摘要:

Sesquiterpenoid Synthesis J. S. Roberts Department of Chemistry University of Stirling Stirling FK9 4LA Scotland Reviewing the literature published in 1983 (Continuing the coverage of literature in Natural Product Reports 1984 Vol. 1 p. 105) 1 Introduction 2 Farnesane 3 Mono- and Bi-cyclofarnesanes 4 Bisabolane and Sesquicarane 5 Santalane and Albane 6 Cuparane and Trichothecane 7 Acorane Cedrane Carotane and Zizaane 8 Cadinane Sativane and Sinularane 9 Himachalane 10 Caryophyllane Clovane Isoclovane Isocomane Modhephane Silphinane and Quadrane 10.1 Caryophyllane Clovane and Isoclovane 10.2 Isocomane 10.3 Modhephane 10.4 Silphinane 10.5 Quadrane 11 Humulane Pentalenane Precapnellane Capnellane Hirsutane and Senoxydane 11.1 Humulane 11.2 Pentalenane 11.3 Precapnellane and Capnellane 11.4 Hirsutane 1 1.5 Senoxydane 12 Germacrane 13 Elemane 14 Eudesmane 15 Vetispirane 16 Eremophilane Valencane Ishwarane and Valerane OHC 17 Guaiane Pseudoguaiane Valerenane and Cycloseychellane 18 Aromadendrane 19 Pinguisane 20 References I Introduction This article details the syntheses of sesquiterpenes which were reported during 1983.Also included are papers which described synthetic approaches to sesquiterpenes those which described the interconversion of sesquiterpenes and a note of full papers whose earlier communications have been referred to in the chapter on sesquiterpenoids in the various volumes of the Specialist Periodical Reports on 'Terpenoids and Steroids' (ref.1) and more recently in Natural Product Reports 1984 Vol. 1 p. 105. Once again the layout is along biogenetic lines grouping together the various carbon skeletons under a number of related headings. As in recent years the apparently inexhaustible ingenuity of the synthetic organic chemist in devising routes to many of the complex natural products is very much in evidence and gives a bird's eye view of the trend which has been established over the past decade. For a more global appreciation of the effort which has been devoted to this area of organic synthesis the admirable monograph2 on the total synthesis of sesquiterpenes 1970-1979 is strongly recommended. v-vii i VIII.1x -SPh HOzC SPh SPh XI XI1 SPh xv xvi xi. xii I I (3) (5) Reagents i H,C=CHOEt Hg(OAc),; ii 140 "C; iii H,C=C(Li)Me; iv Ac,O py; v LiN(C6HI ])Prl; vi ButMezSiC1 HMPA; vii H30+; viii LiAlH,; ix N-chlorosuccinimide Me,S Et3N; x Ph,P=CMe,; xi MeOH H,O,; xii heat; xiii Ac20 (CF,C0j20; xiv NaBH,; xv VO(acac), Bu'0,H; xvi Cr03.2py; xvii MeCH(Li)CH=NC,H, ; xviii aq. (CO,H) Scheme 1 NATURAL PRODUCT REPORTS 1985 2 Farnesane Further examples of the synthetic use of the hydroxy-thioether CHO (1) in terpenoid synthesis have been re~orded.~ The derived aldehyde (2) has been converted into p-farnesene (3) p-sinensal (4) and dendrolasin (5) (Scheme 1). Another synthesis of dendrolasin (5) has been achieved4 by the alkylation of the trimethylsilyl ester anion derived from (6)with bromoacetalde- Two full papers (see refs.15 and 16 in ‘Terpenoids and hyde which proceeds in high yield to give the P-hydroxy- Steroids’ Vol. 12 Ch. 2) have been published6 on the synthesis lactone (7). Dehydration of (7) followed by reduction with of faranal (13) which is the trail pheromone of Pharaoh’s ant BulAlH and acidic work-up gave dendrolasin (5) (Scheme 2). (Monomoriurn pharuonis). Previously (see ref. 32 in Nut. Prod. Rep. 1984 1 lOS) this A stereocontrolled synthesis of davanone (16) has been lactone (7) was used as a key intermediate for the synthesis of achieved by making use of two highly stereoselective reactions aplysistatin (8). The reaction of diketene with Grignard namely the initial aldol condensation that was developed by reagents in the presence of cobalt(11) iodide to yield 3-Heathcock to give (14) and the iodo-cyclization of (15) methylene-carboxylic acids has been put to good use in a short (Scheme 4).’ A new synthesis of the phthalide derivative (18) synthesis of farnesic acid (9).Further application of this previously used for the synthesis of mycophenolic acid (19) has methodology coupled with the tandem [3,3] sigmatropic been accomplished from the isoxazole (17) (Scheme 5). rearrangement of the esters (10) and (1 l) has permitted a non- Ascofuranone (20) which is a hypolipidemic antibiotic with stereoselective synthesis of C,,-Cecropia juvenile hormone (12) antitumour activity has been synthesized9 (Scheme 6) by a (Scheme 3).5 procedure in which the final stages of attachment of the H0.\ \ -Po (7) 0 B Reagents i Me,SiCl Et,N; ii LiNPr;; iii BrCH2CHO; iv MsC1 Et,N; v BuiAlH; vi H+ Scheme 2 lVi vii-x I Reagents i Co12;ii TsC1 py; iii EtMgBr CoI,; iv CH,N,; v AlH,; vi A O C l ; vii LiN(C6HI ,)Pr’; viii Me,SiCl; ix THF heat; x DMF heat; xi xii rn-chloroperoxybenzoic acid Scheme 3 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS Reagents i LiAlH,; ii Ph,CCl base; iii,p-BrC6H4CHzBr base; iv I, NaHCO,; v KOBut; vi OH-; vii CrO, H+; viii Me,C=CHCH,Li Scheme 4 (19) (18) Reagents i NaOAc; ii H, Pd/C; iii H+; iv NaOEt; v BuLi Scheme 5 . HO 11 -OHC -0Thp -\ \ OThp 0 OH iii iv Me0 4 OLi M e Cl 0 (20) (Thp = tetrahydropyran-2-yl) II Reagents i LiN(SiMe,), Me,C(OH)CMe; ii toluene-p-sulphonic acid CH(OMe),; iii H,O+; iv Ac,O py ; v Me,SiOTf Me3SiO[CH21,0- SiMe,; vi aq.K,CO,; vii BuLi; viii TsCl; ix LiBr; x N-chlorosuccinimide; xi 1,8-diazabicyclo[5.4.0]undec-7-ene; xii EtMgBr; xiii CH(OEt) ;xiv heat Scheme 6 (22) Reagents i Me,CuLi; ii Me3SiC1 Et3N; iii MeLi CS, LiN- (SiMe,)?; iv MeI; v (oji;vi aq.HBF,; vii BubCuLi Scheme 7 (23) R =H (27) R =OH R. @@ H H (29) R =H (30) R =OH @@H 0 k (33) [iii NATURAL PRODUCT REPORTS 1985 aromatic portion mirror those employed in an earlier synthesis of ascochlorin (21) (see ref. 30 in Nut. Prod. Rep. 1984,1 105) by the same authors. 3 Mono- and Bi-cyclofarnesanes The unusual furanosesquiterpene myodesmone (22) has been synthesized by the route shown in Scheme 7.1° Full details have been published on the syntheses of polygodial (23),l lvl drimenin (24) cinnamolide (25),’ isodrimeninol (26) warburganal (27) euryfuran (28),13 confertifolin (29),l and valdiviolide (30)13 (see refs.35 36 37 and 39 in ‘Terpenoids and Steroids Vol. 12 Ch. 2). In the course of a general investigation of the use of furans as terminators in cationic cyclizations Tanis and Herrinton14 have shown that epoxy- dendrolasin (31) can be cyclized either with zinc iodide or tri- isopropoxytitanium chloride to give 30-hydroxypallescensin A (32) in over 60% yield. Synthetic pallescensin 1 (33) (see ref. 15 in ‘Terpenoids and Steroids’ Vol.9 Ch. 2) has been converted into pallescensins 2 (34) F (36) and G (35) by the routes shown in Scheme 8.15 Marshall and Conrow16 have published complete details of their synthesis of dihydrospiniferin-1 (37) (see ref. 32 in ‘Terpenoids and Steroids’ Vol. 11 Ch. 1). Attempts to convert this compound into the acid-sensitive naturally occurring spiniferin-1 (40) were unsuccessful and thus a modified approach to (40) had to be adopted (Scheme 9) the key step being the base-catalysed electrocyclic ring-opening of (38) to give the 1,6-methano[ 101annulene derivative (39). Last year (see ref. 33 in Nut. Prod. Rep. 1984 1 105) it was reported that the lactone (41) could be converted indirectly by a mercuric-ion-mediated cyclization into the tricyclic bromo- lactone (42) en route to aplysistatin (8).Now it has been shown that treatment of (41) with aqueous N-bromosuccinimide (NBS) produced (43) which cyclized (in low yield) to give a mixture of (42) and its epimer (44)on reaction with tin@) chloride. 4 Bisabolane and Sesquicarane Full reports have been published on the preparation and use of (45)18 and (46)19 as building blocks in sesquiterpene synthesis. The diene (45) is particularly versatile having been used to synthesize P-bisabolene (47) isobisabolene (48) a-1-bisabolol (49) and a number of cadinenes (see ref. 61 in Nut. Prod. Rep. 1984,1,105). On the other hand the anion that is derived from the vinyl sulphone (46) is equivalent to the synthon (50) and in this capacity it has been used to synthesize zingiberenol (51) (see ref.60 in Nut. Prod. Rep. 1984,1 105). Another synthesis of (2)-a-bisabolene (53a) has been recorded (Scheme 10) in which a fair degree of stereoselectivity is attained by way of preferential formation of the ‘erythro’ product (52).*O The allylic bromide (54) has a number of interesting synthetic applications exemplified by its use in the syntheses of P-vi-viii iii 1 Reagents :i m-chloroperoxybenzoic acid; ii LiNEt,; iii HMPA heat; iv pyridinium chlorochromate; v H3P0,; vi PhSeBr LiNPr5; vii H202;viii LiAlH Scheme 8 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS bisabolene (47) and lanceol (55) (Scheme 1 1).21 A fascinating paper has been published on a biogenetic-type asymmetric synthesis of the bisabolenes.22 In the first instance it was shown that treatment of the biphenol (22,62)-monofarnesyl ether (56) with BuI2AlH gave p-bisabolene (47) a-bisabolene (53a b) [(E):(2)2.7 :11 and y-bisabolene (57a b) [(E):(2)1:31 (37) xiii xiv I in 60% 16% and 9% yields respectively.The same reaction with the (22,6E) diastereoisomer of (56) produced (47) (53a b) [(E):(2)2.6 :11 and (57a b) [(E):(2) 1 :13 in 34% 30% and 7% yields respectively. These reactions clearly demonstrate the metal anchimeric assistance of the aluminium reagent in promoting ionization and cyclization of the allylic substrates. Application of this process to the chiral (+)-(R)-binaphthyl analogue (58) using (2,4,6-tri-t-butylphenoxy)isobutylalumin-ium trifluoromethanesulphonate gave the highest degree of enantioface differentiation.The products [(a-or-, p- (2)-y- (E)-y- and (0-or-bisabolene] were obtained in the ratio of 1 :90 :4 1 :25 in 52% yield and chromatographic separation of vi viii I H02C& // + // a xv 0 II Reagents i KOMe H,C=CHCMe; ii K2C03 MeOH; iii (CH,OH), toluene-p-sulphonic acid; iv LiAlH,; v m-chloroperoxybenzoic acid; vi MsCI Et,N; vii H20 HCl; viii CaCO,; ix Li NH,; x HCO,Et NaOMe; xi 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; xii KOBu' ICH,CO,Et; xiii KN(SiMe3)?; xiv H,O+; xv Cu,O 1,lO-phenanthroline Scheme 9 Reagents i BuLi; ii Me,C=CHCH2Br; iii Scheme 10 NATURAL PRODUCT REPORTS 1985 the major isomer (+)-P-bisabolene (47) showed it to be 76% Another somewhat shorter synthesis of the nor-ketone (62) enantiomerically pure (Scheme 12).These reactions have also has been achieved using the Carroll reaction as outlined in been carried out on the monoterpenoid neryl analogues of (56) Scheme 13.24A Wittig reaction on (62) completes the synthesis and (58) to produce limonene with equally impressive results. of iso-a-curcumene (63). A useful method of synthesis of enones Photolysis of (2E 6E)-farnesyl iodide (59) gave mainly trans- has been incorporated into the synthesis of ar-turmerone (65).z5 p-farnesene (3) with minor amounts of P-bisabolene (47) (a-a- As illustrated in Scheme 14 the key step for the regiospecific bisabolene (53b) and ar-curcumene (60).23 The major product introduction of the enone group is the reaction of the aldehyde in the photolysis of (22,6E)-farnesyl iodide (61) is f3-bisabolene (64) with the lithio bis(pheny1thio)acetal reagent which is (47)with lesser amounts of (3,(53b) and (60).These results are equivalent to acylation of a vinyl anion. very similar to those obtained from solvolytic reactions and A recent synthesis of threo-juvabione (69) (Scheme 15) thus it is considered that a mechanism involving 'hot' illustrates the significant stereocontrol which can be exerted in carbonium ions is operative. the conjugate addition of an organocopper reagent to an 5-i ii (55) Reagents i LiNPrl; ii (54) KI; iii Ph,P=CH,; iv m-chloroperoxybenzoic acid; v NaOEt; vi (Ph,P),NiCl, Me,CHMgI Scheme 11 (53a b) (57a b) BulAl OTf + (53a b) + (57a b) at -130°C ( +H47) Scheme 12 111 Reagents i H,C=CHMgBr; ii MeCOCH,CO,Me Al(OPr'), heat; Scheme 13 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS enone.z6 In the present example the greatest degree of A full paper by Smith and Richmondz7 on their elegant diastereoselection was achieved with the mixed cuprate (66) in synthesis of paniculide A (70) (see ref. 68 in Nat. Prod. Rep. the presence of one equivalent of tributylphosphine to produce 1984 1 105) has been published. Included in this very (67) and (68) in the ratio of 5-6 1. interesting paper is a description of their synthesis of lv (65) (R = SPh) 0 II Reagents i (EtO),PCH,CO,Et NaH ii H, Pd/C; iii LiAlH,; iv pyridinium chlorochromate; v Me2CHC(SPh) Li+; vi toluene-p- sulphonic acid ; vii m-chloroperoxybenzoic acid; viii heat Scheme 14 9 -Me0q+ Me0 PyJ 0&02Me (66) 0 i,,bi,PBu3 I 0 0 A.(69) ii viii ix iv v x xi T Me,CHCH2 Reagents i Bu,P; ii M<,"tpU toluene-p-sulphonic acid; iii aq. Hg(OAc),; iv NaBH,; v MsCl Et,N; vi NaI; vii sg viii H,O+; ix NaH (MeO),CO; x NaOMe; xi AgN03 U' Scheme 15 OEt 1 ii-iv vi-viii __j _I 4 H** d H' 0 HOfi H%R bR OR H -1 OR (R = SiMe,Bu*) J ix-xi xviii xv-xvii Et,Si <Hb t-t- OR Reagents i hv (EtO),C=CH, ii Me3SiC1; iii Pd(OAc), 1,Cbenzoquinone; iv A1203 or 2% KOH; v NaBH, CeC1,; vi pyridinium L1 toluene-psulphonate MeCOEt; vii rn-chloroperoxybenzoic acid; viii chromatography; ix Et,SiCl Et,N 4-dimethylaminopyridine;x LiNPri ; xi Me2C=CHICH2121; xii KN(SiMe3),; xiii Ph2Se,; xiv 0,; xv Pr\EtN H,O,; xvi heat; xvii aq.AcOH; xviii MnO Scheme 16 paniculide B (71)(Scheme 16). Two useful observations have originated from this work. In the first place the authors have demonstrated that potassium amide bases such as potassium bis(trimethylsily1)amideare superior to lithium amide bases for deprotonation of highly oxygenated systems and secondly optimization of electrophilic selenenylations with diphenyl diselenide is best accomplished by bubbling oxygen through the reaction mixture prior to work-up (i.e. removal of the phenylselenenyl anion). These two factors were put to good use in improving the final steps of their earlier synthesis of paniculide A (70).Finally allylic oxidation of paniculide B (7 1) with Mn02 gave naturally occurring paniculide C (72) and oxidation of paniculide A (70) with pyridinium chlorochromate produced paniculide D (73) which has yet to be found as a natural product. A different approach to the synthesis of the bicyclo-[4.1.O]heptane nucleus that is embedded in the sesquicarane framework has been adopted.28 This relies upon the known photochemically induced homo-electrocyclic [3,3]-sigmatropic rearrangement of bicyclo[3.2.2]nonadienones,e.g. (74) and (77),to produce bicyclo[4.1 .O]heptylketenes [being trapped as (75)and (78) respectively]. Application of this methodology has led to the syntheses of sesquicarene (76) (Scheme 17) and isosesquicarene (79)(Scheme 1 8).29The structure of the latter compound had previously been assigned as (80) (see ref.56 in ‘Terpenoids and Steroids’ Vol. 10 Ch. 1). The conventional method of synthesis of sesquicaranes namely insertion of a carbene into the 6-7 double-bond of an appropriate farnesyl precursor has again been utilized in another synthesis of sirenin (83) which is a sperm attractant that is produced by .H (70) R = 60H (73) R = 0 (74) NATURAL PRODUCT REPORTS 1985 female gametes of the water mould Allomyces macrogynus (Scheme 19).30In this particular case the requisite (2E)acyclic precursor (82)is the major product from the low-temperature (0 “C) palladium-catalysed allylic rearrangement of the a-cyano-allylic acetate (8 1) [the corresponding (22) diastereo-isomer of (82)is the major product if the reaction occurs at a somewhat higher temperature (30 “C)].5 Santalane and Albane The recent work3’ on the high degree of asymmetric induction in Diels-Alder reactions between cyclopentadiene and chiral acrylates has been beautifully exemplified with a very efficient enantioselective synthesis of (-)-P-santalene (86) (Scheme 20).32 In chemical terms the route followed an earlier synthesis of (&)-P-santalene (see ref. 62 in ‘Terpenoids and Steroids’ Vol. 10,Ch. I) but in the present case the allenic ester (84)was used as the chiral control unit. Lewis-acid-catalysed cycloaddi- tion with cyclopentadiene led almost exclusively to the adduct (85) in 99% diastereoisomeric excess and in 98% yield as a result of preferential addition to the si face of (84).Continu-ation of the synthetic sequence using Bertrand’s procedure afforded optically pure (-)-P-santalene (86).Several years ago Wolinsky et al. (see ref. 38 in ‘Terpenoids and Steroids’ Vol. 3 Ch. 2) reported the synthesis of p-santalene (86) starting with the camphenesultone (87) but experienced problems in using this starting material for a synthesis of trans-P-santalol (90).A solution to those problems has now been found (Scheme 21),33 the key step being the opening of the sultone (88) with phenyl- lithium to give the sulphone (89) which could then be desulphurized. Over the years the unique norsesquiterpene (-)-albene (91) has been the subject of a number of structural and synthetic investigations.Its absolute stereochemistry however had never been unambiguously established even after the synthesis of ‘( -)-albene’ (92)(see ref. 38 in ‘Terpenoids and Steroids’ Vol. 9 Ch. 2 and ref. 67 in Vol. 10 Ch. 1) from (+)-camphenilone (93) by way of the (+)-chloro-olefin (94)and annelation to ‘( -)-(95)’. It was Money (see ‘Terpenoids and Steroids’ Vol. 9,p. 94)who first pointed out that the suggested endo-3,2-methyl shift in this synthesis lacked