert. ‘The Biosvnthesis of Secondarv Metabolites’. Chapman and Hall London 1981. 8 E. Leete J. Nut. Prod. 1987 50 30. 9 E. Leete Can. J. Chem. 1987 65 266. 10 R. V. Platt C. T. Opie and E. Haslam Phytochemistry 1984 23 2211. 11 T. Hashimoto Y. Yukimune and Y. Yamada J. Plant Physiol. 1986 124 61. 12 E. Zador and D. Jones Plant Physiol. 1986 82 479. 13 L. Fowden J. Exp. Bot.1960 11 302. 14 J. J. M. Meyer and N. Grobbelaar Phytochemistry 1986 25 1469. 15 A. Ide K. Nagano N. Tanaka K. Iwasaki Y. Yamane D. Koga K. Yagishita K. Nakao Y. Kurisu N. Fujioka H. Kohda H. Miyagawa and K. Yamasaki Phytochemistry 1987 26 145. 16 R. J. Parry R. Mafoti and J. M. Ostrander J. Am. Chem. Soc. 1987 109 1885. 17 U. Hildebrand K. Taraz and H. Budzikiewicz Z. Naturforsch. Sect. C 1986 41 691. 18 T. Hartmann and G. Toppel Phytochemistry 1987 26 1639. 19 E. K. Kunec and D. J. Robins J. Chem. Soc. Chem Commun. 1985 1450. 20 E. K. Kunec and D. J. Robins J. Chem. Soc. Perkin Trans. 1 1987 1089. 21 E. K. Kunec and D. J. Robins J. Chem. Soc. Chem. Commun. 1986 250. 22 H. A. Kelly and D. J. Robins J. Chem. Soc. Perkin Trans.I 1987 177. 23 A. M. Fraser and D. J. Robins J. Chem. Soc. Chem. Commun. 1984 1477. 24 A. M. Fraser and D. J. Robins J. Chem. Soc.. Perkin Trans. I 1987 105. 25 W. M. Golebiewski and I. D. Spenser Can. J. Chem. 1985 63 2707. 26 D. J. Robins and G. N. Sheldrake J. Chem. Res. 1987 (S),159; (M) 1427. 27 T. Hemscheidt and I. D. Spenser Can. J. Chem. 1987 65 170. 28 M. Wink and L. Witte Z. Naturforsch. Sect. C 1987 42 197. 29 A. Rother J. Nut. Prod. 1985 48 33; L. A. Pelosi A. Rother and J. M. Edwards Phytochemistry 1985 24 2215. 30 L. A. Pelosi A. Rother. and J. M. Edwards. Phvtochemistrv. 1986 25 2315. 31 F. J. Leeper P. Padmanabhan G. W. Kirby and G. N. Shel-drake J. Chem. Soc. Chem. Commun. 1987 505. 32 H. L. Holland P.W. Jeffs T. M. Capps and D. B. MacLean Can. J. Chem. 1979 57 1588. 33 H.-M. Schumacher M. Rueffer N. Nagakura and M. H. Zenk Planta Med. 1983 48 212. 34 M. H. Zenk M. Rueffer M. Amann B. Deus-Neumann and N. Nagakura J. Nut. Prod. 1985 48 725. 35 M. Rueffer and M. H. Zenk Z. Naturforsch. Sect. C. 1987 42 319. 36 R. Stadler T. M. Kutchan S. Loeffler N. Nagakura B. Cassels and M. H. Zenk Tetrahedron Lett. 1987 28 1251. 37 N. Takao M. Kamigauchi and M. Okada Helv. Chim. Acta 1983 66 473. 38 M. Rueffer and M. H. Zenk Tetrahedron Lett. 1986 27 5603. 39 M. Rueffer M. Amann and M. H. Zenk Plant Cell Rep. 1986,5 182. 40 Y. Kobayashi H. Fukui and M. Tabata Plant Cell Rep. 1987,6 185. 