literature analogy Reagents i H2C=CH2 heat; ii Me,C=CH[CH,],Br CuI; iii Me3SiC1; iv N-bromosuccinimide; v LiBr Li,CO,; vi hv MeOH; vii LiAlH,; viii Cr03.2py; ix (Ph3P)3RhCl heat Scheme 17 LO yC0,Me \/\/CN viii v ix x / L( -CHO xiv v xiii xv xvi viii xi-xiii -Yl-TYsi OCOPh ‘d (79) Reagents i H2C=CH2 heat; ii MeI Li ultrasound; iii pyridinium chlorochromate; iv hu MeOH; v LiAlH,; vi TsCl py; vii NaCN; viii Bu’,AlH ; ix Bu‘Me,SiCl 4-dimethylaminopyridine (DMAP) Et,N ; x rn-chloroperoxybenzoic acid ; xi (PhC0)20 DMAP Et3N ; xii H,O+; xiii Cr03.2py; xiv Ph,P=CMe2; xv MeLi; xvi POCl, DMAP py Scheme 18 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS 105 and suggested an alternative and better precedented mecha- nism which if correct would not have led to (95) but to its enantiomer i.e. (-)-(95) from (+)-(94). The implication of this interpretation would require (-)-albene to have the absolute stereochemistry that is depicted in (91). This has now been fully confirmed in two papers by Baldwin and Bar- vi-viii (83) Reagents i Me,SiCN KCN 18-crown-6; ii H,O+; iii Ac20 4-dimethylaminopyridine,py; iv Pd(PPh,),; v aq.NaOH; vi Cr03.2py; vii N2H, Et,N; viii MnO,; ix CuI; x SeO,; xi Bu',AIH' Scheme 19 Reagents i BrCH2COBr AgCN; ii Ph,P; iii MeCOCI Et,N; iv 0, TiC1,(OPr')z at -20 "C; v NaBH, Ni(OAc)? H,; vi LiNPr',; vii Me,C=CH[CH,],I; viii LiAIH,; ix pyridinium chlorochromate; x NzH4 KOH Scheme 20 & -& -4,-woThp -+ i ii iii so iv v SO2 vi OH OThp SO,H SO? (87) (88) (89) vii/ (Thp = tetrahydropyran-2-yl) Reagents i NaBH,; ii TsCI py; iii 126 "C; iv BuLi; v B1fCH,1,0Thp; vi PhLi; vii 6%Na/Hg HMPA; viii SOCI, py; ix toluene-p-sulphonic acid MeOH; x Cr03.2py; xi MeCH=PPh,; xii CH,O; xiii Et,N MeOH Scheme 21 106 NATURAL PRODUCT REPORTS 1985 den.34.35 In the first of these34 they converted (-)-(94) of 92% optical purity [derived from (-)-camphenilone] into the (+)-tricyclic ester (96) (28% optical purity) and into (-)-p-santalene (86) (28% optical purity) by a retro-ene reaction (Scheme 22).Since the absolute stereochemistry of (-)-p-santalene (86) is well established and since (-)-(95) has been converted into (-)-albene it follows that (-)-albene must be (91). A second important point which emerges from this paper is the considerable racemization which occurs in the conversion of (-)-(94) into (+)-(95) on treatment with formic acid. This aspect as well as a detailed analysis of the mechanism of the annelation reaction is thoroughly investigated in the second paper.35As a result of a cleverly constructed set of experiments with singly labelled (13C) and doubly labelled (I3C and 2H) versions of the (+)-chloro-olefin (94) and subsequent n.m.r.spectral analysis of the labelled (+)-ketone (95) product it has been comprehensively demonstrated that the major pathway in the transformation of (& )-(94) into (+ )-(95) does not involve an endo-3,2-methyl migration nor does the minor route which is responsible for the racemization. Thus the complete mechanis- I ___f kCC1Me -8=, 0 tic picture of this intriguing story is depicted for (+)-(94) in Scheme 23. Dreiding et al.36have recently completed another synthesisof (&)-albene (Scheme 24) in which the key step is the thermal a-alkynone cyclization of (97) to (98).This strategy of annelation of a cyclopentenone at a saturated position has been very successfully used by the same authors in the syntheses of modhephene (see ref. 159 in ‘Terpenoids and Steroids’ Vol. 10 Ch. 1) and A9(12)-capnellene (see ref. 192 in Nat. Prod. Rep. 1984 1 105) (see also ref. 127). 6 Cuparane and ‘Trichothecane The Reetz procedure (see ref. 77 in ‘Terpenoids and Steroids’ Vol. 12 Ch. 2) of gem-dimethylation of a carbonyl group using dimethyltitanium dichloride is the most direct method for effecting this transformation. In a recent paper however Posner and Kogan3’ have uncovered a potential drawback of this method when they carried out the dimethylation of the op- tically active ketone (99) its racemate having been previously converted into cuparene (100) with Me2TiC1,.The fact that (+)-(96) Reagents i HC0,H; ii I? KI OH-; iii CH2N2;iv Ph,P=CH,; v 550°C. lo- Torr Scheme 22 dr- (+H94) (R = [CH2],CH=CClMe) major t- 4PClMe minor [exo 3.2RJ I -(W-M = Wagner-Meerwein rearrangement) Scheme 23 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS racerniccuparene (1 00) was obtained as the major product from optically active (99) clearly indicates that at least in this instance a carbonium ion rearrangement has occurred in the dimethylation process. It remains to be seen whether this is a general phenomenon or is simply related to the fact that the keto-group in (99) is flanked by a quaternary centre one substituent of which is an aryl group which would assist a Wagner-Meerwein shift.Greene et al.38have reported a short high-yield synthesis of a-cuparenone (102) (Scheme 25) based on their recently developed methodology of cyclopentanone annelation of olefins. The final step involved a double reductive cleavage-methylation sequence on the dichloro-ketone (1 01). The synthesis of trichothecanes has once again featured strongly in the year under review.39 Prompted by the relative scarcity of naturally occurring trichodiene (1 04) Schlessinger and Schultz40 have developed a neat stereoselective synthesis of the sesquiterpene (Scheme 26). This stereoselectivity which emanates from the regio- and stereo-selective production of the Diels-Alder adduct (103) ensured that the difficult separation of trichodiene (104) and its diastereoisomer bazzanene (109 was not required.Roush and his co-workers have been particularly successful in advancing their earlier synthetic endeavours through to completion. Thus the key bicyclic lactone (106) (see ref. 94 in Nat. Prod. Rep. 1984 1 105) has been elegantly elaborated to verrucarol(ll0) (Scheme 27).41The key steps in this which is the third recorded synthesis of verrucarol include the Diels- Alder reaction1 of (107) with l.acetoxy-3-methylbuta-~ -+ ,3-diene II SiMe iii 1V + H Reagents i heat; ii Me3SiC_CSiMe3 AICI,; iii aq. Na2B40,; iv 580°C; v H2 Pd/C; vi TsNHNH,; vii MeLi Scheme 24 Reagents i CI,C=C==O; ii CH2N2; iii Me2CuLi Me1 (twice) Scheme 25 Reagents i (Me2N)2CHOBut heat; ii NH, Li Bu'OH; iii MeI; iv Et,N; v,\ / Et2AlCl at 60 "C; vi NH, Li; vii LiAlH,; viii KPh 1,5-diazabicycl0[4.3.O]non-5-ene,CS, Me1 ; ix EtOCH-CH, pyridinium toluene-p-sulphonate (PPTS); x LiNPr5 ;xi (Me,N),POCl; xii Li EtNH, Bu'OH; xiii MeOH PPTS; xiv pyridinium chlorochromate; xv Ph3P=CH2 Scheme 26 NATURAL PRODUCT REPORTS 1985 to produce an epimeric mixture of adducts (108) and the macrocyclic trichothecane verrucarin J (1 22) (Scheme 29).subsequent conversion of both of these into the tricyclic trio1 Initially the idea was to construct an end-differentiated (1 09). Manipulation of the functional groups in rings B and c derivative of the diacid (1 16) which could be coupled to the was achieved after the previously reported temporary masking hydroxyl groups at C- 15 and C-4 of verrucarol(ll0) in a regio- of the primary hydroxyl group at C-15.Having laid the controlled manner. While the first part of this exercise was foundation for their synthetic work in this area (see ref. 93 in achieved (see refs. 98 and 99 in Nat. Prod. Rep. 1984 1 105) .~~ Nat. Prod. Rep. 1984,1 105) Brooks et ~1have transformed the coupling ,process ran into problems associated with the E)-muconate portion to the the optically active ring c precursor (1 1 1) into anguidine (1 15) substantial isomerization of the (2 (Scheme 28). Two key features stand out in this synthesis the (15,E)-configuration. A solution to this problem has now been first being the stereoselective Robinson annelation of (1 12) to achieved by initial attachment of the C(l’)-C(S) unit to the give eventually the tetraol(ll3).Although this tetraol could be hydroxyl group at C-15 followed by further elaboration to the cyclized with toluene-p-sulphonic acid to give up to 50% of the seco-acid (121) and final macrolactonization onto the hydroxyl desired diol corresponding to the monoacetate (1 14) complica- group at C-4. Two methods for the first part of this sequence tions arose from an alternative cyclization mode involving the were developed. In the first of these the acid (1 17) was coupled hydroxyl groups at C-9 and C-15. This was overcome by with verrucarol(ll0) to give an inseparable mixture of the two selective hydrolysis of the two secondary acetate groups of the diastereoisomers of (1 18) [(E):(Z)3 l)].On the other hand 2,3,15-triacetate corresponding to (1 13) to give the 15-coupling of verrucarol with the acid (1 19) yielded a separable monoacetate which cyclized to yield (1 14) exclusively. Roush mixture of (1 20) [(E):(2)4 13 and after chromatography the and Blizzard43 have also developed a synthesis of the @‘)-isomer was converted into the (E)-isomer of (1 18). Subsequent condensation with malealdehydic acid and final lactonization uiu the mixed anhydride produced verrucarin J (1 22). In their enantio- and diastereo-selective synthesis of tricho- verrol B (1 26) (Scheme 30) Roush and S~ada~~ have developed a method for esterification at C-4 of the monoprotected verrucarol derivative (1 24) without isomerization of the (2, E)-V HO HO xii ix-xi vii viii Ho* Br f--f-Ho2b Br \ Reagents i MeCH(OMe), toluene-p-sulphonic acid; ii LiNPri; iii CH20; iv nOAc ; v LiAlH,; vi pyridinium toluene-p-sulphonate wet benzene; vii N-bromosuccinimide wet MeCN ; viii Ac,O py ; ix Cr03,H+ x Ph3P=CH2 ; xi rn-chloroperoxybenzoic acid; xii Zn/Ag Scheme 27 i ii iv-vi -OR (1 11) R = SiMe,But c- Ac OR II Reagents i CH(NMe,), heat; ii H,O+; iii H2C=CHCMe PriEtN; iv LiNPri; v MsCI imidazole; vi MeLi; vii LiAIH,; viii Ac20 py; ix NH40H ;x toluene-psulphonic acid; xi Ph3P=CH2 ; xii Bu,NF; xiii rn-chloroperoxybenzoic acid Scheme 28 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS HC=C[CH2]20H i ii OH 0 CH2PO(OMe)2770 II0 OCCH ,PO(OMe) (1 17) +*TOHDCC DMAP HO viii ix ___ __fx xi %3 H OLOCCH II0 PO(0Me) xiii.xiv t- Reagents i Me,Al CI,ZrCp,; ii C1CO,CH,CCl3; iii CF,CO,COCH,PO(OMe),; iv Zn KH,PO,; v Bu'Me,SiCl imidazole; vi BuLi; vii CO,; viii (1 lo) dicyclohexylcarbodi-imide(DCC) 4-dimethylaminopyridine (DMAP); ix chromatography; x AcOH H,O; xi (MeO)?PCH,CO?H DCC DMAP; xii "'6" KOBu'; xiii Me,CCOCI Et,N ; xiv, II n v Scheme 29 (1 16) dienoic acid portion. In the first part of the synthesis the chiral (2,E)-dienoic acid derivative (1 23) was synthesized the enantioselectivity resulting from the Sharpless kinetic resolu- tion epoxidation procedure. The success of the coupling process between the mixed anhydride (1 23) and (1 24) depended upon the use of a non-nucleophilic base (NaH) as opposed to the nucleophilic acylation catalyst 4-dimethylaminopyridine which is suspected of causing the isomerization from (2,E)-to (E,E)-diene by a reversible Michael addition.This coupling process could also be carried out on the bis(t-butyldimethylsilyl) ether analogue of (123). Final deprotection of (125) gave optically active trichoverrol B (1 26). A completely different approach to the basic trichothecane nucleus has been developed from model studies by Kuwajima et (Scheme 31). In this process the key steps are the ester- enolate Claisen rearrangement of (127) to produce the vinylsilane (1 28) and its subsequent intramolecular acylation to produce (1 29). Additional work on the synthesis of optically active verrucarinic acid (130) which is a portion of the macrocyclic ring of verrucarin A ( 13 l) has appeared.In a full paper Tamm et uI.~~ have described three separate enantioselective routes to this compound and its derivatives. The first of these (Scheme 32) used the Sharpless epoxidation method to achieve high enantioselectivity and complete regioselectivity attended the opening of the epoxide with trimethylaluminium. The second method (see ref. 96 in Nut. Prod. Rep. 1984,1,105) (Scheme 33) owes its success to the enantioselective hydrolysis of dimethyl 3-methylglutarate by pig liver esterase. The a-hydroxylation of the ester (1 32) produced both epimers the desired (2s)-epimer being the predominant one (2 :1). The third route starting from anhydromevalonolactone (1 33) (see Scheme 34) was designed NATURAL PRODUCT REPORTS 1985 Xlll c- (125) = SiMe2Buf) Reagents i Ti(OPr'), Bu1O2H,( -)-Pr102CCH(OH)CH(OH)C02Pr';ii ButMe2SiC1 imidazole; iii RuCl, NaIO ;iv toluene-p-sulphonic acid ; v Me,SiCI py; vi LiNPri vii ;viii m-chloroperoxybenzoic acid; ix heat; x KOBu'; xi Bu'COCl; xii NaH; xiii Bu,NF [@-I2 Scheme 30 Q-+ WSiMe3 C02H Reagents i LiNPr' (LDA) MeCH(SiMe3)C02Et; ii OH-; iii I- 4-dimethylaminopyridine,Et,N ; iv LDA ; v Me,SiCl Me heat; vi SnCl Scheme 31 0 (R = SiMe2But) I ThpO..CO2H viii-x -Hot;,,. (131) LOR to take advantage of the asymmetric induction in the hydroboration of (134) with dilongifolylborane (see ref. 143 in (Thp = tetrahydropyran-2-yl) 'Terpenoids and Steroids' Vol.12 Ch. 2). In the event the Reagents i aq. KOH; ii MeI; iii Bu'Me,SiCl Et3N 4-dimethyl- predicted attack on the si-si face of (134) only led to a 50% aminopyridine ;iv Bu; AIH ;v (-)-Et0,CCH(OH)CH(OH)C02Et enantiomeric excess of (135). In a completely different Ti(OPr'), BurO,H; vi NaH PhCH,Br Bu,NI; vii Me,AI BuLi; approach to (-)-verrucarinolactone (142) Yamamoto et viii dihydropyran toluene-p-sulphonic acid; ix,H2 Pd/C ;x RuCI3 NaIO, have studied the reactions of various glyoxylate esters with but- 2-enyltributylstannane (I 36) and with 9-(but-2-enyl)-9-borabi-Scheme 32 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS cyclo[3.3. llnonane (1 37) to determine the diastereoselectivities with the organometallic reagents.In the case of the stannane the erythro-isomer (1 38) was formed preferentially while with the organoborane the threo-isomer (1 39) was the predominant one. By incorporation of the chiral auxiliary 8-phenylmenthyl group in the glyoxylate (140) followed by reaction with (136) the major diastereoisomer (141) was formed by preferential attack on the si-face of (140) as shown. This could then be converted into (-)-verrucarinolactone (142) (Scheme 39 which was obtained in 91% enantiomeric excess. 1 ii iii LR vii viii\ (132) R = SiMe,Bu' -OR (Thp = tetrahydropyran-2-yl) Reagents i pig liver esterase; ii BH,.Me,S; iii ButMe2SiC1 Et3N 4-dimethylaminopyridine;iv LiNPrk; v MOO .py.HMPA; v i, chromatography; vii dihydropyran toluene-p-sulphonic acid; viii KOH MeOH Scheme 33 Q (1 33) kii-.Hoc;iph +vi vii OCH2Ph LR (135) (134) R = SiMe2Bu1 Reagents i aq. KOH; ii MeI; iii Bu1Me2SiC1 Et,N 4-dimethyl- aminopyridine; iv BulAIH; v PhCH,Br NaH Bu,NI; vi dilongifolylborane; vii H,O, OH-Scheme 34 -+ HCC02R II __+ (136) M = SnBu 0 (137) M = 9-BBN (9-BBN = 9-borabicyclo[3.3. Ilnonan-9-yl) OH I1 1 7 Acorane Cedrane Carotane and Zizaane Following on from some model studies Oppolzer et al.48have reported the synthesis of a-acoradiene (148) (Scheme 36). One of the crucial steps in this synthesis was the intramolecular [2 + 21 photoaddition of (143) which gave the three products (144)-(146) in the ratio of 5 :3 1. It is suggested that the predominant formation of (144) can be rationalized in terms of there being less steric repulsion between the methyl group at C-4 and the hydrogen atom at C-6 in the biradical (149) as compared with the biradical that is epimeric at C-4.Transfer of a hydrogen atom from C-12 to C-6 in both biradicals accounts for the formation of the bicyclic product (145). Reductive fragmentation of both C-1I epimers of (144) yielded the spiro- ketone (147); this same compound was also obtained as a major product from the reduction of the spiro-chloro-ketone (145). The synthesis of a-acoradiene (148) was completed by regioselective methylation of (147) followed by a thermodyna- mically controlled formation of an enol phosphate and subsequent reduction. Another synthesis of (-)-a-acoradiene (1 48) starts from (+)-pulegone (1 50),which was converted first of all into cis,trans-puleganolide (1 51) (Scheme 37).49 Selective formation of an enol ether from (1 52) proved to be a problem and only with 2-diazopropane could the desired enol ether (I 53) be obtained along with its isomer (I 54) in a ratio of 2 :1.Since acid-catalysed cyclization of (-)-a-acoradiene (1 48) with ethanolic hydrogen chloride has been reported to produce (-)-a-cedrene (155) this constitutes a formal synthesis of the latter compound as well. An interesting new synthesis of a-cedrene (155) has been reported.50 The original synthetic plan was designed to construct the tricyclic carbon framework of (161) in a single step by way of an inter- followed by an intra-molecular Michael addition sequence involving the bicyclic enone (156) and the activated cyclopropane derivative (1 57) (Scheme 38).In the event the kinetic enolate of the desmethyl compound (158) failed to react with (157) and the anion of the corresponding 0-keto-ester (1 59) only underwent the initial intermolecular reaction with (1 57) to give (1 60). This problem was surmounted by allowing the kinetic enolate of (156) to react with 2-nitrobut- 2-ene and after transposition of the nitro-group for an oxo- group the desired intramolecular Michael reaction could be carried out (Scheme 39). This route eventually produced a mixture of or-cedrene (155) and its C-7 epimer. In another synthesis of the cedrane nucleus Landrysl has completed the synthesis of cedrane-8,14-diol(l66) by a route in which the key step is an intramolecular Diels-Alder reaction of the appropriately functionalized cyclopentadiene derivative (164).This was generated in situ by a retro-Diels-Alder reaction of (162) followed by a [1,5]-sigmatropic rearrangement of the initially formed 5-substituted cyclopentadiene intermediate (163) (Scheme 40). This strategy for the construction of a tricyclo[5.2.1.O1v5]dec-8-ene derivative (169 which required further ring-expansion of the two-carbon bridge has previously +ozR + y O 2 R OH OH (138) (139) (R = Me Prl or Bun) LHiv RO OH -Hobo (141) (R = 8-phenylmenthyl) ( 142) (140) Reagents i (I 36) BF Et,O; ii BH -SMe2 ;iii NaOH H202; iv toluene-p-sulphonic acid Scheme 35 NATURAL PRODUCT REPORTS 1985 (143) lv c1 \ Reagents i MeCH(Li)[CH,l2C=CMe2; ii H30+; iii Bu'02H SeO,; iv N-chlorosuccinimide Me2S; v hv;vi Li NH,; vii ,MeI; ii viii LiNPri Bu'OH at 20 "C; ix ClPO(OEt),; x Li MeNH, BdOH Scheme 36 ' b Reagents i Br,; ii NaOEt; iii HCl; iv LiNPr',; v 0 ; vi Bu'OK ; vii MeI 1,8-diazabicyclo[5.4.O]undec-7-ene;viii Me2C0 I[CH,],-dMe toluene-p-sulphonic acid; ix Me2CN2; x LiAlH,; xi H30+; xii Ph,P=CH2; xiii Na NH Scheme 37 R' + :$$R* 0 (156) R' (158)R' ii59j RI = Me RZ = R2 = H = H ~2 = CO,Me = H (160) R' = H,R2 = C 02Me (161) R' = Me R2 = H Scheme 38 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS i ii -&(- h 0 0 OH I x xi vii-ix f--4T-(155) Reagents i LiNPr',; ii MeCH=C(Me)NO iii NaNO, PrNO, DMSO; iv Bu'O-; v (CH,OH), HC(OEt), toluene-p-sulphonic acid; vi Ph,P=CH,'; vii H,O+; viii LiB[CH(Me)Et],H (L-Selectride@)'; ix EtzZn CH,I, CH,I, 0,;x Rh PtO, AcOH; xi POCI, py Scheme 39 xii xiii I xiv c- xxii I eH / xxiv xvii xviii xix xx ix xxi I ___+ __* xxiii xxiv c1 (Thp = tetrahydropyran-2-yl) Reagents i r? ; ii CIC0,Et; iii NaBH,; iv dihydropyran H+; v LiN(C,H ,)Pri;vi Et,SiCI; vii heat; viii aq.MeOH; ix LiAIH,; x -MeOCH,Br; xi H,O+; xii pyridinium chlorochromate; xiii Ph,P=C(Me)CO,Me; xiv 180 "C; xv CHCl, OH-; xvi OH- heat; xvii 20% H2S0,; xviii H+ MeOH; xix chromatography; xx TsCl xxi MnO,; xxii H2 Pd/C; xxiii H2C=C(OMe)Me; xxiv MeLi; xxxv H+ Scheme 40 NATURAL PRODUCT REPORTS 1985 ,OH Meo’co i-iii o& iv-vi vii viii @-OSiMe2Bui ___f - 0 0 xiv-xvi xiii vi t-- AcO @-OH Me,SiO@: H xvii-xix.xviii xx xi \ Reagents i H,C=CHCMe; ii LiAIH,; iii MnO,; iv Ag,O I,; v AgOAc; vi KOH; vii Bu‘Me,SiCl; viii Bu‘OK MeI; ix NaEH,; x Ac,O py; xi H,O+; xii H2 PtO,; xiii CrO, H+; xiv MeOH H+; xv Me,SiCN SnCl,; xvi chromatography; xvii NaOH; xviii CH,N2; xix NaI Me,SiCI ; xx Ac,O toluene-p-sulphonic acid ; xxi PCI Scheme 41 (169) R = H (171) R = Me been used by Breitholle and Fallis (see ref. 43 in ‘Terpenoids and Steroids’ Vol. 7 Ch. 2) in their synthesis of or-cedrene (1 55) itself. The carotane sesquiterpenoid aspterric acid (168) has been synthesized by the route depicted in Scheme 41.52 A sequence of Robinson annelation and formation of an iodo-ether was used to construct the tricyclic framework of (167).The requisite ring-contraction was effected in the penultimate step. Two full papers on the synthesis of 2-desmethylzizaene (169)53 (see ref. 121 in Nat. Prod. Rep. 1984 1 105) and the tricyclic ketone (170)54 (see ref. 115 in ‘Terpenoids and Steroids’ Vol. 12 Ch. 2) which is a synthetic precursor of zizaene (1 71) have been published. Having recently reported an elegant synthesis of (_+)-khusimone (1 76) which involved a regio- and stereo-selective intramolecular type-I1 magnesium- ene reaction (see ref. 117 in Nat. Prod. Rep. 1984 1 l05) Oppolzer et ~71.~~ !lave now added an enantioselective feature to this synthesis.This has been achieved by the very clever use of a chiral control element in the initial dienolate addition- alkylation sequence (172) -+ (173) (Scheme 42). Based on an appreciation of steric repulsions and electronic factors in the transition state and backed up by model studies it was predicted that the transition state that is depicted in (1 77) with si-dienolate attack on the si-face of the enone would be preferred thus leading (after alkylation) to the predominant formation of the (lR,SS,6S)-isomer (1 73). This indeed proved to be the case with (173) being formed preferentially to the extent of 48%. The other minor products included the (1 R,5S 6R)- (1R,5R,6R)- and (lS,SR,6S)-diastereoisomers of (173).This remarkable double n-face-selective addition permitted the elaboration of (173) to the alcohol (174) [with regeneration of the chiral control (175)] and thereafter through the same sequence of steps as has previously been described to (-)-khusimone (1 76). i. ii iii iv 0-0 &* 0-[R = BUG:$] Reagents i Me,C CHCO,R LiNPr’,; ii H,C CHCH,Br; iii HO[CH,],OH toluene-p-sulphonic acid; iv NaOEt; v AlH Scheme 42 (177) 8 Cadinane Sativane and Sinularane The photochemical cycloaddition of a substituted cyclobutene derivative with a cyclohexenone followed by a thermally induced transannular ene reaction has been shown to be a NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS powerful method for the construction of substituted decalins (see refs.102 and 103 in ‘Terpenoids and Steroids’ Vol. 10 Ch. 1,refs. 97 and 228 in Vol. I 1,Ch. 1 refs. 122 and 267 in Vol. 12 Ch. 2 and ref. 40 in Nut. Prod Rep. 1984 1 105) which have been converted into a variety of bicyclic sesquiterpenoids. Continuing on this theme Williams et al.s6 have elaborated the previously described bicyclic hydroxy-ester (1 8I) by way of (183) to (-)-zonarene (1 84) which is the major hydrocarbon component of the brown seaweed Dictyopteris zonarioides Farlow (syn. Dictyopteris undulata Okamura) (Scheme 43). A shorter route to this compound has also been developed starting from I-methylcyclobutene a slight disadvantage of this route being that thermolysis of the photo-adduct (178) to give (180) only proceeds in 50% yield unlike the almost quantitative yield that is obtained in the thermal conversion of (1 79) into (I 8 1).A single step is required to convert (1 82) into (-)-zonarene (1 84). Originally the structure of isoepicubenol isolated from species of the genus Heterotheca was assigned as (185). This compound has now been synthesized (Scheme 44)s7a and is not identical with the natural product. It has now been identified as epicubenol (186).57b Sclerosporin which is the major sporogenic substance of Sclerotiniu fructicolu and its related metabolite sclerosporal were recently formulated as guaiane-type sesquiterpenoids with structures (1 87) and (1 88) respectively. A compound whose structure corresponded to that of (188) was in fact synthesized last year (see ref.370 in Nat. Prod. Rep. 1984 1 105) and shown not to be sclerosporal. This uncertainty has now been clarified by the original authorss8 on the basis of a detailed analysis of the high-field n.m.r. spectra of the compounds in question together with the confirmatory synthesis of both sclerosporin (191) and sclerosporal (190)’ starting from the previously reported bicyclic ketone (1 89) (see ref. 104 in ‘Terpenoids and Steroids’ Vol. 10 Ch. 1) (Scheme 9; y&f-+&I.< 0 (178)R = Me (179)R = C02Me (180)R = Me (181)R = C0,Me A (182)R = Me (583) R = COzMe iv-vii (184) Reagents i hv; ii heat; iii HZ Pt; iv POCl, py; v AIH,; vi Ac20 py; vii Li NH Scheme 43 Meom + 0 kV, xvi q (185) Reagents 1 AICI,; ii MeOH HCI; iii Me,CHMgI; iv H,PO,; v LiAIH,; vi Li NH, EtOH; vii KOBu‘; viii Ac,O; ix NaBH,; x pyridinium dichromate; xi LiB[CH(Me)Et] H (L-Selectride@); xii (C13CCO)20 Et,N py; xiii rn-chloroperoxybenzoic acid; xiv KOH; xv MsCI Et,N 4-dimethylaminopyridine; xvi 1,8-diazabicyclo[5.4.O]undec-7-ene;xvii Cn-; xviii AlH ;xix NH,OSO,H OH- Scheme 44 116 NATURAL PRODUCT REPORTS 1985 45).The furano-cadinane verboccidentafuran (1 92) has been The remarkable structure of the cadinane derivative known synthesized by a route involving an initial Diels-Alder reaction as qinghaosu (198) was elucidated five years ago. The novelty of which ensured the cisstereochemistry of the ring junction of the basic decalin ring system (Scheme 46).59 R q':g its structure together with its potent plasmodicidal properties and its extensive clinical trials in China for the treatment of drug-resistant malaria has made it a challenging synthetic problem.Schmid and Hofheinz,60 working for Hoffman-La Roche in Basel have now brilliantly succeeded in achieving this synthesis. The key steps as depicted in Scheme 47 include the conversion of (-)-isopulegol (193) into the menthone derivqtive (194) followed by the stereoselective steps to (195) and (1 96). The high stereoselectivity in the conversion of (1 95) (187) R = COzH into (196) could only be achieved by using a ten-fold excess of ( 186) (188) R = CHO lithium methoxy(trimethylsilyl)methylide resulting in a kinetic (190) Reagents i PhSCH(Li)OMe; ii SOC12 py; iii NaIO,; iv heat; v CrO, H+ Scheme 45 vii viiy / bH (192) (Thp = tetrahydropyran-2-yl) Reagents i heat; ii LiAlH,; iii H,O+; iv AczO py; v Me,CuLi; vi HBr aq.AcOH; vii Hz Pd/C; viii Li NH,; ix LiNPrl,; x MeCOCH20Thp; xi toluene-p-sulphonic acid Scheme 46 - i ii iii-v vi vii Me,Si \ viii \ ___ HO'. MeO-0. H.. .. -.H (1 93) HO PhCHzO PhCHl OCHZPh (195) (196) R = SiMe, (194) xiv x-xii Me,Si ' c-c-- -Me0 Me Me -H (197) Reagents i CICH20Me PhNMe,; ii BzH6 OH- H202; iii PhCH,Br KH; iv MeOH HCI; v pyridinium chlorochromate; vi LiNPri; vii ICHzCH=C(SiMe3)Me; viii MeOCH(Li)SiMe3 ;ix Li NH3 ;x mchloroperoxybenzoic acid; xi CF,CO,H; xii Bu,NF; xiii lo2, at -78 "C MeOH; xiv HC02H Scheme 47 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS (204) (202) (203) Reagents i KOH; ii (COCl),; iii AlCI,; iv MeLi; v BuLi TMEDA; vi DMF; vii Et,SiH CF,CO,H; viii sunlight; ix BBr,; x toluene-p-sulphonic acid; xi H, Pd/C Scheme 48 1iii (207) Reagents i MelCHMgBr; ii HC0,H; iii H, Pd/C; iv Pd/C heat; v K,CO, Me,SO Scheme 49 resolution of the racemic organolithium reagent by the chiral ketone (195). The penultimate step depended critically on the temperature and the solvent that was used for the photo- oxygenation reaction and some earlier work on the various modes of addition of singlet oxygen to enol ethers proved to be particularly valuable. Although a complex mixture was obtained in this step it was assumed that a major product must have been (197) as predicted from the work of Asveld and Kellogg,61 since treatment of the crude product with formic acid gave qinghaosu (198) in 30% yield identical in every respect with the natural material.Complexation of an arene with the chromium tricarbonyl group confers an element of control for both nuclear lithiation of the arene ring and the stereospecific introduction of a substituent into an alicyclic ring that is attached to the aromatic ring. Both of these aspects have been put to good use in the synthesis of cis-(204) and trans-7-hydroxycalamenenes (203) (Scheme 48).62 Friedel-Crafts cyclization of the acid chloride corresponding to (199) gave principally the exo-product (200) along with a minor amount of the endo-isomer (201).Methylation of (200) followed by directed lithiation and quenching with DMF gave exclusively (202) which could then be converted into trans-7-hydroxycalamenene (203). A similar reaction sequence was used to convert the endo-isomer (201) into cis-7-hydroxycalamenene (204). Alternatively the cis-isomer (204) could be obtained from (202) as shown in Scheme (209) R' = R' = H (210) R' = H R' = Pr' (211) R' = OH or OAc R' = H (212) R' = OH or OAc R2 = Pr'; (4R) or (4s) 48. The syntheses of y-calacorene (206) calamenene (207) and 4-methoxyisocadalene (208) have been described starting from the tetralone (205) (Scheme 49).63 A study of the intramolecular Diels-Alder reaction of a series of spiro[2,4]heptadiene derivatives (209)-(2 12) has revealed that an oxygen-containing substituent at the &position on the dienophilic side-chain is necessary for a successful cycloaddi- tion process.Thus whereas no reaction took place for (209) and (210) the tetracyclic products (213) and (214) were obtained from (211) and (212) re~pectively.~~ It is suggested that the oxygen-containing substituent ensures that the requisite transi- tion state for intramolecular cyclization can be attained. The synthetic potential of these tetracyclic adducts rests on the premise that controlled cleavage of the cyclopropane ring can be effected. Thus in principle cleavage of each of the cyclopropyl bonds a b and c in (215) could ultimately lead to sinularene (216) longifolene (21 7) and sativene (21 8) respec-tively as depicted in Scheme 50.Following this line of reasoning Fallis et al.65 have examined various reductive modes of cleavage of the tetracyclic compounds (219)-(221). To date they have found methods for cleavage of bonds a and b as depicted in Scheme 51. Thus the sinularene-type compound (222) is obtained exclusively by catalytic hydrogena- tion of (219) whereas reduction of (220) and of (221) by (213) R’ = OH or OAc R? = H (214) R’ = OH or OAc R’ = a-or fl-Pr’ NATURAL PRODUCT REPORTS 1985 chromous sulphate gives exclusively or mainly the longifolene- type compounds (223) and (224). 9 Himachalane The complete details of the elegant synthesis of P-himachalene (225) by Piers and RuedigeF have been published (see ref.116 in ‘Terpenoids and Steroids’ Vol. 10 Ch. 1). Chemists searching for exceptions to “Murphy’s Law” should note that the key step in this synthesis was the Cope rearrangement of the ~-(2-vinylcyclopropyl)-a~-unsaturatedketone (226). A very clean thermal rearrangement took place to give the desired bicyclic ketone (227). If “Murphy’s Law” had been operative the products would have been either (228) arising from a [1,5]-sigmatropic hydrogen migration or the isomerized ketone (229). Two syntheses of the seco-himachalene sesquiterpenoid himasecolone (230) have been recorded (Scheme 52).67 R x (215) R = H or Me Scheme 50 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS acyclic o-keto-ester has been further exemplified in a very 10 Caryophyl lane Clovane Isoclovane Isoco-mane Modhephane Silphinane and Quadrane short synthesis of isocaryophyllene (233) (Scheme 53).68 Thus the keto-ester (23 l) prepared from ethyl geranylacetate and 10.1 Caryophyllane Clovane and Isoclovane dichloroketene in two steps underwent high-dilution cycliza- The use of McMurry’s low-valency titanium reagent (TiC13- tion (in 38% yield) to give the bicyclic ketone (232) rather than LiA1H4) to bring about the intramolecular coupling of an the trans-isomer (234) which is the potential precursor of (230) Reagents i Me2C=CH[CH2],CH(OAc)Me BF3.EtzO; ii OH-; iii Al(OPri)3 cyclohexanone; iv Ac,O NaOAc heat; v B,H,; vi BrCHtCOMe Bu‘ OK Scheme 52 iii iv ’r lv H’ g-lg +g 0 (233) (235) (234) Reagents i CI,CCOCl POC13 Zn/Cu; ii Zn/Cu AcOH; iii TiCl, LiAIH, Et,N; iv H,O+; v Ph3P=CH2 Scheme 53 (238) (237) Reagents i LiNPr;; ii MeI; iii Br[CH2],C1; iv LiAlH,; v H,O+; vi H,C=C(Et)CH2Br; vii KB[CH(Me)Et],H (K-Selectride@); viii 0,; ix KOH EtOH Scheme 54 NATURAL PRODUCT REPORTS 1985 caryophyllene (235).It is thought that isomerization of the the key step being the efficient intramolecular alkylation of the double-bond takes place during the cyclization process which chloro-enone (236).69 Isoclovene (240) on the other hand is occurs on the surface of insoluble titanium particles. one of many dehydration products of caryolan-1-01 (0-Clovene (238) is one of the products of the acid-catalysed caryophyllene alcohol) (241) which in turn is the other major rearrangement of caryophyllene (235) and has been the subject product from the acid-catalysed rearrangement of caryophyl- of previous synthetic endeavours the first of which was lene (235).The structure of isoclovene rests on an early X-ray accomplished by way of the tricyclic enone (237). A new analysis of its hydrochloride. Now two independent syntheses synthesis of this compound has now been reported (Scheme 54) of isoclovene (240) have been disclosed. The first of these70 Me& ix XII (R = SiMe,) 1 xvi x xv xiii xiv -%3 0 (239) HO (241) Reagents i OsO, ; ii Pb(OAc), C1,CCO2H MeOH; iii LiNPr;; iv Me,SiCI; v TiCl,; vi NaBH,; vii NaH CS2 MeI; viii (;I Me/\ 0-Bu,SnH; ix Me2CHSH AICl,; x MeLi; xi H,O+; xii CrO,; xiii KOH; xiv H, Pd/C; xv DMSO heat; xvi P,O Scheme 55 PO i-iii iii v-viii __.._f b bo 0c#3+02Et H -b H \C02H cH20H I ix ii x-xiii 0 xiv xv H \C02H xvii xviii I (240) Reagents i Ph3P=CHC02Et; ii (CH20H), H+; iii LiAlH,; iv MeC(OEt), EtC02H heat; v pyridinium chlorochromate; vi Pd/C at 200 "C; + vii B2H6 HzOr OH-; viii CrO, H+; ix CH2N2; x C5H5NH Br3-; xi 1,8-diazabicyclo[5.4.0]undec-7-ene;xii aq.K2C03; xiii H,O+; xiv (NCNb=O; xv Mg02CCH2C02Et; xvi K2C03 EtOH; xvii aq. DMSO NaCl; xviii Me<t H+; xix N2H4 OH-; xx MeMgI; 0 u xxi I? Scheme 56 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS hinged upon the construction of an appropriately functiona- lized bicyclo[4.3. Ildecyl derivative (239) followed by an intramolecular aldol closure to secure the tricyclo-[6.2.2.04.* Oldodecane nucleus (Scheme 55).The second synthe- sis7' was based on a different strategy and involved the P-keto- ester (242) as the key intermediate which underwent an intramolecular Michael reaction to bring about the formation of the tricyclic skeleton of isoclovene (240) (Scheme 56). 