41 T. Suzuki T. Yoshioka Y. Hara M. Tabata and Y.Fujita Plant Cell Rep. 1987 6 194. 42 M. Suzuki N. Nakagawa H. Fukui and M. Tabata Plant Cell Rep. 1987 6 260. 43 C. Funk K. Giigler and P. Brodelius Phytochemistry 1987 26 401. 44 U. Wieczorek N. Nagakura C. Sund S. Jendrzejewski and M. H. Zenk Phytochemistry 1986 25 2639. 45 B. K. Cassels E. Breitmaier and M. H. Zenk Phytochemistry 1987 26 1005. 46 J. P. Kutney Heterocycles 1987 25 617. 47 J. E. Isaac R. J. Robins and M. J. C. Rhodes Phytochemistry 1987 26 393. 48 R. B. Herbert in ‘Indoles Part 4 The Monoterpenoid Indole Alkaloids’ ed. J. E. Saxton Wiley New York 1983 p. 1. 49 S. E. Skinner N. J. Watson R. J. Robins and M. J. C. Rhodes Phytochemistry 1987 26 721. 50 A. H. Scragg P. Morris and E. J. Allan J. Plant Physiol.1986 124 371; R. J. Robins J. Payne and M. J. C. Rhodes Planta Med. 1986 220; M. J. C. Rhodes J. Payne and R. Robins ibid. p. 226. 51 C.-T. A. Chung and E. J. Staba Planta Med. 1987 206. 52 N. J. Walton A. J. Parr R. J. Robins and M. J. C. Rhodes Plant Cell Rep. 1987 6 118. 53 J. I. Smith N. J. Smart M. Misawa W. G. W. Kurz S. G. Tall- evi and F. DiCosmo Plant Cell Rep. 1987 6 142. 54 K. Hirata A. Yamanaka N. Kurano K. Miyamoto and Y. Miura Agric. Biol. Chem. 1987 51 1311. 55 F. Majerus and A. Pareilleux Plant Cell Rep. 1986 5 302. 56 P. Morris Plant Cell Rep. 1986 5 437. 57 V. DeLuca J. Balsevich R. T. Tyler U. Eilert B. D. Panchuk and W. G. W. Kurz J. Plant. Physiol. 1986 125 147. 58 P. M. Frischknecht M. Battig and T. W. Baumann Phytochem-istry 1987 26 707.59 L. Polz H. Schiibel and J. Stockigt Z. Naturforsch. Sect. C 1987 42 333. 60 W. R. Erickson and S. J. Gould J. Am. Chem. SOC.,1985 107 583 1. 61 W. R. Erickson and S. J. Gould J. Am. Chem. Soc. 1987 109 620. 62 T. Hoshino T. Kondo T. Uchiyama and N. Ogasawara Agric. Biol. Chem. 1987 51 965. 63 L. A. Anderson C. A. Hay M. F. Roberts and J. D. Phillipson Plant Cell Rep. 1986 5 387. 64 N. Crespi-Perellino A. Guicciardi and G.Malyszko J. Nat. Prod. 1986 49 814. 65 H. G. Floss,P.J. Keller and J. M. Beale,J. Nat. Prod. 1986,49,957. 66 M. J. Zmijewski Jr. V. A. Palaniswamy and S. J. Gould J. Chem. Soc. Chem. Commun. 1985 1261; M. J. Zmijewski Jr. M. Mikolajczak V. Viswanatha and V. J. Hruby J. Am.Chem. Soc. 1982 104 4969; M. J. Zmijewski Jr. J. Antibiot. 1985 38 819. 67 V. A. Palaniswamy and S. J. Gould J. Am. Chem. Soc. 1986 108 565 1. 68 M. Sugita K. Furihata H. Seto N. dtake and T. Sasaki Agric. Biol. Chem. 1982 46 11 11 ; M. Sugita T. Sasaki K. Furihata H. Seto and N. dtake J. Antibiot. 1982 35 1467. 