10.2 Isocomane In the six years since its identification isocomene (245) has been the subject of no less than five independent syntheses. To add to these is a new synthesis (Scheme 57) by Wenkert and Arrheni~s'~ in which a key step was the acid-catalysed rearrangement of the a-oxycyclopropylcarbinol (243) to the cyclobutanone (244) other examples of which have been used previously by Wenkert and co-workers in other sesquiterpenoid syntheses to good effect.The final steps in this synthesis involved ring-expansion of the cyclobutanone ring and deoxygenation of the resultant cyclopentanone. Another method of constructing the basic tricyclo[6.3.0.01 .5]undecane skeleton of isocomene has been described by Hudlicky et al.73 in their syntheses of isocomenic acid (254) and epi-isocomenic acid (255) (Scheme 58). Neither of these compounds has yet Me Me6 Me \\ \ \ \ Qii,xv-xvii :i-xiii 9 ,p 1 --_-----*-HO." 0' Me6 , Me6 (245) 0 0 \ (244) (243) Reagents i KOEt ii LiAIH,; iii MeCHI, ZnEt,; iv CrO, py AcOH; v LiNPri Me,SiI; vi CH212 ZnEtz; vii NaOH MeOH; viii Me0,SPh; ix MeLi; x H,O+; xi MeSCH,Li; xii MeI; xiii NaH; xiv LiI; xv BuLi (Me,N),POCI; xvi Me2NH; xvii Li EtNH Scheme 57 I (247) X t xiiI xiv ___ Q0,Et (253)1xiv Ixv Reagents i NaBH,; ii MeC(OEt), Hg(OAc),; EtCO,H heat; iii 0,;iv Zn AcOH; v BrCH2CH=CHC02Et Zn/Cu; vi 1,8-diazabicyclo[5.4.0]undec-7-ene, at 0°C; vii (COCI),; viii MeCHN,; ix CuSO, Cu(acac), heat; x 580 "C; xi H, PtO,; xii Ph,P=CH,; xiii NaOAm ; xiv toluene-p-sulphonic acid ; xv KOH Scheme 58 NATURAL PRODUCT REPORTS 1985 been discovered in Nature although the probability is quite high in view of the existence of other terpenoid acids in which a secondary methyl group has been enzymatically oxidized.An ‘abnormal’ Reformatsky reaction of (246) was used to generate the bicyclic lactone (247) which underwent base-induced opening to the acid (248).Conversion of this compound into a diazo- ketone followed by intramolecular cyclopropanation secured the tricyclic keto-ester (249) which then gave (250) after a thermal vinylcyclopropane-cyclopentene rearrange-ment. A Wittig reaction on (251) at room temperature yielded predominantly (252) together with a minor amount of the epimer (253); this latter compound could also be obtained quantitatively by base-induced epimerization of (252). 10.3 Modhephane Modhephene (260) the unique propellane sesquiterpene has also been the focus of considerable synthetic interest with five independent syntheses having been recorded so far. Now a sixth synthesis has been reported (Scheme 59).74Initially it was planned that the secondary methyl group could be introduced by conjugate copper-promoted addition to the tetracyclic ketone (257) which is readily obtained from the ketone (256).This proved to be impossible and hence an additional methoxycarbonyl activating group had to be introduced. Thus treatment of (258) with lithium dimethylcuprate gave the desired tricyclic compound (259) which was readily converted into modhephene (260). 10.4 Silphinane Yet another example of a triquinane sesquiterpene is silphin- ene (263). Last year the first synthesis of this hydrocarbon was announced (see ref. 159 in Nat. Prod. Rep. 1984 1 105) and full details of the elegant route that was used have now been described.75 A second synthesis of silphinene has also been accomplished recently starting from the ketone (261) which is derivable from dicyclopentadiene (Scheme 60).76A common feature of both syntheses is the key bicyclic enone (262) which is an ideal substrate for elaboration of the third cyclopentane ring.(259) Reagents 1 NaH HC0,Et; ii Et,NH TsN,; iii CuSO, heat; iv MeI KOBu‘; v Bu‘Li; vi CO,; vii HCI; viii CHtN2; ix Me,CuLi; x LiI collidine; xi LiAlH,; xii Ph,S[OC(CF,),Ph] Scheme 59 - i ii- IV __+ m M e -0 vii viii I Xlll xii ix-xi .t-%Me‘-6 % xvi xvii xviii xix xx xi ___ @H Reagents i (CH,OH), toluene-p-sulphonic acid; ii NaIO, OsO,; iii NaBH,; iv MeOH HCI; v CrO, H+; vi CH,N,; vii LiNPr;; viii MeI; ix Li AlH,; x pyridinium chlorochromate; xi NzH4 KOH ; xii Me,SiCl NaI ; xiii 1,8-diazabicyclo[5.4.O]undec-7-ene; xiv BrMg[CH,],- C$) CuI; xv H,O+; xvi POCI, py; xvii MeLi; xviii S0Cl2 py; xix rn-chloroperoxybenzoic acid; xx BF,-Et,O Scheme 60 NATURAL PRODUCT REPORTS 1985 ~-J.S. ROBERTS 10.5 Quadrane The cytotoxic properties and unusual tetracyclic structure of quadrone (268) have elicited a great deal of synthetic interest culminating in four well-designed syntheses to date. The past year has seen a continuation of this synthetic activity with three new syntheses and a modification of an earlier route being described. In essence the tricyclic enone acid (267) has been the terminus in all three syntheses since Danishefsky in the very first synthesis (see ref. 153 in ‘Terpenoids and Steroids’ Vol.11 Ch. l) converted this compound into quadrone in three steps. The Yoshii synthesis (Scheme 61)77is based upon an entirely different strategy for the construction of the crucial intermediate (267) and started off with the bicyclic ketone (264) which featured in Corey’s historic synthesis of caryophyllene. 111 Elaboration of this ketone to the propargyl carbinol (265) set the scene for the ensuing acid-catalysed rearrangement to the bicyclo[3.2. lloctyl derivative (266). A model study on the desmethoxymethyl analogue of (265) had shown that this rearrangement could be accomplished in 75% yield. With the intervention of “Murphy’s Law” however a variety of experimental conditions had to be examined before a yield of 40%of (266) could be realised.Thereafter the route through to (267) was uncomplicated. The strategy that was adopted in the next two syntheses of the ketone (267) ran along very similar lines the cornerstone being the intramolecular Diels-Alder reaction of the enone (269). In the Schlessinger synthesis (Scheme 62)78 this cyclization was carried out in toluene/acetonitrile at 120 “C to LVi.vii &0 $402H 0 ti (267) Reagents i LiNPr’, Me,SiCI; ii MeOCH,CI CH,12 Zn/Cu; iii Al HC=CCH2Br; iv HC0,H; v aq. NaOH; vi pyridinium chlorochromate; . vii HgO H,O+; viii Am‘OH NaH; ix BBr,; x CrO, H+ Scheme 61 i-v vi vii Me0,C -6 I + __3 (273) i viii .. .\ IX 7 xv xiii. xiv i xii f--%COIH %OSiMe bSiMe (267) Reagents i LiNPr;; ii I[CH2I2CH=CHCH=CH2; iii LiCI aq.DMSO; iv (Me,N),CHOBu‘; v BuiAlH; vi 120°C; vii CrO, 3,5- dimethylpyrazole; viii MeI; ix H? Pd/C; x Me3SiI 1,1,1,3,3,3-hexamethyldisilazane; xi OsO, ;xii Me,SiCI; xiii 0,;xiv NaIO, (9 Me’ ’0-CrO,; xv NaH Scheme 62 NATURAL PRODUCT REPORTS 1985 give exclusively the tricyclic ketone (270). From there on synthesized by a slightly different route was subjected to a oxidative modification of the cyclohexene ring followed by variety of conditions to effect cyclization (toluene at 110 "C; methylation and oxidative cleavage provided the diketo-acid chlorobenzene at 135 "C; dichloromethane/tin(Iv) chloride at (271) which underwent an aldol cyclization to provide (267). In 0 "C; water/acetonitrile at 90 "C).In all four cases the major the Vandewalle synthesis (Scheme 63)79 the same enone (269) product was (270) but the axial epimer (272) was also obtained v-vii l3 1 0 0 il i x xi b -< 0 (273) :d xii-xv xxii 81.-COzH 0 0 (267) Reagents 1 LiNPr;; ii I[CH2I2 CH=CHCH=CH,; iii NaBH,; iv LiAlH,; v TsCl Et,N; vi CrO, H+; vii 1,8-diazabicyclo[5.4.0]undec-7-ene; viii 110 "C; ix CrO, 3,5-dimethylpyrazole; x MeI; xi H, Pd/C; xii Me,SiI 1,1,1,3,3,3-hexamethyldisilazane; xiii 0,;xiv Zn AcOH; xv CH,N,; xvi (CH,OH), H+; xvii LiBEt,H; xviii o-NO,C,H,SeCN Bu,P py; xix H,O,; xx H,O+; xxi Am'OH NaH; xxii RuO Scheme 63 PO(OMe) (274) lf!02Me PO(OMe) Scheme 64 NATURAL PRODUCT REPORTS. 1985 -J. S. ROBERTS I25 to varying degrees {[(272)] :[(270)] was 1 3 1 :9 1 :2 1 :2 corresponding to the above reaction conditions).The initial objective was then to convert (270) into (275) for subsequent epimerization to (277) this compound also being derivable in principle from (272) (Scheme 64). In the event the intramol- ecular Horner reaction of (274) did indeed give (275) but epimerization to (277) was completely unsuccessful. To add salt to the wound the corresponding cyclization of (276) to yield (277) also met with failure. Salvation was achieved by the completely independent conversion of both (270) and (272) into the enone (273). Using a somewhat different strategy to Schlessinger's route this enone was converted into Dani- shefsky's acid (267) thus constituting a formal synthesis of quadrone (268).Before leaving this beautiful piece of work it should be noted that Vandewalle et a/. also synthesized the enone (278) the idea being that its intramolecular Diels-Alder adduct (279) would be amenable to conversion into quadrone. Unfortunately this cyclization could not be achieved and in fact some earlier exploratory work by Danishefsky towards quadrone also revealed that the formation of the C-1-C-8 bond by an intramolecular mode could not be effected. The lack of success has been attributed to an increased torsional strain in the transition state. In their previous synthesis of quadrone (see ref. 160 in Nat. Prod. Rep. 1984 1 105) Burke et a/. used the ketal-aldehyde (280) as a precursor for the keto-ester (281) which is a relay compound in the Danishefsky synthesis of quadrone.Although (280) is a C compound it had one carbon too many at C-8 and one carbon too few at C-5. Thus they had to resort to a dehomologation process to obtain (281). In order to preserve the fifteen carbon atoms of (280) they have now reporteds0 an alternative strategy (Scheme 65) for the synthesis of quadrone which involves an intramolecular aldol closure of the keto- aldehyde that was derived from (280) followed by oxidative cleavage of the resultant cyclopentene derivative (282). The penultimate oxidation step [with pyridinium chlorochromate (PCC) or Ag,CO,/Celite] was non-regioselective and an equal amount of the regioisomeric lactone (283) was formed at this stage. 11 Humulane Pentalenane Precapnellane Capnellane Hirsutane and Senoxydane 11.1 Humulane A new synthesis of humulene (288) has been achieved (Scheme 66) based upon Takahashi's method of intramolecular alkyla- tion of a protected cyanohydring1 (see also refs.101-103). Prior to this crucial step homologation of the aldehyde (284) gave the two enals (285) and (286) in the ratio of 3 1. The (E)-enal(285) could then be transformed into humulene (288) via the enone (287). Cyclization of the (Z)-enal(286) was rather less efficient producing (289). Treatment of the cyanohydrin corresponding to (289) with a base caused isomerization of the conjugated double-bond to give a 1 :1 mixture of (287) and (290). In another study Shirahama et a/.82have converted humulene 1,2- epoxide (291) into the (lE,4E,8Z)-isomer of humulene (295) (Scheme 67).Allylic oxidation of (291) gave the three products (292)-(294) the major one (292) having an isomerized 8-9 double-bond and being convertible in three steps into (295). Although this isomer of humulene has not yet been detected in Nature the corresponding C-5 cation (296) has for some time been considered as a possible intermediate en route to the himachalane (297) longi bornane (299) longifolane (300) and longipinane (298) sesquiterpenoids by way of a 1,3-hydride shift and subsequent cyclization modes (Scheme 68). Indeed some time ago Nozaki et a/. (see ref. 85 in 'Terpenoids and Steroids' Vol. 9 Ch. 2) attempted to mimic this process by carrying out the solvolysis of the mesylate corresponding to (296).Instead this produced the ring-contracted germacradiene derivative (301) and in the absence of an external nucleophile I. II -JB 0 Bu'Me SiO OAc viii ix c- & H 0 Bu'Me,Sid Reagents i H,O+; ii AcOH H,SO,; iii 400°C; iv LiAlH,; v Bu'Me2SiC1 imidazole; vi 0, Me,S; vii NaBH,; viii pyridinium chlorochromate or Ag,CO,/Celite; ix CrO, H+ Scheme 65 126 NATURAL PRODUCT REPORTS. 1985 XI. XI1 I 1 I vii-x 1.1 XlllXV OEt $.:- -p p/o c-(Lp-5 XI.XlI (287) (288) (290) (289) + (287) Reagents i SnCI,; ii NaBH,; iii Hg(OAc)* H2C=CHOEt; iv 140 "C; v BdN=CHCMe(Li)SiMe,; vi H,O+; vii Me,SiCN 18-crown-6; viii t PhCH2NMe3F-; ix H,C=CHOEt H+; x NaN(SiMe,),; xi toluene-p-sulphonic acid; xii OH-; xiii BuiAlH; xiv Ac20,py;xv Li EtNH Scheme 66 (292) R = CH,OH (294) "c(293) R = CHO 111 (292) IV.v II -$2 (295) Reagents i SeO, Bu'OZH; ii LiAIH,; iii KOBu'; iv LiAIH, TiCl,; v y-collidine LiCI MsCl Scheme 67 the triene (302). Following on from their synthesis of (295) Shirahama et a/.83have carried out the oxymercuration of (295) with Hg(N03)2,which gave (after reductive demercuration) the tricyclic ether (303). This compound only differs in the relative stereochemistry of the ring junction with respect to (304) which was the product if the same reaction was carried out on humulene (288) (see ref. 82 in 'Terpenoids and Steroids' Vol. 7 Ch. 2). Another cyclization was carried out on the epoxide (305) using trimethylsilyl triflate.After desilylation the two bicyclic alcohols (306) and (307) were obtained in almost equal amounts (Scheme 69). It has been suggested that the alcohol (306) could arise from the TT conformer (308) and/or the CC conformer (309) of (305) by interaction of the 1-2 double-bond with epoxide opening and formation of a bond (300) (299) Scheme 68 between C-1 and C-4 although an inspection of molecular models does not indicate that this process would be concerted. In any case the configuration of the hydroxyl group in (306) and (307) should be p rather than a.The two naturally occurring humulene acids humulen-13-0ic acid (310) and lychnocolumnic acid (31 1) have been obtained by oxidation of the correspond- ing aldehydes with sodium chlorite.84 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS I I ___t I (305) (306) (307) Reagents i rn-chloroperoxybenzoic acid; ii NaBH4; iii LiAlH4 TiCl,; iv y-collidine LiCl MsCl; v LiAlH,; vi Me,SiOTf; vii KF Scheme 69 ii viiI I;r r! + Q02Me C0,Me + Me,SiO--k (319) xi-xiv / (322) (320) (321) Reagents i BzH, H20, OH-; ii CrO, H+; iii HC02H; iv Na,CO, MeOH; v SeO?;vi NaCN MnO, AcOH MeOH; vii Me,SiOTf Et,N ; viii N-bromosuccinimide; ix Me,SiOTf Et,N NaHCO,; x Me,SiOTf (Me,Si),NH; xi rn-chloroperoxybenzoic acid; xii NaIO,; xiii NaBH,; xiv HCl; xv H,O,; xvi LiOH Scheme 70 11.2 Pentalenane The full details of the first total synthesis of pentalenene (312) by Paquette and Annisg5 have been published (see ref.188 in Nut. Prod. Rep. 1984,1 105).Shirahama and Matsumoto (see ref. 84,in ‘Terpenoids and Steroids’ Vol. 7 Ch. 2 and ref. 131a in Vol. 10,Ch. 1) have already been able to obtain pentalenene (3 12) from humulene (288)by a biogenetically inspired process. Following on from this success they have now prepared both pentalenolactone E (321)and pentalenolactone F (322)from humulene (Scheme 70).86This was achieved by starting from the bicyclic ether (313) which had previously been obtained from humulene (see ref. 177 in ‘Terpenoids and Steroids’ Vol. 12,Ch. 2).Hydroboration-oxidation of (313) gave the ketone (314)(together with a minor amount of the methyl epimer) which on treatment with formic acid and subsequent hydrolysis furnished the pentalenene-type alcohol (315).After hydroboration the two diols (3 16) and (317)could be converted separately (in six steps) into a mixture of the enol ethers (318) and (319)(Scheme 70 shows the sequence for one of these diols). Subsequent elaboration of this mixture provided the a-methylene lactone ester (320),which was hydrolysed to give pentalenolactone E (321);further epoxidation and hydrolysis yielded pentalenolactone F (322)(in addition to the epoxide epimer). 