69 T.4. Wu J. Duncan S.-W. Tsao C.-J. Chang P. J. Keller and H. G. Floss J. Nat. Prod. 1987 50 108. 70 C. A. Claridge J. A. Bush T. W. Doyle D. E. Nettleton J. E. Moseley D. Kimball M. F. Kammer and J. Veitch J. Antibiot. 1986 39 437. 71 R. B. Herbert and J. Mann J. Chem. SOC.,Chem. Commun. 1983 1008. 72 R. B. Herbert and J. Mann J. Chem. SOC.,Chem. Commun. 1984 1474. 73 K. M. Cable R. B. Herbert and J.Mann J. Chem. Soc. Perkin Trans. 1 1987 1593. 74 L. J. Slieker and S. J. Benkovic J. Am. Chem. Soc. 1984 106 1833. 75 K. M. Cable R. B. Herbert V. Bertram and D. W. Young Tet-rahedron Lett. 1987 28 4101. 76 D. J. Aberhart and D. J. Russell J. Am. Chem. Soc. 1984 106 4902; ibid. p. 4907. 77 M. Edenborough and R. B. Herbert Nat. Prod. Rep. 1988 5 229. 78 K. M. Cable and R. B. Herbert Tetrahedron Lett. 1987 28 3159. 79 S. E. Yeulet P. G. Mantle J. N. Bilton H. S. Rzepa and R. N. Sheppard J. Chem. Soc. Perkin Trans. I 1986 1891. 80 U. Keller J. Bid. Chem. 1987 262 5852. 81 K. Ochi Agric. Biol. Chem. 1987 51 829. 82 G. H. Jones J. Nat. Prod. 1986 49 981. 83 K. Lindsey Phytochemistry 1986 25 1986. 84 E. P. Abraham and J. E. Baldwin Nat.Prod. Rep. 1988 5 129. 85 G. Ranko A. L. Demain and S. Wolfe J. Am. Chem. SOC.,1987 109 2858. 86 S. E. Jensen B. L. Keskiw L. C. Vining Y. Aharonowitz D. W. S. Westlake and S. Wolfe Can. J. Microbiol. 1986 32 953. 87 G. Revilla F. R. Ramos M. J. Lopez-Nieto E. Alvarez and J. F. Martin J. Bacteriol. 1986 168 947. 88 J. Cortes P. Liras J. M. Castro and J. F. Martin J. Gen. Micro- biol. 1986 132 1805. 89 S. M. Samson R. Belagaje D. T. Blankenship J. L. Chapman D. Perry P. L. Skatrud R. M. VanFrank E. P. Abraham J. E. Baldwin S. W. Queener and T. D. Ingolia Nature (London) 1985 318 191. 90 L. G. Carr P. L. Skatrud M. E. Scheetz 11 S. W. Queener and T. D. Ingolia Gene 1986 48 257. 91 J. E. Baldwin J. Gagnon and H.-H. Ting FEBS Lett.1985,188 253. 92 J. E. Baldwin S. J. Killin A. J. Pratt J. D. Sutherland N. J. Turner M. J. C. Crabbe E. P. Abraham and A. C. Willis J. Antibiot. 1987 40 652. 93 J. E. Baldwin R. M. Adlington A. E. Derome H.-H. Ting and N. J. Turner J. Chem. Soc. Chem. Commun. 1984 1211. 94 J. E. Baldwin R. M. Adlington S. L. Flitsch H.-H. Ting and N. J. Turner J. Chem. SOC.,Chem. Commun. 1986 1305. 95 S. E. Jensen D. W. S. Westlake R. J. Bowers L. Lyubechansky and S. Wolfe J. Antibiot. 1986 39 822. 96 A. L. Demain Y.-Q. Shen S. E. Jensen D. W. S. Westlake and S. Wolfe J. Antibiot. 1986 39 1007. NATURAL PRODUCT REPORTS 1988 97 J. E. Baldwin R. M. Adlington M. J. C.Crabbe G.C. Knight T. Nomoto and C. J. Schofield J. Chem. SOC.,Chem. Commun. 