11.3 Precapnellane and Capnellane Full details of the elegant synthesis of epiprecapnelladiene (323),which is the epimer of naturally occurring precapnella- //-\ 0 (330) NATURAL PRODUCT REPORTS 1985 diene (324),and of its cyclization to A8(9)-capnellene (325)have been publisheds7 (see ref.202 in ‘Terpenoids and Steroids’ Vol. 12,Ch. 2 and ref. 191 in Nut. Prod. Rep. 1984,I 105). Another full paperg8 relates the total synthesis of A9(I2)-capnellene (326) using the intramolecular I ,3-diyl trapping process (see ref. 203 in ‘Terpenoids and Steroids’ Vol. 12,Ch. 2)which has also been used very successfully in the synthesis of hirsutene (see ref. 92). Mehta et aLg9have also achieved the synthesis of A9(I 2)-capnellene(326),using a strategy similar to the 9ne that they used for hirsutene (see ref. 196 in ‘Terpenoids and Steroids’ Vol. 12,Ch. 2). In this process (Scheme 71) the key cis,syn,cis-bis-enone (328)was obtained by thermolysis of the pentacyclic diketone (327) which in turn was derived from methylcyclopentadiene and p-benzoquinone in two steps.Isomerization of (328)to give (329),followed by appropriate manipulation of the functional groups led to the tricyclic ketone (330),which has previously been converted into A9(I *)-capnellene (326).Finally in this section is the reportg0 on the synthesis of the tricyclic diol (331) (Scheme 72) which is the desmethyl analogue of the naturally occurring diol (332). (323) (327) (329) Reagents i hv ii 530 “C; iii 1,8-diazabicyclo[5.4.0]undec-7-ene; iv H2 Pd/C; v Ph,P=CH,; vi CH212 Zn/Cu; vii H, PtO, AcOH Scheme 71 6 H /i-viii (331) (Thp = tetrahydropyran-2-yl) Reagents i (MeO),CO NaH; ii KOBu‘ ICH,C(OMe)=CHCO,Et; iii LiI y-collidine; iv H,O+; v NaOEt; vi NaBi-I, CeC1,.7HZO; vii /O\ dihydropyran H+; viii BuiAlH; ix OsO, (+) ; x MsCl Et,N; xi 1,8-diazabicyclo[5.4.0]undec-7-ene;xii Me,SiLi dNb-Scheme 72 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS H (332) 11.4 Hirsutane Once again there has been considerable synthetic activity directed towards the linearly fused cis,anti,cis-tricyclopentane ring system of hirsutene (336) and the more highly oxygenated derivatives hirsutic acid (347) and coriolin (357). Several novel and ingenious routes to these compounds have been described in the year under review. One of these is the new synthesis of hirsutene (336) (Scheme 73)9' which used a homoenolization process to convert the tricyclo[5.3.1 .02,6]undecen-8-ones (333) (as a mixture of double-bond isomers) into a 1 1 mixture of A3-and A4-tricyclo[6.3.0.02~6]undecen-9-ones (334).This clean rearrangement was anticipated on the basis of earlier homoeno- lization studies on simpler bicyclic ketones. Four straightfor- ward steps were used to convert (334) into the tricyclic ketone (335) and its 5-keto isomer which were separated chromatogra- phically. This constitutes a formal synthesis of hirsutene since this ketone (335) has been converted into hirsutene in five steps. In their previous synthesis of hirsutene Little and Muller (see ref. 195 in 'Terpenoids and Steroids' Vol. 12 Ch. 2) used the diazene (337) which incorporated an activated diylophile grouping. On thermolysis (337) gave principally the desired tricyclic ester (339) [with a small amount of (341) in the ratioof 9 :11 which ultimately required the removal of the methoxycar- bony1 group (by decarbonylation of the corresponding alde- hyde) at a later stage in the synthesis.A shorter route to hirsutene called for the unactivated analogue (338). This immediately posed the three problems of (i) intermolecular dimerization versus intramolecular trapping of the diyl (ii) the stereoselectivity of the ring fusion (cis,anti-versus cis,syn) in the absence of the secondary orbital interactions that are associat- ed with the methoxycarbonyl group and (iii) the regiochemical outcome of the intramolecular trapping reaction. In the event thermolysis of (338) gave the two products (340) and (342) (Scheme 74) in the ratio of 5 l.92 This indicates that dimerization of the diyl is not a competitive process in this case and that the decrease in stereoselectivity for ring fusion from 9 1 for (337) to 5 1 using (338) is related to the absence of secondary orbital interactions that can reduce the energy of the transition state in the diyl intermediate that is derived from (338).In terms of regioselectivity both of the diyls that are derived from (337) and (338) cyclize to give the linearly fused tricyclopentanoid ring system but intriguingly,88 the diyl that was derived from (343) gave after hydroboration-oxidation the three ketones (344)-(346) in the ratio of 1.6:l :6.6 demonstrating that the major product (346) arises by a reversed regiochemical trapping of the diylophile double-bond by comparison with (337) and (338).In 1980 Greene (see ref. 131 in 'Terpenoids and Steroids' Vol. 11 Ch. 1) used an iterative three-carbon-annelation sequence to construct hirsutene with an economy of steps. He and his group have now reported a new synthesis of hirsutic acid (347)93 which is based on the same methodology (Scheme 75). In their synthesis of hirsutic acid last year Ikegami et al. (see ref. 198 in Nut. Prod. Rep. 1984,1 105) used the keto-ester (352) as a principal building block. They have now presented ' (333) I I vi vii (336) (335) Reagents i LiNPri Me,SiCI; ii CH,12 Zn/Ag; iii NaOH; iv NaNH, MeI; v Bu'O- at 185 "C; vi N,H, OH-; vii rn-chloroperoxybenzoic acid; viii LiAIH,; ix KzCr20, H+; x h.p.1.c. Scheme 73 (339) R = CO,Me ii ii (336) (340) R = H -I (335) (337) R = COzMe (338) R = H .H It (341) R = C0,Me (342) R = H Reagents i heat; ii BIH, H201 OH-; iii pyridinium chlorochromate Scheme 74 130 NATURAL PRODUCT REPORTS 1985 an alternative route to this key intermediate,94 based on the agents the best value of 2.3 :1 for the ratio [(350)] :[(351)] was chelation-controlled methylation of the epimeric esters (348) achieved in diethyl ether using the methoxyethoxymethyl and (349) which were obtained in the ratio of 5 :1 by the (MEM) ether and methyl iodide.The reason for the preferen- procedure that is shown in Scheme 76. After investigating a tial methylation on the concave face of (348)/(349) is attributed variety of solvents alcohol-protecting groups and methylating to the chelated enolate intermediate (353).viii ix I xiii-xv \ (347) Reagents i Me2C=CH2 H2S0,; ii LiNPrl,; iii MeI; iv Cl,CCOCl POCI, Zn/Cu; v CF,C02H; vi Me,CuLi; vii CH2N,; viii NaBH,; ix Cr(CI0.J2 H,N[CH,],NH,; x Zn AcOH; xi PdCI, Pd(OAc),; xii AIBr, ;xiii (Me,Si)?NLi; xiv HC0,Me; xv CH20 K,CO,; xvi H20, NaOH Scheme 75 @HOIMe v 1 -111 MEMO@- IV- VII MEMO H (348) PE0,Me + MEMO H (349)1viii Q'2 V H r;l c-PC0,Me P H zMe HO O MEMO H 1 iii (MEM = MeOCH,CH,OCH,) Reagents i aq. N-bromosuccinimide; ii Bu,SnH; iii pyridinium chlorochromate; iv Ph,P=CHOMe; v H,O+; vi CrO, H+; vii CHzNz; viii LiNPri MeI Et,O Scheme 76 NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS 13 1 A new and very neat synthesis of coriolin (357) (Scheme 77)95 and mag nu^^^ in which the intramolecular cyclization of the starts with the one-pot dialkylation of (354) to produce (355).ene-yne (358) promoted by dicobalt octacarbonyl (Scheme 78) This facile construction of the bicyclic intermediate paved the is a prominent feature. Not only is the yield very acceptable way for subsequent transformations into the tricyclic hydroxy- (50%) but the reaction is also stereoselective (3.3 1) in favour of enone (356) in an overall yield of 20.5%. This enone has already the desired 8a-derivative (359). By following essentially the featured as an important intermediate in other syntheses of procedure that has been described by Ikegami et a/.(see ref. 198 coriolin (see ref. 136 in 'Terpenoids and Steroids' Vol.1 1 Ch. 1 in Nat. Prod. Rep. 1984,1 IOS) the enone (359) was converted and ref. 199 in Nat. Prod. Rep. 1984 1 105). A completely into the tricyclic enone (360) and thence through to (361) different approach to coriolin (357) has been described by Exon which has appeared in three other syntheses of coriolin (357) (see refs. 199 201 and 203 in Nat. Prod. Rep. 1984 1 105). Wender and co-workers have enjoyed considerable success in the past three years with their arene-olefin photocycloaddi- tion route to a variety of tricyclic sesquiterpenes (see ref. 107 in 'Terpenoids and Steroids' Vol. 12 Ch. 2 and refs. 150 153 and 196 in Nat. Prod. Rep. 1984 1 105). They have now extended this very efficient methodology to two syntheses of a more (353) highly oxygenated intermediate en route to ~oriolin.~~ In the Me0 MeO Me0 \ \ OBu' H OBu' (354) (355) J BzO x xi viii.ix I OAc xii I BzO xiii XIV -w HIOAc H (356) (3571 .I Reagents i 2 equivalents of LiNPt-5; ii ICH_IC(Me)2CHO; CuBr.Me,S; vii aq. iii MeOCH2CI;iv MeLi; v H,O+; vi Br[CH2I2H<I NH,Cl; viii; BzCI py; ix 1,8-diazabicyclo[5.4.0]undec-7-ene; x NaBH, CeCI,; xi Ac20 py; xii CrO, 3,5-dimethylpyrazole; xiii Zn,AcOH; xiv LiOH Scheme 77 I H (R = SiMe,Bu') (358) H (359) x/ RO x-XIV H w -w OH OH (360) (357) (361) + Reagents 1. LiC=CSiMe,; ii Bu'Me,SiC; iii PhCH,NEt C1- KF.2H,O; iv BuLi MeI; v Co2(CO), CO at 110 "C; vi H1 Pd/C; vii LiNPri; viii BrCH2CH=CH2; ix PdC12 H,O; x KOBu'; xi AcOH; xii rn-chloroperoxybenzoic acid; xiii 1,8-diazabicyclo[5.4.O]undec-7-ene; xiv [HFI,;py Scheme 78 NATURAL PRODUCT REPORTS 1985 -iii iv (357) (364) Reagents i hv; ii LiAlH,; iii pyridinium dichromate; iv Li NH, EtOH; v PhSH heat Scheme 79 viii-x vii (357) -OCHO (368) (367) + Reagents i 0,; ii Ph,3P-CH=CHOEt Br- NaOEt; iii hv; iv PhSH; v Li NH3 EtOH; vi rn-chloroperoxybenzoic acid (MCPBA) H,O; vii BF,; viii LiNPr’ (LDA) Me,SiCl; ix Pd(OAc),; x LDA PhSS0,Ph; xi H,O+; xii MCPBA; xiii heat Scheme 80 first route (Scheme 79) the photo-adduct (362) which was previously used in their earlier synthesis of hirsutene (see ref.196 in Nat. Prod. Rep. 1984 1 105) was oxidized to the corresponding ketone which underwent reductive cleavage protonation and further reduction to give the tricyclic alcohol (363).Alternatively this same alcohol could be obtained from (362) by radical-induced cleavage [to yield the allylic sulphide (364)] followed by reductive desulphurization. This alcohol was prepared by Mehta et ul. (see ref. 203 in Nut. Prod. Rep. 1984 1 105) and formally converted into coriolin (357). The second route (Scheme 80) to coriolin incorporates a greater degree of functionality in the initial substrate. Thus photolysis of (365) followed by the two-step reductive opening of the cyclopropane ring gave the hydroxy-acetal(366). Treatment of (366) with rn-chloroperoxybenzoic acid (MCPBA) in the presence of water brought about all the desired transformations namely hydroly- sis of the acetal Baeyer-Villiger oxidation of the resultant aldehyde and epoxidation.A further six conventional steps were used to convert (367) into (368) which is an established late intermediate in Danishefsky’s first synthesis of coriolin (see ref. 133 in ‘Terpenoids and Steroids’ Vol. 11 Ch. 1). Finally Schuda et al. (see ref. 207 in Nat. Prod. Rep. 1984 1 105) reported last year the synthesis of the potential coriolin intermediate (369). To circumvent the problems of selective ester/carbonate hydrolysis they have carried out a modifica- tion on their key intermediate (370) (Scheme 81).98 Pivaloyla-tion of the diol (371) gave the desired monopivaloate (372) in 48% yield two other products (the regioisomeric monoester and the dipivaloate) and unaltered diol.The two unwanted products and the unaltered diol were separated from (372) and alkaline hydrolysis of this mixture gave a sample of the original (369) diol (371); the cycle was repeated twice more so that the cumulative yield of the desired product (372) was 86%. After conversion of the unprotected primary alcohol into a methyl group the ester (373) was hydrolysed and oxidized with RuO (the benzyl group being oxidized to a benzoate in the process) to give (374). Hydrolytic decarboxylation of (374) gave a 4 1 mixture of (375) and (376) the latter of which has featured in a recent synthesis of coriolin (see ref. 199 in Nat. Prod. Rep. 1984 1 105). To complete the third ring the mixture of (375) and (376) was taken through the six-step sequence that is shown in Scheme 81 to give (377) which has already been converted into coriolin (357) (see ref.205 in Nat. Prod. Rep. 1984 1 105). Another potentially useful route to the cis,anti,cis linearly fused tricyclopentane system is described in work by Demuth et al.99 (Scheme 82) the key point being the acid-catalysed ring- opening of the t ri c yclo[ 3.3.0.0 *~*]oc tan-3 -one derivative (3 7 8) to give (379). A number of other transformations of (379) have also been presented. 11.5 Senoxydane In 1979 Bohlmann and Zdero assigned the structure of senoxydene which is a sesquiterpene from Senecio oxyodontus as (380) as a result of a detailed n.m.r. spectral analysis of the 133 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS n BzO PhCO H V VI-VIII ix x __* __+ I0 H OH H CO,H (37 1) (373) (374) (370) OHCO PhCQ2 PhCO xvi xvii xii xiii t-0-t-0 A H H H H (377) (376) (375) ll (357) /O\ Reagents i,KH Bu,NI BzBr; ii OsO, (+) ;iii NaIO,; iv NaBH,; v Bu'COCI py; vi (CF3S02)20 py; vii Bu,NI; viii Zn; ix KOH; x Me"'0-RuO? NaIO,; xi H,O+ ; xii CH(OMe), toluene-p-sulphonic acid (PTSA); xiii HOCH2C(CI)=CHCH2SPr PTSA; xiv Bu,NOH; xv Hg(OAc)? HC0,H; xvi KOBuI; xvii PTSA Scheme 81 I H H H H (379) vii J IX t- vii or viii HW t- __+ VI H H H H Reagents i NaH MeI; ii CICH2C(Me)=CH2 KOBu'; iii OsO, NaIO,; iv NafionSiMe,; v AgOAc I,; vi 1,5-diazabicyclo[4.3.0]non-5-ene; vii KOBu'; viii toluene-p-sulphonic acid; ix Me3SiI Scheme 82 hydrocarbon and its epoxide (see ref.148 in 'Terpenoids and Steroids' Vol. 10 Ch. 1). Being yet another example of an angular triquinane derivative which on paper is biogenetical- ly linked to humulene or caryophyllene its structure has posed an interesting synthetic challenge to Paquette et ~ 1 As . shown in Scheme 83 they have achieved a neat and unambi- guous synthesis of the compound with structure (380) but there were significant differences between the n.m.r. spectra of natural senoxydene and synthetic (380). Thus the correct structure of this sesquiterpene awaits final determination. 12 Germacrane The use of the intramolecular alkylation of a protected cyanohydrin carbanion for the construction of medium-sized rings has been amply demonstrated in the recent papers of Takahashi et ~1.~~' (see also ref.81). This approach has led to the syntheses of acoragermacrone (381)Io2 (Scheme 84) and germacrone (382)Io3 (Scheme 85). Despite the fact that a large body of biologically active germacranolides are now known with varying degrees of oxygenation the synthesis of these compounds has been virtually non-existent principally because of the lack of suitable methods for the construction of the ten-membered ring with its array of appropriate functional groups. Some years ago Still (see ref. 160 in 'Terpenoids and Steroids' Vol. 10 Ch. 1) ~~~ showed that the oxy-Cope rearrangement provided an entry into the germacrane ring in the form of the synthesis of periplanone-B (383).Still and his co-w~rkers~~~ now have extended this methodology to the synthesis of the cytotoxic germacranolide eucannabinolide (388) (Scheme 86) starting from (+)-camone. The cyclobutenone ketal portion of (384) served the dual function of providing the requisite 1,5-diene moiety for the crucial oxy-Cope transformation and for the ultimate a-methylene-y-lactone grouping of (388). This pro- duced a mixture of (385) and its C-7 (trans)isomer in a ratio of nearly 1 :1 ;on thermodynamic equilibration in the presence of a base this mixture gave the more stable cis-isomer (385) as the major product. Guided by the considerations of molecular mechanics calculations the keto-lactone (386) was transformed into the isomeric keto-lactone (387) and thence through to eucannabinolide (388).Biological oxygenation can be achieved by various means including hydration epoxidation etc.; with the increasing 134 NATURAL PRODUCT REPORTS 1985 lviii. ix Reagents 1 H,C=CH[CH&MgBr CuBr.Me,S; ii 320 "C; iii HCO,Et NaOMe; iv BUSH H+; v LiNPr',; vi MeCH=C(SiMe,)CH,I; vii KOH; viii rn-chloroperoxybenzoic acid NaHCO,; ix H,O+; x KOBu'; xi Li NH,; xii NaBH,; xiii POCl, py Scheme 83 %TCHO 2 22(-Y& OEE 2p+22 OEE p& OEE OEE NC (38 1 ) [ EE=CH( Me)OEt] + Rwgents i MezCHMgBr; ii TsCl py; iii H,O+; iv MnO,; v Me,SiCN KCN 18-crown-6; vi PhCHINMe F-; vii EtOCH=CH2 H+; viii (Me,Si),NLi; ix toluene-p-sulphonic acid MeOH; x NaOH Scheme 84 Reagents i Pd(OAc), Ph,P; ii NaH (EtO),POCl; iii Me,CuLi; iv Ph,P CCl,; v Bu',AlH; vi MnO,; vii Me,SiCN KCN 18-crown-6; viii PhCH,NMe F-; ix EtOCH=CH2 H+; x NaN(SiMe,),; xi toluene-p-sulphonic acid MeOH; xii NaOH Scheme 85 (383) number of naturally occurring hydroperoxides it is tempting to suggest that the biological equivalent of oxygenation by lo2 could play an important role.Thus El-Feraly er d.lo5 have investigated the photo-oxygenation of certain sesquiterpenoid lactones (see also p. 137) and thereby achieved some interesting biogenetic-type conversions. For instance the two hydroperox- ides (390) and (391) were derived from laurenobiolide (389) by addition of singlet oxygen (Scheme 87). Reduction of these with tin@) chloride gave tulirinol (392) and dihydrochrysanolide (393) respectively.On the other hand treatment of (391) with acetic anhydride in pyridine gave chrysanolide (394). 13 Elemane The stereoselective synthesis of ( +)-&elemenone (395) has been recorded starting from ( -)-cyclohex-2-en-1-01 (Scheme 88).lo6The keto-diol(396) which has previously been obtained from thujone (397) and used in a synthesis of (+)-carissone (398) (see ref. 306 in Nut. Prod. Rep. 1984 1 l05) has now been transformed into (-)-p-elemol (399) (Scheme 89).Io7A similar type of strategy for the modification of ring A of artemisin (400) has been adopted to bring about the conversion into temisin (401) and melitensin (402) (Scheme 90).lo8 Another route to the elemanolides 8-deoxymelitensin (408) 11,12-didehydr0-8-deoxymelitensin(409) and saussurea lact- one (410) depends upon a novel fragmentation reaction.O9 Thus the ketal-lactone (404) obtainable in eight steps from or-santonin (403) was converted into the epoxy-mesylate (405) (Scheme 91). Treatment of this mesylate with aluminium isopropoxide gave the allylic alcohol (406) as the minor product NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS 1xii xv (388) Reagents i LiAlH,; ii m-chloroperoxybenzoic acid; iii PhCH20CH2CI Pr\NEt; iv PhSeK LiBr; v H202 NaHC03 NaOAc; vi CrO, H+; Li vii OMe ; viii KN(SiMe3)2; ix K,C03 MeOH; x aq. (C02H)2,SiO,; xi H202 Ti(OPrl), Pr’,NEt; xii NaBH,; xiii Cr03-2py; OMe xiv 1,8-diazabicyclo[5.4.O]undec-7-ene; xv H, Pd(OH),/C; xvi trimethylsilylimidazole py; xvii LiNPri; xviii CH,O; xix MsCl Et3N 4-dimethylaminopyridine ; xx Bu,N F ; xxi AcOH dicyclohexylcarbodi-imide(DCC) xxiii pyridinium toluene-p-sulphonate Scheme 86 HOO +wOAc 0 OAc (390) -.A (391) * ii ii bAc I 1 -1 HOO (394) G OAc o OAC (392) (393) Reagents i ‘Or;ii SnC12; iii Ac20 py Scheme 87 136 NATURAL PRODUCT REPORTS 1985 vii-ix I (395) Reagents i VO(acac), BulO,H; ii MsCl Et,N; iii NaI; iv 1,8-diazabicyclo[5.4.0]undec-7-ene; v H,C=CH(Me)CuCNLi; vi pyridinium chlorochromate; vii MeMgBr Cur; viii PhSeBr; ix NaIO,; x (H,C=CH),CuCNLi,; xi LiN(SiMe,)? CS,; xii LiN(SiMe,), Mel; xiii Me,CuLi Scheme 88 and the elemane-type compound (407) as the major product.The latter compound could also be derived from (406) if the reaction was allowed to continue for a longer period.The formation of (407)can be rationalized in terms of a Grob-type fragmentation of the aluminium alkoxide corresponding to (406) (to give the ring-opened aldehyde) and Meerwein-Ponndorf reduction to the primary alcohol (407) (ring-opening of the y-lactone with transesterification also took place in this 'OH (396) (399) reaction). This fragmentation thus permits entry to the three elemanolides (408)-(410). 14 Eudesmane A very neat synthesis of (-)-p-selinene (414) has been announced in which the key step is the alkoxide-accelerated vinylcyclobutene-cyclohexene rearrangement (Scheme 92). O Thus reduction of (412) by lithium aluminium hydride followed by treatment of the 2-vinylcyclobutanols with potas- sium hydride in refluxing THF gave the ring-expanded cyclohexenols (413).Starting from (-)-perillaldehyde (41I) this procedure gave (-)-p-selinene (414). For an interesting short synthesis of the enantiomer (+)-p-selinene (420) ii-iv - \OH o q o v vi I . Reagents i H, Pd for 4 hours; ii TsCI py; iii LiAIH,; iv CrO, py; v TsNHNH, BF,.EtzO); vi MeLi; vii 0,; viii NaBH,; ix o-NO,C,H,SeCN Bu,P py; x NaIO Scheme 89 eH qo-H-0 0 (400) i. ii tvii ix 1 HO- ,O R v. VI vii viii x ix (R = SiMe,Bu') (402) Reagents i H, Pd/C; ii BulMe,SiC1 imidazole; iii TsNHNH, BF,; iv LiNPr;; v 0,;vi NaBH,; vii o-NO,C,H,SeCN Bu,P; viii H,O,; ix Bu,NF; x SeO, Bu102H Scheme 90 137 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS M SO i-iii --b-' __+ Q--0 b (403) (404) (405) lv MsQ HO (409) Reagents i H30+; ii LiAl(OBut),H ;iii m-chloroperoxybenzoic acid; iv MsCl py ; v AI(OPI-')~ ; vi toluene-p-sulphonic acid ; vii LiNPr; Ph2Se,; viii H202; ix Ac20 py; x Li NH,; xi Cr03.2py Scheme 91 0 .. ... 11 111 I vii vi -q3*.r-p*.f OH 0 HO (4 14) (41 3) Reagents 1 H30+;ii LiAIH,; iii KH heat; iv Cr03 H+; v AI,O,; vi MeCuBF,; vii Ph3P=CH2 Scheme 92 Wolinsky et all * have carried out the sequence that is shown in (425) and (i-)-p-selinene [(414) (42O)l.l * A similar reaction Scheme 93. (-)-P-Pinene (415)underwent an ene reaction with sequence for (424) (with appropriate protection of the hydroxyl acryloyl chloride to produce the bicyclic acid chloride (416) group) has led to (+)-P-dictyopterol(426).A re-investigation of which on dehydrochlorination with tri-n-butylamine at the aprotic Robinson annelation of (-)-dihydrocarvone (428) 150 "C gave the tricyclic enone (418). This step almost which was derived from (+)-camone (427) has shown that the certainly involves an intramolecular ene reaction of the thermodynamic enolate can react with ethyl vinyl ketone to intermediate ketene (417) followed by isomerization. A further give the ketol (429) in 92%yield.l13 Dehydration of this ketol thermal reaction promotes a retro-ene reaction to produce gave (+)-6-epi-or-cyperone (430) (Scheme 95). Alternatively (419).This bicyclic ketone may also be formed in a single low- the same enolate could be generated in situ [by the reduction of yield step by heating (-)-0-pinene with acryloyl chloride in a (+)-camone (427) with lithium bronze] and then allowed to sealed tube at 150 "C for 48 hours.Conjugate addition of a react with ethyl vinyl ketone to give (430) (after dehydration) in methyl group to (419) gave all four diastereoisomeric ketones an overall yield of 67%. Although the yields with methyl vinyl the two major ones having the desired cis-relationship of the ketone are not so good this re-investigation does point to the methyl group and the isopropyl group. A Wittig reaction fact that the problems of polymerization that are associated followed by purification completed the synthesis of (+)-f3-with the aprotic Robinson annelation sequence can be selinene (420).overcome. A general method for the synthesis of the bicyclic keto-ketals As already mentioned on p. 134 the use of singlet oxygen to (423) and (424) starting from (421) and (422) respectively has introduce oxygenation in a regio-and stereo-chemically been developed (Scheme 94) and as exemplified for (423) in controlled manner can pave the way for some useful transfor- this Scheme this has permitted the syntheses of (f)-eudesmol mations. In the paper already cited El-Feraly et al.lo5have NATURAL PRODUCT REPORTS 1985 r 1 Cl'b09 (4 16) (417) 1iv I 0 / 0 (419) (420) Reagents i H,C CHCOCI at 70 "C for 48 hours; ii Bu,N at 150 "C for48 hours; iii at 265 "C for 45 minutes; iv at 150 "C for several hours; v H,C CHCOCl at 150"C for 48 hours; vi MezCuLi; vii Ph,P CH Scheme 93 (424) [R = OAc] iv.ix T R boboAc -b0-cis,A o a H MOMe e ? (421) R = H HO OH (422) R = OAc (423) Reagents i Ac,O H+; ii m-chloroperoxybenzoic acid; iii HBr; iv CH(OMe), H+; v Ph,P=CH,; vi H,O+; vii LiC(OMe)SiMe,; viii HgCI, I H+ MeOH; ix NaOMe; x MeLi SPh Scheme 94 described how this can be used to convert santamarine (431) precursor in previous syntheses of a-vetispirene (437) p-into a-santonin (403) (Scheme 96) and costunolide (432) into vetivone (438) hinesol (439) and its acetate (440) and arbusculin-C (433),tanacetin (434) and artemin (435) (Scheme agarospirol (441). 97). 15 Vetispirane 16 Eremophilane Valencane Ishwarane and Complete details of the synthesis of the key spiro-ketone (436) Valerane (see ref.173 in 'Terpenoids and Steroids' Vol. 9 Ch. 2) have (+)-Flourensic acid (443) has been synthesized from (-)-been presented.*I4 This compound has been used as the eremophilone (442) (Scheme 98).'15The bicyclic enone (444) NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS previously used in the synthesis of eremophilane derivatives (see ref. 332 in Nut. Prod. Rep. 1984 1 105) has been converted in five steps (Scheme 99) into rishitinone (449,'l6 which is a stress metabolite of diseased potatoes. A very interesting synthesis of the antifertility agent 7,12- secoishwaran-12-01(450) has been recorded (Scheme 100). The synthesis started from the tricyclic ketone (446) which featured in a much earlier synthesis of ishwarane (451) itself i iv v iii iv 1 1 (430) (429) Reagents 1 Li NH, Bu'OH; ii NH,CI; iii 0.9 equivalents of LiNPr? at 20 "C; iv H,C=CHC(O)Et at -78 to 20 'C; v KOH EtOH Scheme 95 HO HO iv i 1 (see ref.156 in 'Terpenoids and Steroids' Vol. 4 Ch. 2). Conversion of this ketone into the ring-opened ketone (447) followed by intramolecular cycloaddition of the benzyl nitrone that was derived from (447) gave the tetracyclic isoxazolidine (448). Reductive cleavage of this compound and subsequent hydrodeamination furnished the tricyclic alcohol (449) which was readily converted into (450). Based on an earlier investigation of the intramolecular cycloaddition of isolated double-bonds to 3-oxidopyrylium species Sammes and Street' l8 have described a novel route to the three valerane sesquiterpenoids cryptofauronol (457) fauronyl acetate (458) and valeranone (459) (Scheme 101).Oxidation of the furan (452) followed by acetylation gave the key acetylated pyranulose (453); thermolysis of this compound furnished the cyclo-adduct (453 uia (454) in 62% yield. Treatment of the derived hydroxy-ether (456) with titanium tetrachloride induced the rearrangement to cryptofauronol (457) which in turn could be converted into fauronyl acetate (458) and valeranone (459) by known methods. 17 Guaiane Pseudoguaiane Valerenane and Cycloseyche1Iane As noted above the intramolecular cycloaddition of an olefin with a 3-oxidopyrylium species provides a rapid entry to the perhydroazulene skeleton.Sammes and Street' * have put this to practical advantage in a synthesis of P-bulnesene (461) (Scheme 102). Unfortunately the configuration of the methyl H? HO .. ... II 111 _3 b H (Q Q/ Q- 0 '0 0 (434) (435) Reagents i SOCI 10,;iii Ph,P; iv m-chloroperoxybenzoic acid; v NaBI Scheme 97 (439) R = H (440) R = OAc (44 1 1 I40 NATURAL PRODUCT REPORTS 1985 (442) iii iv 1 OSiMe & (& gJ-+ v GOMe ,I1 C02H CHO PhSe OCOCF (443) H Reagents 1 0,; ii Me,SiCl; iii Ph,POCH(Li)OMe; iv PhSeC1 AgO,CCF,; v H,O+; vi H,02; vii CrO, H+ Scheme 98 (444) (445) CHZ II Reagents i Me,CO toluene-p-sulphonic acid; ii NaBH ; iii Ac,O 4-dimethylaminopyridine; iv MeCMgBr CuI ; v KOH Scheme 99 iv v (450) (449) Reagents i HBr hv; ii Li NH,; iii PhCH,NHOH EtOH Na,SO,; iv H, Pd(OH),; v NH,OSO,H NaOH; vi o-NO2,C6H,SeCN Ph3P; vii 0,; viii rn-chloroperoxybenzoic acid ; ix LiAIH Scheme 100 these two compounds (Scheme 104) both involve as key steps an intramolecular cyclopropanation followed by thermolysis of the resultant vinylcyclopropanes.The very elegant chemistry which had led to the syntheses of the guaianolides compressanolide (468)’ (see ref. 360 in ‘Terpenoids and Steroids’ Vol. 12 Ch. 3) and estafiatin group at C-4 in the major cyclo-adduct (460) is ct (arising from (469)lz1 (see ref. 371 in Nat. Prod. Rep. 1984 1 105) the the less sterically congested transition state) and thus in the pseudoguaianolides bigelovin (470)’ 22 (see ref.3 15 in ‘Terpen- final step P-bulnesene (461) and its C-4 epimer (462) were oids and Steroids’ Vol. 10 Ch. l) mexicanin I (471)122 and formed in the ratio of 17 :83. Another interesting route to the linifolin A (472)’ 22 (see ref. 3 16 in ‘Terpenoids and Steroids’ perhydroazulene nucleus involves the intramolecular addition Vol. 10 Ch. l) and carpesiolin (473)123 (see ref. 361 in of the nitrile oxide that was derived from the nitro-olefin (463) ‘Terpenoids and Steroids’ Vol. 12 Ch. 2) has been described in (Scheme 103).l l9 The isoxazoline product (464) obtained in full papers. 83% yield could then be elaborated to the bicyclic keto-diester Valerenane sesquiterpenoids constitute a fairly rare group of (465). Hudlicky et allzo have reported the syntheses of (466) naturally occurring compounds ; with one exception (see ref.and (467) which are potential intermediates for guaiane and 239 in ‘Terpenoids and Steroids’ Vol. 11 Ch. l) very little pseudoguaiane sesquiterpenoids respectively. The routes to synthetic work has been carried out in this area. Baudouy et NATURAL PRODUCT REPORTS 1985 -J. S. ROBERTS 141 Me I + BrMg[CH,I3C=CH OH (453) ~ & & t-c-f-viii vii v vi c- 0 I (459) 0 I I (458) I HO I (457) I (456) I I (455) Reagents i lo3;ii PPh,; iii Ac20 py; iv 150°C; v Me2CHMgI CuBr-Me,S; vi MeMgI; vii TiCI,; viii Ac,O NaOAc Scheme 101 Me I +BrMg[CH,],CHCH=CH2 -QCHO OH I iii (462) (461 1 (460) Reagents i mi-chloroperbenzoic acid; ii Ac20 py; iii 50 “C; iv H, Pd/C; v MeMgI; vi SOCI, HMPA; vii Na Et20; viii Cr03.2py; ix Me2C=PPh3 Scheme 102 iii IV V vi vii OLQ4-d -@ 0 (464) (465) (E =C02Me) (463) Reagents i HCl; ii NaCH(CO,Me),; iii NaH CI[CH2],Br; iv NaI AgNO,; v Et,N PhNCO; vi 0,; vii toluene-p-sulphonic-acid Scheme 103 al.12j have now developed a route to valerenal (477) and its 18 Aromadendrane epimer (478) (Scheme 105).This was achieved by initial Having completed the synthesis of (484) in both racemic and formation of the vinyl-allene (474) by a mixed cuprate laevorotatory forms last year (see ref. 392 in Nat. Prod. Rep., displacement of the tosylate of but-2-yn- 1-01. Acetoxythallation 1984 1 105) Taylor and Smith126 have now reported the of (474) gave the two cyclopentenones (475) and (476) in the conversion of the (-)-enantiomer into the seco-aromaden- ratio of 45 :55 and deoxygenation followed by elaboration of drane sesquiterpenoid (+)-hanegokedial (487) (Scheme 107).the side-chain produced the natural product (477) together with The two alcohols (485) and (486) were obtained in the first step its epimer (478). in the ratio of 2 1 the minor isomer having the desired Last year (see refs. 390 and 391 in Nat. Prod. Rep. 1984 I stereochemistry for conversion into (+)-hanegokedial (487). 105) the structure of cycloseychellene was revised to (483) on All attempts to convert this compound into (+)-ovalifolene the basis of n.m.r. spectral analysis coupled with the synthesis (488) have so far been unsuccessful.of (479) the structure of which had previously been assigned to cycloseychellene. This revision has now been put on a firm footing following the unambiguous synthesis of (483) (Scheme 19 Pinguisane 106),*25 starting from the tricyclic keto-alcohol (482) which Dreiding er al.lt7 have synthesized a stereoisomer (494) (of had previously been used in the syntheses of seychellene (480) unidentified stereochemistry) of the liverwort constituent and patchouli alcohol (481) (see ref. 352 in ‘Terpenoids and ptychanolide (495). The synthesis (Scheme 108) started with Steroids’ Vol. 10 Ch. 1). the nitrile (489) which had previously been prepared for a NATURAL PRODUCT REPORTS. 1985 [28 :721 Jr..v Pa, %O,Me (466) 0 H (467) Reagents i CuSO, heat; ii heat; iii Lil DMF; iv OH-; v CH,N2 Scheme 104 (R = SiMelBul) (474) I viii xi] +- + @ CHO CHO I lxiii xv (475) I I ?CHO (478) (477) Reagents i Na HC02Et; ii NaH AlH,; iii Bu'Me,SiCl imidazole; iv ArSO,NHNH,; v Bu'Li; vi MeOC(Me),C=CCu MeC=CCH,OTs; vii TI(OAc), AcOH; viii BubAlH; ix AcCl; x Li NH,; xi H,O+; xii DMSO (COCI),; xiii Me,SiCH(Me)CH=NCMe,; xiv (CO,H),; xv pyH+ C1-Scheme 105 NATURAL PRODUCT REPORTS 1985 -J.S. ROBERTS Scheme 106 OAc Reagents i [(EtO),CHC+CuLi; ii CH,O; iii Ph,P=CH,; iv Cr03.2py; v H,O+; vi AcOH or Ac2O Or Ac20 H' Scheme 107 \ XVll XIX (493) (494) Reagents i KOH HO[CH,],O[CH,],OH at 200 "C; ii H, Pt/C; iii SOCl,; iv Me,SiC=CSiMe, AICI,; v Na2B,0,; vi 620 "C; vii Me,CuLi; viii NaH (MeO),CO; ix NaH MeOCH,CI; x Li NH,; xi LiNPr5; xii BrCH,CH=CH2; xiii 0,; xiv Me,S; xv KOH; xvi H,O+; xvii PhSH MeS0,H; xviii rn-chloroperoxybenzoic acid; xix P(OMe), heat Scheme 108 product.The lack of stereochemical definition arises from the difficulty in stereochemical assignment after allylation of the ester (493); normally attack on the convex face of (493) would be expected but the presence of three cis-methyl groups on the cyclopentane ring could alter this preference. (495) synthesis of A9('*)-capne1lene (see ref. 192 in Nat. Prod. Rep. 20 References 1984 1 105). Drastic basic hydrolysis of (489) gave (rather surprisingly) the rearranged acid (490) (in addition to a smaller 1 'Terpenoids and Steroids' (Specialist Periodical Reports) ed.J. R. Hanson The Chemical Society London Vol. 7 Ch. 2; Vol. 8 Ch. amount of the expected product) which was elaborated to the 2; The Royal Society of Chemistry London Vol. 10 Ch. 1 ; Vol. a-alkynone (49 1). By following Dreiding's procedure this was 11 Ch. 1 ; Vol. 12 Ch. 2. thermolysed to give the bicyclic enone (492). At the end of the 2 S. L. Graham C. H. Heathcock M. C. Pirrung F. Plavac and reaction sequence a crystalline diastereoisomer of ptychan-C. T. White 'The Total Synthesis of Natural Products' ed. J. olide was obtained which was different from the natural ApSimon Wiley-Interscience New York Vol. 5 1983. 3. T. Mandai M. Kawada and J. Otera J. Org. Chem. 1983 48 5 183. 4. G. A. Kraus and P. Gottschalk J.Org. Chem. 1983 48 5356. 5. T. Fujisawa T. Sato Y. Gotoh M. Kawashima and T. Kawara Bull. Chem. Soc. Jpn. 1982 55 3555. 6. (a)D. W. Knight and B. Ojhara J. Chem. SOC.,Perkin Trans. I 1983,955 (6)R. Baker D. C. Billington and N. Ekanayake ibid. p. 1387. 7. P. A. Bartlett and C. P. Holmes Tetrahedron Lett. 1983,24 1365. 8. S. Auricchio A. Ricca and 0. Vajna de Pava J. Org. Chem. 1983 48 602. 9. K. Mori and T. Fujioka Tetrahedron Lett. 1983 24 1547. 10. R. K. Dieter and J. W. Dieter J. Chem. SOC.,Chem. Commun. 1983 1378. 11. M. Jalali-Naini D. Guillerm and J.-Y. Lallemand Tetrahedron 1983 39 749. 12. D. M. Hollinshead S. C. Howell S. V. Ley M. Mahon N. M. Ratcliffe and P. A. Worthington J.Chem. SOC.,Perkin Trans. 1 1983 1579. 13. S. V. Ley and M. Mahon J. Chem. SOC.,Perkin Trans. I 1983 1379. 14. S. P. Tanis and P. M. Herrinton J. Org. Chem. 1983 48 4572. 15. T. Matsumoto and S. Usui Bull. Chem. SOC.Jpn. 1983 56 491. 16. J. A. Marshall and R. E. Conrow J. Am. Chem. Soc. 1983 105 5679. 17. P. Gosselin and F. Rouessac Tetrahedron Lett. 1983 24 5515. 18. H. Sakurai A. Hosomi M. 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Kuwajima J. Chem. SOC. Chem. Commun. 1983 499. 46. P. Herold P. Mohr and C. Tamm Helv. Chim. Acta 1983 66 744. 47. Y. Yamamoto N. Maeda and K. Maruyama J. Chem. Soc. Chem. Commun. 1983 774. 48. W. Oppolzer F. Zutterman and K. Battig Helv. Chim. Acta 1983 66 522. 49. D. Solas and J. Wolinsky J. Org. Chem. 1983 48 670.50. M. Horton and G. Pattenden Tetrahedron Lett. 1983 24 2125. NATURAL PRODUCT REPORTS 1985 51. D. W. Landry Tetrahedron 1983 39 2761. 52. T. Harayama Y. Shinkai Y. Hashimoto H. Fukushi and Y. Inubushi Tetrahedron Lett. 1983 24 5241. 53. H. M. R. Hoffmann and R. Henning Helv. Chim. Acta 1983,66 828. 54. A. J. Barker and G. Pattenden J. Chem. Soc. Perkin Trans. 1 1983 1901. 55. W. Oppolzer R. Pitteloud G. Bernardinelli and K. Baettig Tetrahedron Lett. 1983 24,4975. 56. J. R. Williams J. F. Callahan and C. Lin J. Org. Chem. 1983 48 3162. 57. (a) F. Bohlmann and W. Giencke Tetrahedron 1983,39,443; (b) A. Talvitie and A. K. Borg-Karlson Finn. Chem. Lett. 1979 93. 58.M. 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Simoni Tetrahedron Lett. 1983 24 5669. 72. E. Wenkert and T. S. Arrhenius J. Am. Chem. Soc. 1983 105 2030. 73. R. P. Short J-M. Revol B. C. Ranu and T. Hudlicky J. Org. Chem. 1983 48 4453. 74. J. Wrobel K. Takahashi V. Honkan G. Lannoye J. M. Cook and S. T. Bertz J. Org. Chem. 1983 48 139. 75. L. A. Paquette and A. Leone-Bay J. Am. Chem. Soc. 1983 105 7352. 76. T. Tsunoda M.Kodama. and S. It8 Tetrahedron Lett. 1983 24 83. 77. K. Takeda Y. Shimono and E. Yoshii J. Am. Chem. SOC.,1983 105 563. 78. R. H. Schlessinger J. L. Wood A. J. Poss R. A. Nugent and W. H. Parsons J. Org. Chem. 1983 48 1146. 79. J. M. Dewanckele F. Zutterman and M. Vandewalle Tetra- hedron 1983 39 3235. 80. S. D. Burke C. W. Murtiashaw and J. A. Oplinger Tetrahedron Lett. 1983 24 2949. 81. T. Takahashi K. Kitamura and J. Tsuji Tetrahedron Lett. 1983 24 4695. 82. H. Shirahama G. S. Arora and T. Matsumoto Chem. Lett. 1983 281. 83. H. Shirahama G. S. Arora E. Osawa and T. Matsumoto Tetrahedron Lett. 1983 24 2869. 84. 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ISSN:0265-0568    