1987 806.98 J. E. Baldwin A. J. Pratt and M. G.Moloney Tetrahedron 1987 43 2565. 99 J. E. Baldwin R. M. Adlington A. Basak and H.-H. Ting J. Chem. Soc. Chem. Commun. 1986 1280. 100 J. E. Baldwin R. M. Adlington J. B. Coates M. J. C. Crabbe J. W. Keeping G. C.Knight T. Nomoto C. J. Schofield and H.- H. Ting J. Chem. SOC.,Chem. Commun. 1987,374; J. E. Baldwin R. M. Adlington M. J. C. Crabbe G.C. Knight T. Nomoto C. J. Schofield and H.-H. Ting Tetrahedron 1987 43 3009. 101 J. E. Baldwin R. M. Adlington T. W. Kang E. Lee and C.J. Schofield J. Chem. Soc. Chem. Commun. 1987 104. 102 J. M. Luengo J. L. Iriso and M. J. Lopez-Nieto J. Antibiot. 1986 39 1565. 103 C. A. Townsend and S.-S.Mao J. Chem. Soc. Chem. Commun. 1987 86. 104 D. R.Houck K. Kobayashi J. M. Williamson and H. G. Floss J. Am. Chem. SOC.,1986 108 5365. 105 T. M. Zydowsky L. F. Courtney V. Frasca K. Kobayashi H. Shimizu L.-D. Yuen R. G. Matthews S. J. Benkovic and H. G. Floss J. Am. Chem. SOC.,1986 108 3152. 106 B. Miiller A. Hadener and Ch. Tamm Helv. Chim. Acta 1987 70 412. 107 M. Yamato T. Takeuchi H. Umezawa N. Sakata H. Hayashi and M. Hori J. Antibiot. 1986 39 1263. 108 S. Ju V. A. Palaniswamy P. Yorgey and S. J. Gould J. Am. Chem. SOC.,1986 108 6429. 109 H. Kobayashi S. Iwasaki E. Yamada and S. Okuda J. Chem. Soc. Chem. Commun. 1986 1702. 110 Y. Sato and S. J. Gould J. Am. Chem. Soc. 1986 108 4625. 11 1 R. J. Parry and R. Mafoti J. Am. Chem. SOC.,1986 108 4681. 112 T. Kobayashi T.Uozumi and T.Beppu J. Antibiot. 1986,39,688. 113 L. K. N. Cho J. A. Lowe R. B. Maguire and J. C. Tsang Ex-perrentia 1987 43 397. 114 H. Malina C. Tempete and M. Robert-Gero J. Antibiot. 1987 40 505. 115 M. B. Purvis D. G.I. Kingston N. Fujii and H. G. Floss J. Chem. Soc. Chem. Commun. 1987 302. 116 J. W. Reed and D. G. I. Kingston J. Nat. Prod. 1986 49 626. 117 Y. Yamada K. Sugamura K. Kondo M. Yanagimoto and H. Okada J. Antibiot. 1987 40 496. 118 S. K. Goda W. Al-Feel snd M. Akhtar J. Chem. SOC.,Perkin Trans. I. 1986 1383. 119 M. J. S. Eward W. Al-reel and M. Akhtar J. Chem. SOC.,Chem. Commun. 1983 20. 120 S. K. Goda and M. Akhtar J. Chem. Soc. Chem. Commun. 1987 12. 121 T. Toyokuni W.-Z. Jin and K. L. Rinehart Jr. J. Am. Chem. Soc.1987 109 3481. 122 E. Leete G. E. Davis C. R. Hutchinson K. W. Woo and M. R. Chedekel Phytochemistry 1974 13 427. 123 E. Leete L. L. Louters and H. S. P. Rao Phytochemistry 1986 25 2753.

ISSN:0265-0568    

DOI:10.1039/NP9880500523

出版商:RSC    

年代:1988

数据来源: RSC