DOI:10.1039/NP9850200097

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Natural Sesquiterpenoids B. M. Fraga lnstituto de Productos Naturales Organicos CSIC La Laguna Tenerife Canary Islands Spain Reviewing the literature published in 1983 (Continuing the coverage of the literature in Natural Product Reports 1984 Vol. 1 p. 105) 1 Farnesane 2 Mono-and Bi-cyclofarnesanes 3 Bisabolane 4 Herbertane Laurane and Trichothecane 5 Chamigrane 6 Carotane and Zizaane 7 Cadinane Cubebane Oplopanane and Picrotoxane ?OH OH 8 Himachalane Longipinane Longibornane and Longifolane 9 Caryophyllane and Related Compounds 10 Humulane Bicyclohumulane Pentalenane Marasmane Lactarane and Illudane 11 Germacrane 12 Elemane 13 Eudesmane 14 Vetispirane and Related Compounds (3) 15 Eremophilane and Aristolane 16 Guaiane and Pseudoguaiane OH 17 Aromadendrane / yy" 18 Miscellaneous Sesquiterpenoids 19 References (4) 1 Farnesane The new nerolidol derivative arteincultone (1) has been isolated from Artemisia incultu,* whilst the nerolidol hydroperoxide (2) and (3) were obtained from Schistostephium crutuegifolium.* (5) 0 The (3E) and (32) isomers of the new farnesane derivatives (4) 11 z and (5) and the (3E)/(3Z)isomeric mixtures of the two epimers (Ang = -CCMe=CHMe) at C-7 of (6) have been identified in Ageratumf~stigiatum.~ The essential oil of Santolina oblongifolia4 contains the cis-and two trans-isomers of (7).The absolute configuration of the phytoalexin (+)-ipomeamarone (8) has recently been deter-mined.5 This was opposite to the configuration reported The structures of (+)-myomontanone (9) and isomyomontanone (lo) which are furanoid sesquiterpenoids I I from Myoporum montanum have been established from their chemical and spectroscopic data and they were shown to be the aldol condensation products of (+)-myoporone (1I) which is also present in this plant.8 A novel sesquiterpene agelasidine A (12) which has antispasmodic activity has been isolated from a species of the genus Agelas; the sponges were obtained from the sea near Okina~a.~ Continuing with the study of Australian soft corals Bowden et a1.I0have isolated twelve new structurally related furanoid sesquiterpenes [(13)-(24)] from Sinularia capillosa.Compounds (13) (14) and (17) were extremely acid-sensitive and unstable on storage.Carbon-1 3 n.m.r. assignments were reported for all compounds. The product (14) was also isolated from Sinularia firma.1° The dehydrovernopolyanthofuran (25) was obtained from Vernonia polyanthes. 2 Mono-and Bi-cyclofarnesanes Drimane constituents of eight species of porostome nudibranch of the genera Dendrodoris and Doriopsilla have been studied and the new sesquiterpenes olepupuane (26) and the methoxy- NATURAL PRODUCT REPORTS 1985 R R (14) R =Me (15) R =COzMe (18) R =Me (19) R =C02Me (16) R =C02H AcO ROzC \ // (23) R =Me H (21) R =Me (24) R =H (22) R =H AcO PCH0I &rR 0H O ZCHzOH H (29) R =a-OH,P-Me (30) R =ct-Me,P-OH (35) R =CH2OH (33) (36) R =CH.3 P CO,H R P HOO (40) R =CH,OAC OOH \ (44) Rl (41) R =CHO (42) (43) (45) RI acetal (27) have been identified.1-2 The nudibranchs use these sesquiterpenes of the drimane series in chemical defence.Olepupuane (26) was shown to inhibit the feeding of the Pacific damsel fish Dascyllus aruanus. The biologically active sesqui- terpene warburganal and related drimane-type compounds have been characterized in extracts from Polygonum hydro- piper. The structure of mukaadial (28) which is a molluscide from Warburgia stuhlmannii and W. ugandensis has been determined.14 Two new alcohols (29) and (30) in this series were isolated from the culture filtrate of the fungus Aspergillus oryzae. The full paper on the structures of striatene striatol and 0-monocyclonerolidol from the liverwort Ptychanthus striatus has been published.16 The structure of a new abscisic acid metabolite (3 l) which was isolated from cell suspension cultures of Nigeria damascena to which [2-14C]abscisic acid had been fed was determined by spectroscopic methods.The incorporation of a-ionylideneethanol and a-ionylideneacetic acid into abscisic acid by the fungus Cercospora rosicola has been studied. Penlanfuran (32) which is a furanoid sesquiter- penoid with a novel skeleton was isolated from the marine sponge Dysidea fiagilis obtained from Brittany. Specimens of the same species from Hawaii contained different sesquiter- penoids. Penlanfuran (32) has a rare skeleton related to the non-furanoid plant product humbertiol (33).20 It can be derived biogenetically from cyclization of an unknown (6Z)-farnesyl derivative (34).19 Other routes are also possible.Sesquiterpene coumarin ethers have been isolated from Artemisia tripartita,= Achillea ochroleuca,2 vt2 Ferula karata- p CH20H (37) (39) 0 ~op~y =OMe Rz =H (46) R' =C02H R2 =H =H R2 =OAc (47) R' =H R2 =C02H ~ica,~~ The 13C n.m.r. F. lehmannii,24and F. microl~ba.~~~~~ data of this type of compound have been studied.22 3 Bisabolane The curcumene derivatives (35) and (36) have been isolated from Gochnatia pani~ulata.~' The structure of curlone (37) which is a new bisabolane sesquiterpenoid obtained from the rhizomes of Curcuma longa has been determined.28 Helianthol A (a sesquiterpenoid alcohol isolated from Helianthus tubero- SUS~~) has the structure (38).The bisabolane compound (39) has been obtained from Vernonia neo~oryrnbosa.~~ Bohlmann et al. have identified the following bisabolane derivatives :(40) and (41) in Brasilia si~kii,~] (42) and (43) in Schistostephium crataegifolium,2 and (44)and (45) in Coreopsis fasci~ulata.~~ Two juvabione analogues (46) and (47) have been isolated from Abies sachalinen~is.~~ The structure of isose~quicarane~~ has been revised to (48).35 4 Herbertane Laurane and Trichothecane (-)-Herbertenediol (49) and (-)-herbertenolide (50) two new ent-herbertane sesquiterpenes were found in the liverwort Herberta adun~a.~~ Two new laurane sesquiterpenoids isobaz- zanene (51) and isocyclobazzanene (52) have been isolated from the liverworts Bazzania angustifolia and B.fa~riana.~~ The structure and absolute configuration of a sesquiterpene (53) obtained from the alga Luurencia obtusa have been determined by X-ray cry~tallography.~~ NATURAL PRODUCT REPORTS 1985-B. M. FRAGA AcO II (Ang = CCMezCHMe) Hr \ I Two new trichothecene derivatives verrol (54) and 12,13- deoxytrichodermadiene (59 were isolated as minor metabo- lites from a culture of Myrothecium ~errucuriu.~~ Roridin L-2 was obtained from a fermentation of Myrothecium roridum40 and its structure was determined as (56) by chemical and spectroscopic met hods. 5 Chamigrane The alga Laurenciu nipponicu Yamada has continued to be studied by Japanese workers. The structures of two new halogenated chamigrane sesquiterpenes (57) and (58) from this red alga have been determined by X-ray analysis.41 This technique was also used to determine the structures of (-)-obtusane (59),42 laureacetal-D (60),43 laureacetal-E (61),43 and laurencial (62),44 all of which were isolated from L.nipponicu. Laurencial(62) contains an ap-unsaturated aldehyde moiety which may have arisen from the ring-contraction of a chamigrane skeleton.44 Three other chamigrane derivatives have been obtained as minor constituents from Laurenciu nipponicu Yamada.45 The digestive gland of the sea hare Aplysiu ductylomela contains two new isomeric chamigrane sesquiterpenes with the structures (63) and (64).46 (63) R' = Br R2 = H (64) R1 = H R2 = Br R2 I /i H H0,C' H ! A (76) R' = OH R2 = H (74) (75) (77) R' = R2 = H 6 Carotane and Zizaane The new carotane esters lapiferin (65)47 and lapiferinin (66)48 have been isolated from the roots of Ferufa fupidosa.Their structures were assigned by spectroscopic methods. Two new jaeschkeanadiol esters (67) and (68) were isolated from another species of this genus F.ef~eochytris.~~ Another new ester of the carotane series was siol acetate (69) obtained from fruits of Its Sium f~tifofium.~~structure was determined by X-ray analysis. Bohlmann et ~1.~ have isolated a carotanolide from Ageratum fastigiatum. Its structure was identical to that given for hercynolactone (70).51 (see Nut. Prod. Rep. 1984 1 125). The structure of jinkohol I1 (71) which is the first epiprezizaene to be isolated from natural sources has been elucidated.This sesquiterpene was obtained from an agarwood of type B derived from a species of the genus Aquifaria (probably A. mul~ccensis).~~ 2-epi-Zizanone (72) was isolated from Indian vetiver 7 Cadinane Cubebane Oplopanane and Picrotoxane Two new cadinanes isolated from Euputorium ~denophorum,~~ were characterized as (73) and the nor-derivative (74). The structure and absolute configuration of the antibiotic heptelidic acid which is -found in the fungus Gliocladium uirens were determined as (75) by X-ray analysis. Feeding experiments with carbon-1 3-labelled acetate showed that trans,trans-or cispans-farnesyl pyrophosphate is the probable biosynthetic precursor of heptelidic acid.55 The calamenene derivative (76) has been isolated from Osteospermum barberiaes6 and its epimer (78) as a phytoalexin from Tilia x europaea L.57(+)-8-Hydroxycalamenene (77) was obtained from Dysoxylum acutangulum and D.alliace~m.~~ The heartwood of Thespesia populnea (Malvaceae) contains six quinones of the mansone group with a sesquiterpene cadalene skeleton. Four were identified as mansanones C D E and F whilst the other two thespesone (79) and thespone (80) are new natural products.s9 (+)-Cubebol has been found in a Cespitularia species60 and the cubebol derivative (8 1) in Osteospermum auri~ulatum.~~ a-Oplopenone (82) an unusual rearranged cadalenic sesquiter- pene has been isolated from Santolina ~blongifolia.~ The X-ray analysis of picrotoxin (83) has been reported.61 8 Himachalane Longipinane Longibornane and Longifolane 3-Hydroxy-2,10-oxidohimacha1-4-ene(84) has been isolated from Artemisia$lifolia.62Two allohimachalane derivatives (85) and (86) have been obtained from Schistostephium crataegifo- hum.cis-Longipinane-2,7-dione(87) was isolated from the flowers of Tanacetum uu1ga1-e.~~ Its structure was determined by n.m.r. c.d. and X-ray analysis. Artemisia jlifolia62 also contains longipinan-2-one (88) 2P-hydroxylongibornane 2a,4a-endoperoxide (89) 2,4-dioxo-3,4-secolongibornane(90) and 2,3-secolongiborn-3-en-2-a1 (9 1). The structure of alloiso- longifolene has been revised from (92) to (93) on the basis of an X-ray crystallographic study of alloisolongifolol p-nitro- benzoate.64 (86) R = 0 NATURAL PRODUCT REPORTS 1985 9 Caryophyllane and Related Compounds Only caryophyllane and isocomane derivatives have been found in Nature in this group of sesquiterpenes during 1983.The caryophyllane sesquiterpene (94) has been isolated from A Osteospermum scariosum var. scario~um.~~new type of sesquiterpenoid lactone derived from caryophyllene and exemplified by lychnosalicifolide (95) and 2-epi-lychnosalicifo- lide (96) has been obtained from Lychnophora sali~ifolia.~~ Four new isocomene derivatives [(97) (98) (99) and (loo)] have been found in Schistostephium artemisigolium. 10 HumuIa ne BicycIohumuIane Pen ta Ien a ne Marasmane and llludane A new sesquiterpene chatferin (101) has been obtained from the roots of Ferula tschatcalensis.66 A bicyclohumulenedione (102) was isolated from Lippia integrif~lia.~~ The isolation and structural elucidation of pentalenolactone F (103) from Streptomyces UC53 19 has been described.68 Stearylvelutinal (104) and (6-ketosteary1)velutinal (109 which are two com- pounds with the marasmane skeleton have been isolated from the fungi Lactarius vellereus and L.necator. Velutinal esters have been shown to be the only sesquiterpenoids originally present in L. uellereus. They readily undergo solvolysis to afford a number of the fungal sesquiterpenoids with a lactarane or secolactarane skeleton which were described earlier.69 The sesquiterpene furan alcohol (106) has been obtained from L.uellere~s.~~ A norsesquiterpene glucoside ptaquiloside (107) with a novel illudane-type skeleton has been isolated from the bracken fern (Pteridium aquilinum var. lati~sculum).~ *72 11 Germacrane The essential oil of myrrh from Commiphora molmol contains the furanosesquiterpenoids (108)-( 11 l).73 Tanacetols A (1 12) NATURAL PRODUCT REPORTS 1985-B. M. FRAGA H OH OGlc xlp H (109) R = Me (104) R = stearyl (110) R = Ac (105) R = 6-ketostearyl (y&O;ng (y& H2C11'; "R2 OH OH CHO R' (1 16) (1 17) OH (1 14) R' = OH R2 = H (112) R = 0 (115) R' = H R2 = OH RZ (1 13) R =a-OH,P-H 1 HO QH ..OR' HO" 0 0 (125) R' = H R2 = OAc (123) R = OH (126) R' = OAc RZ = OH (119) R' = H R2 = A ng (124) R = H (127) R' = Pr'CO, R2 = OH (120) R' = Ang R2 = H (121) R' = H R2 = Sen (122) R' = Sen R2 = H nk OSen 0 Q ' OH Costunolide derivatives Laurenobiolide Laurenobiolide (128) R' = H R2 = OH Laurenobiolide derivative (1 37) derivative (1 38) (129) R' = OH R2 = H 0 derivatives (130) R' = OAc R2 = H (134) R = Pr'CO R' (131) R' = OMebu R2 = H Costunolide (135) R = Mebu (132) R' = Oval' R2 = H derivative (I 33) (136) R = Val' OAc Chrysanolide derivatives (143) RI = a-OOH,P-H; R2 = Meacr p-& 0 wowo (144) R' = z-H,P-OOH; RZ = Meacr OH (145) R1 = a-OOH,P-H; R2 = H (146) R' = a-H,P-OOH; R2 = H Laurenobiolide derivatives Laurenobiolide Laurenobiolide (147) R' = a-OH$-H; RZ = H (139) R = Sen derivative (141) derivative (142) (148) R' = a-H,P-OH; R2 = H (140) R = Ang (149) R' = a-OH,P-H; R2 = Ac 0 F) " z II II II (Ang = -CCMe=CHMe Sen = -&H=CMe, Mebu = -CCHMeEt Tig = -CCMe&HMe Val' = -CCHZCHMe, 0 II Meacr = -CCMe=CH,) and B (1 13) have been isolated from Tanacetum vulgare and Many new germacrane lactones have been isolated from their structures elucidated by X-ray analysi~.~~,~~ The structure natural sources during the year.The structures (1 19)-( 154) and chemistry of hallerin which is a mixture of anomeric and (1 58)-( 173) represent the new germacranolides and sesquiterpenoids (1 14) and (1 15) from Lmerpitium halleri have (185)-( 193) and (200)-(205) the heliangolides. Table 1 shows been described.76 Hydrolysis of hallerin afforded hallerol(l16) the species from which these lactones were obtained.Several the stereostructure of which was determined by X-ray-points should be noted in relation to these sesquiterpene crystallographic analysis.77 A germacrane aldehyde (1 17) has lactones. The structure of inuolide previously isolated from been obtained from Vernonia glabra var. glabra.30 The two Inula indica has been determined by X-ray analysis.80 The monoacetates of the bicyclogermacrane (1 18) have been epoxyangelate (1 23) and its 7-dehydroxy-derivative (124) are isolated from cultured cells of the liverwort Calypogeia the new structures that have been assigned to two lactonic gran~lata.~~ The three germacrane derivatives (1 55)-( 157) compounds that were obtained from Montanoa pterop~da.~~,~ have been obtained from Pegolettia senegalensis.* * The structure (1 58) represents a new skeleton.82 The structure 152 NATURAL PRODUCT REPORTS 1985 WC02H 0 '0 0 Laurenobiolide (155) R = Tig (150) R = CH (152) R various (153) derivative (1 54) (156) R = Mebu (151) R = a-MeJ-H (157) R = Val' R*' Pertic acid derivatives 8-Hydroxy-0 I OR R' = n W pegolettiolide (158) (159) R = H (163) R2 = (1 60) R = 1-@p-D-glUCOSyl Herbolide D (162) (164) R2 = 0 '? OH qig Rig @$ 0' 0 0 Grazielic acid Grazielolide derivative (165) R = CO,H derivative (166) '0 Hirsutinolide derivatives Neoliacine (1 72) (173) R' R2 various Table 1 Sources of germacrane lactones (A) Germacranolides Artemisia herba-albaB6 Campovassouria bupleurifolias8 Carpesium abrotanoidess5 Chrysanthemum cinerariaefoliuma" Grazielia serratag9 Liatris asperago Liriodendron tulipiferas Montanoa atriplicijolia7' Neolitsea aciculatag' Pegolettia senegalensis8 Pertya glabrescenss7 Piptocarpha opaca9 Schistostephium crataegifolium? Schistostephium heptalobum? Vernonia polyanthes' I Vernonia poskeana30 (B) Heliangolides Brasilia sickii3 I Centratherum punctatum' O2 Leucanthemopsis pulverulenta9a Liatris acidotagO Liatris mucronatagO Stecia m~nardaejolia~~ Syncretocarpus sericeusl O7 Vernonia poskeana30 (C) Melampolides Magnolia x souIangianalo8 (D) cis,cis-Germacranolides Melampodium rosei' O -R (174) R (175) R (1 62) (165) (161) (1591 (160) ( 166) (1 67) (1 49) (119)-(122) (172) ( 150)-( 154) (1631 (164) (170) (171) (1 34)-( 148) (1 25)-( 133) (168) (169) (1 73) (200)-(203) ( 194) (1 85)-( 188) (1 91)-( 193) ( 190) (189) (205) (204) (206) (207) (209)-( 211) 0 OAc OR 0 0 0 Hirsutinolide derivatives Hirsutinolide derivatives HO (168) R = a-OMe (170) R = Tig (167) (169) R = (3-OMe (171) R = Meacr mo(xpo .'O I R = OH (176) R = OH = H (177) R = H *o p+ 0 OH (179) R = Sen (181) R = OH (180) R = Ac (182) R = H (1 83) of eriolin has been confirmed as (161).85 The configuration of simsiolide (176)93 has been revised to (174)* and the stereo- structure of the senecionate (178) from Vernonia nud~J7m-a~~ has had to be amended to (1 79) because its spectral data were close to those of (I 80).* The 6-desoxy-lactone (1 77) was isolated from Inula heleni~m,~~ and Telekia spe~iosa~~ I.royle~na,~~ and its structure was also revised to (175).* The structure of compound (181) from Mikania goyazensz~,~~ [see Nat. Prod. Rep. 1984 1 145 structure (504)] has also been changed to (183).* The structure(I 82)that has been given to a lactone that was isolated from a species of the genus In~la~~ will probably have to be modified to (184).2 Isocentratherin (199 which is a sesquiter- pene lactone that has been isolated from Centratherum punctaturn,lOO~lO1 has been assigned the new structure (194) on the basis of an X-ray analysis,lO* confirming a previous suggestion of Herz.Io3 The structure of centratherinlo4 should be revised from (196) to (197) the latter being identical with that of lychnophorolide A whose structure has been deter- mined by X-ray crystallography. O5 The absolute stereoche- mistry of tagitinin F (198) was established by its synthesis from tagitinin C (199).lo6 Two novel melampolides (206) and (207) have been isolated from Magnolia x soulangiana. O8 The crystal structure of NATURAL PRODUCT REPORTS 1985-B. M. FRAGA (184) (185) R = 0 6 (187) R = Ac (186)R = CX-H,P-OAC (188)R = H 1 1,13-Dihydroeucannabinolide(1 89) Q". 0 R (190)R' = OH,R2 => ,R3 = CH2 (192)R = CH2 (193)R = a-Me,B-H OH \OH (191)R1 = R2 = H R3 = a-MeJ3-H 0 0 1 HO Ang 0 @ OAc OMebu (201)R1 = H R2 = Mebu (202)R1 = Ac R2 = Mebu (203)R1 = Ac R2 = Pr'CO f"" Q 0 melampodin A (208) has been pub1i~hed.l~~ The cis,cis-germacranolides melrosin A (209) melrosin B (210) and melrosin C (21 1) were found in Melampodium rosei' lo and longicornins A B C and D in M.longicorne.' The structures of the melrosins indicate that the published structures of melcanthins A-C1 should be altered. (See also Nut. Prod. Rep. 1984 1 148.) 12 Elemane Bohlmann et a1.82 have isolated two new elemanolide esters (2 12) and (2 13) from Pegolettia senegalensis. A new sesquiter- pene lactone 11,13-dihydrovernodalin (214) which was ob-tained from Vernonia amygdalina,' showed antifeedant activity against the African armyworm (Spodoptera exempta).The new elemanolide verafinin B (215) was isolated from 0 (199) 9 0 (205) (204) 0 HO 0 (209)R' = OH R2 = COzMe (211)R1 = H R2 = C02Me Verbesina afl. coahuilensis. l4 The new lactone zinaflorin IV (216) was found in Zinnia peruviana and its structure deter- mined by X-ray crystallographic analysis. ''s Consequently the structures of two closely related lactones that had been isolated from the same species and formulated' l6 as (219) and (220) should be revised to (217) and (218) respectively. These compounds belong to the unusual H-33 C-14cr series named zinnolides. Another new lactone zinaflorin V (221) was isolated from Z. peruviana. The known elemanolides zinaflorin I,' zinaflorin 11,' l7 and epoxyzinamultifloride' l8 were also obtained from this species and their structures revised to (222) (223) and (224) respectively.These authors have also postulated the necessity of a structural revision of all of the elemanolides with a y-lactone function that have been isolated from the genus Zinnia. The sesquiterpene lactones (225) (226) and (227) have been obtained from Montanoa atriplicifolia.79 NATURAL PRODUCT REPORTS 1985 HO 03 (212) R =,/* 0 0 (210) R = C02Me (213) R =/+ OH 0 OH OR2 OR ,I ?H OH Ro *o OR1 (216) R = Ang OHC bTig (222) R1 = R2 = Ang (217) R = Tig (219) R = Tig (223) R' = Ang R2 = H (225) R = Ang (218) R = Meacr (220) R = Meacr (224) R' = Meacr R2 = H (226) R = Sen ..OAng R'f& I aH (y+ pq R2'.H 0 CinO ; 0 H AH (231) (232) (228) R1 = OH R2 = H (227) (229) R' = H R2 = OH (234) R' R2 various 13 Eudesmane The structures of two eudesmane alcohols isolated from verbesina virgata were established as (228) and (229).119 The new eudesmane sesquiterpenoid (230) was isolated from senecio micro~~ossus. 120 The essential oil of myrrh from Commiphora molmol contains two furanoeudesmanes with the structures (231) and (232). The structure of a cuauhtemone ester (233) from Pluchea indica has been determined.122 Four novel eudesmane derivatives of (234) have been isolated from another species of this genus Pluchea odorata.' 23 The structure and absolute configuration of a new volatile sesquiterpene from Lycium chinense were defined as (235).124 A eudesmane aldehyde (236) has been found in Vernonia glabra var.glabra.30 A new class of phytoalexin represented by (237) and (238) has been isolated from Ipomoea batatas that was infected by Ceratocystis jimbriata. 25 The three sesquiterpene alkaloids alatusamine (239) neoalatamine (240) and alatusine (241) were obtained from Euonymus alatus var. striatus. 26 The fruits of Torilis japonica contain a eudesmane sesquiter- pene (242) a cycloeudesmane derivative (243) and the oppositanes (244)-(247). A possible precursor of these last compounds could be epoxygermacrane D (248).l27 This is the first example of the isolation of oppositanes from a higher plant. Previously these have been found in marine algae. Two sesquiterpene acids (249) and (250) were obtained from Schistostephium rotundfolium.New eudesmanolides have been isolated from different plants (see Table 2) and their structures shown to be (251)-(278). Steiractinolides (252) are a new group of sesquiterpene (230) (238) R = CHO lactones obtained from species of the genera Steiractinia and Aspilia.' 29 Their structures have been determined by X-ray analysis of a tetrahydro-derivative of one of these lactones. The steiractinolide structure was also assigned to lactones that had previously been isolated from Wedelia hookeriana. 30 A novel Table 2 Sources of eudesmanolides Aspilia pluriseta' 29 Artemisia barrelieri' 36 Artemisia canariensis' 37 Artemisia cretacea' 38 Artemisia fragrans' 39 Artemisia paucgora' 40 Artemisia umbellijormis' 31.'42 Chiloscyphus polyanthus' 44 Frullania brotheri' 33 hula racemosa ' hserpitium siler' Liatris laevigata' 35 Pegolettia senegalensisa Pluchea dioscoridis' 43 Schistostephium crataegifolium2 Schistostephium heptalobum2 Schistostephium rotundijolium2 Sonchus macrocarpus' 41 Steiractinia mollis' 29 Tanacetum vulgare' 34 NATURAL PRODUCT REPORTS 1985-B.M. FRAGA OAc sesquiterpene lactone isosilerolide (263) with a transjunction at AcO (?Ac C(5)-C(l0) and a cis at C(6)-C(7) constitutes a new group of eudesmanolides found in Laserpitium siler. 32 A 4,5-secoeudes-mane derivative (277) has been isolated from Artemisiu The umbelliformi~.~~~ structure that had been given to a compound that was previously isolated from Chiloscyphus I.polyanthes' 44 has been revised from ent-5a-hydroxydiplophyl-R4 '1 lolide to ent-7a-hydroxydiplophyllolide(279) by spectroscopic methods. 45 R2wo :O Desacylchrysanin Desac yltanapsin HO derivatives derivatives (258) R = Sen or Meacr (259) R = Ang Sen or Meacr H? HO 6Me q 0 0 1-epi-Reynosin (260) 1a,3a-Di hydroxyarbusculin (26 1) Me0 AcO AcO (245) 0 \ '%CO2H 0 QO 0 Ang Douglanin acetate (262) Isosilerolide (263) I (249) R = a-OHJ3-H (250) R = 0 (248) OR? 0 R30 OR' m0 (+)-Frullanolide (264) (+)-Brothenolide (265) (251) Alloalantone Steiractinolides (252) R' R? R3 various 0@ (Q 0 HO' 0 H I -epi-Ludovicin (266) (267) (253) a-OOH and 0-OOH 0 0 (254) HO 0 3$5ig (Q -1 1 0 Hd 0 (268) A3(4) 0 (269) A4(5) Barrelin (271) R = H (257) Dentatin acetate (270) A4(I5) Acetyltabarin (272) R = OAc NATURAL PRODUCT REPORTS 1985 0 HO HO 1 Q-oq..QH b OHC 0 0 0 0 Umbellifolide (277) Taurin (273) Artapshin (274) Artepaulin (275) Sonchucarpolide (276) AngO ?H Q p:Fo(& H OH 0 (279) A-OH Cyclocostunolide derivative (278) I (280) R = CHO OH H (281) R = COzH (283) OH HoH2co Ho OGlC OH HO )-CO H (298) R' = H R2 = OAc Me% o/ (295) (297) (299) R' = OH R2 = H (300) R = CHIOAC (301) 14 Vetispirane and Related Compounds Two new sesquiterpenes baimuxinal (280) and baimuxinic acid (28 l) have been isolated from Aquilaria sinensis.146 Flue-cured tobacco contains the new sesquiterpene 2,3-didehydro- solanascone (282)' 47 and the new sesquiterpene glycosides 3-hydroxysolavetivone P-glucoside (283) 3-hydroxysolanascone P-sophoroside (284) and rishitin P-sophoroside.14* 15 Eremophilane and Aristolane Jinkoheremol (285) was isolated from a species of the genus Aquil~ria.~* The structure of 13-deoxyphomenone (286) which is a fungitoxic sesquiterpene from Hansfordia pulvinata has been e1~cidated.l~~ Petasol (287) has been obtained from Petasites fragrans. ISo Senecio ochoanus contains the eremophi- lane (288),l *O S.$laginoides the furanoeremophilane ester (289) and S.pinnatus the angelate (290).l 51 The eremophilane lactone (291) has been isolated from Senecio aureus.' 52 The sesquiter- pene aldehyde (292) has been found in Vitex negundo.lS3 The most likely stereostructure for cacalone acetate has been shown to be (293) by using computer simulation of a shift-reagent experiment.54 An aristolane sesquiterpenoid (294) has been isolated from the sea pen Scytalium splendens. 55 The aristolane compounds from marine sources are enantiomeric to those that have been found in terrestrial sources. 16 Guaiane and Pseudoguaiane Two new guaiane sesquiterpenes alismol(295) and alismoxide (296) have been isolated from the rhizomes of Alismaplantago-aquatica var. orientale.Is6 Lindera glauca contains a new sesquiterpenoid acid glaucic acid (297) 57 and Jungia stuebelii two novel ketones (298) and (299).Is8 A compound [12- acetoxyjungistueb-4-en-3-one (300)] with a new skeleton (jun- gistuebane derived from guaiane) has also been obtained from this plant.A new furanoguaiane (301) has been found in the essential oil of myrrh from Comrniphora m~lrnol.'~ A fairly unstable trinorguaiane sesquiterpene clavukerin A (302) has been obtained from the Okinawan soft coral Clavularia koellikeri. s9 Its absolute stereochemistry was determined by spectral methods and by X-ray analysis of its diepoxide. A trinorsesquiterpene analogue (303) which was assigned a different configuration at one centre was isolated NATURAL PRODUCT REPORTS 1985-B. M. FRAGA from another soft coral a Cespitularia species.60 The optical rotations of the two products are very similar and it is probable that the two compounds have the identical structure (302).The configuration that is given by the Australian authors for (303) is not based on experimental data. The cultured cells of the liverwort Calypogeia granulata produce another two norsesqui- terpenes (304)' 6o and (305);78 the latter was named trinoranas- traptene. Biosynthetic studies employing 3C-labelled acetate showed the terpenoid origin of these substances. Guaiazulene was obtained from a blue coral a new species of the genus Alcyoniurn.60This compound was previously isolated from the gorgonian Euplexaura erecta. Several new guaianolides have been obtained from plant sources as shown in Table 3. Table 4 shows the novel guaian- 6a,l2-olides which have been isolated and other lactones are depicted by structures (322)-(328).loylshairidin (322)17* and guillonein (323),173 both obtained from Guillonea scabra have been Table 3 Sources of guaianolides Ajania fastigiata' 69*1lo Arctotis grandis' 65 Bahia oppositifolia' Campovassouria bupleurifolias8 Centaurea clementei' l6 Centaurea kotschyi'62 Crepis capillaris' 6' Decachaeta thieleana' 77 Ferula penninervis' 68 Gochnatia paniculata27 Guillonea scabra'72* '13 Helenium puberulum ' Liriodendron t~lipifera~~ Otanthus maritimus' l1 Pyrethrum parthenifolium' 66 Saussurea afinis' 64 Saussurea lappa' 63 Stevia achalensis' Table 4 Novel guaian-6a 12-olides Name Structure 8-epi-Desacylc ynaropicrin Linichlorin B (derivative) Isozaluzanin C Isodehydrocostus lactone Saussureolide Zaluzanin C (derivative) Zaluzanin C (derivative) Pyrethrin Bahia-111 Des-sarracinyl bahia-I I I 1,l O-Hydrobahia-111 Ferolide Ajafin Ajafinin Artecanin derivatives (3-Cyclolipi ferolide crystallographic analysis.This same technique has been used in the structural elucidation of achalensolide (326) from Stevia achalensis. 74 The isolation and structure elucidation of clementein (328) which is the first oxetane-containing sesqui- terpene lactone to be reported has been published. Clemen- tein was found in Centaurea clementei. 76 Bohlmann et al. have found the dimeric sesquiterpene lactones (329) and (330) in Gochnatia pani~ulata~~ and (331) in Decachaeta thie1eana.l" Two pseudoguaiane derivatives (332) and (333) have been isolated from Brasilia sickii3 and another (334) from Jungia stuebelii.s8 The new pseudoguaianolides which have been isolated from a variety of sources (see Table 5) are represented The structures of desange- determined by X-ray- 14 by structures (335)-(342). QH 0 0 Shairidin derivative (322) 0 Guaiagrazielolide derivative (324) Position of double bond(s) 4-15 10-14 11-13 4-15 10-14 11-13 4-15 10-14 11-13 3-4 10-14 11-13 10-14 4-15 10-14 10-14 10-14 3-4 10-1 11-13 3-4 10-1 11-13 3-4 11-13 3-4 10-1 10-1 11-13 11-13 -10-14 11-13 Substituents and configurations 3P-OH; 8P-OH 3P-OH ; 8a-OR' 3a-OH -QH 0 Guillonein (323) Arctolide derivative (325) References 161 162 163 163 3P-OH ; 4a-OH; 8a-OH ; 15-OH ; 1la 164 3P-OH ; 8a-OGlc; 1la 165 3P-OH ; 9P-OH; 4~; 11 165 3,4-epoxy; 8a-OPr 166 8P-R2 167 @-OH 167 8P-R2; 1Oa-OH 167 2-0x0 8a-OSen ; 11-0Ac 168 2P-OH; 3-0x0; 4-OMe; 8a-OH 169 1.2-epoxy; 3-OH ; 4-OH; 1O-OH 170 lp,2P-epoxy; 3P,4P-epoxy; 8P-OR3 ; 10a-OH 171 4a-OH ;8a-OAc 83 Rl = R2 = {\o / ; R3 = various v 0 HOI NATURAL PRODUCT REPORTS.1985 0 HO" 0 Aco& 0$+ Helenium lactone Achalensolide (326) derivative (327) (328) Clementein I HI 0 ,-H 0 0 0 (331) (332) R = H (333) R = Me ' 'OH (334) (330) H HIQoRO Acd Chamissonolide 0 O< Et Helenalin derivatives (335) R various derivative (336) Arnicolide G (337) 6-epi-Picrohelenin derivative (338) 6-epi- Autumnolide derivative (339) 0 Spathulin 0 Pulchelloid C (340) derivative (34 1) Psilostachynolide derivative (342) dR2 \ Q...cq/ R' R2 A (351) R' = COZH R2 = H (354) (348) R' = 0;R2 = H2 (350) (352) R1= Me R2 = H (349) R1= OH,H; R2 = H2 (353) R1 = Me R2 = OAc OH 18 Miscellaneous Sesquiterpenoids Table 5 Sources of pseudoguaianolides The stereostructure of ptychanolide (343 which is a pingui- Ambrosia cumanensis' (342) (3361 (337) sane sesquiterpene that had previously been isolated from Arnica chamissonis' 79 (335) Ptychanthus striatus has been determined by X-ray analysis.Arnica montana' 78 Gaillardia aristatnI8' (341) Eight new 'isocedrane' sesquiterpenoids [(346)-(353)] have Gaillardia pulchella'80 (340) been isolated from Jungia stuebefii.58 These compounds are Helenium puberulum' ' (3381 (339) characteristic of the subtribe Nassauviinae (Compositae). Roberts (see 'Terpenoids and Steroids' Vol. 10 p. 99) has suggested that the name of this skeleton must be changed. 17 Aromadendrane The structure of faurinone (354) which is a sesquiterpene The aromadendrane derivatives (343) and (344) have been ketone that has been isolated from Vaferiana oficinafis has isolated from Brasilia sickii3' and a variety of Humufus been determined.184 Therefore the structure (355) that was lupulus respectively. given by Hikino et to a compound with spectroscopic NATURAL PRODUCT REPORTS 1985-B.M. FRAGA (359) properties that are identical with those of faurinone must be amended to (354). The structure of manicol (356) [a sesquiter- pene that had previously been isolated from Dulacia guainen- has been revised to (357) by X-ray analysis.ls7 Three sesquiterpenoid stress compounds [(358) (359) and (360)]have been isolated from Nicotiana rustica that had been inoculated with tobacco mosaic virus. 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Kato Tennen Yuki Kugobutsu Toronkai Koen Yoshishu 26th 1983 I (Chem.Abstr. 1984 100 82 976). 149 Y. Tirilly J. Kloosterman G. Sipma and J. J. Kettenes-van den Bosch Phytochemistry 1983 22 2082. 150 K. Sugama K. Hayashi T. Nakagawa H. Mitsuhashi and N. Yoshida Phytochemistry 1983 22 1619. 151 M. S. A. De Salmeron J. Kavka and 0. S. Giordano Planta Med. 1983 47 221. 152 R. J. Nachman Phytochernistry 1983 22 780. 153 S. P. Vishnoi A. Shoeb R. S. Kapil and S. P. Popli Phytochemistry 1983 22 597. 154 J. B. Chaisson E. Diaz and K. Jankowski Proc. Indian Natl. Sci. Acad. Part A 1983 49 193. 155 M. N. Do and K. L. Erickson J. Org. Chem. 1983 48 4410. 156 Y. Oshima T. Iwakawa and H. Hikino Phytochemistry 1983,22 183. 157 H. Nii K. Furukawa M. Iwakiri and T.Kubota Nippon Nogei Kagaku Kaishi 1983 57 725 (Chem. Abstr. 1984 100 99 863). 158 F. Bohlmann C. Zdero R. M. King and H. Robinson Phytochemistry 1983 22 1201. 159 M. Kobayashi B. W. Son M. Kido Y. Kyogoku and I. Kitagawa Chem. Pharm. Bull. 1983 31 2160. 160 R. Takeda and K. Katoh J. Am. Chem. Soc. 1983 105 4056. 161 W. Kisiel Planta Med. 1983 49 246. 162 S. Oksuz and E. Putun Phytochemistry 1983 22 2615. 163 P. S. Kalsi S. Sharma and G. Kaur Phytochemistry 1983 22 1993. NATURAL PRODUCT REPORTS 1985-B. M. FRAGA 164 S. Das R. N. Baruah R. P. Sharma J. N. Baruah P. Kulanthaivel and W. Herz Phytochemistry 1983 22 1989. 165 A. F. Halim A. M. Zaghloul C. Zdero and F. Bohlmann Phytochemistry 1983 22 15 10. 166 A. I. Yunusov and G.P. Sidyakin Khim. Prir. Soedin. 1983 532. 167 P. Nelson and R. 0. Asplund Phytochemistry 1983 22 2755. 168 M. R. Nurmukhamedova Sh. Z. Kasymov and G. P. Sidyakin Khim. Prir. Soedin. 1983 533. 169 M. I. Yusupov Sh. Z. Kasymov G. P. Sidyakin and N. D. Abdullaev Khim. Prir. Soedin. 1983 390. 170 M. I. Yusupov Sh. Z. Kasymov N. D. Abdullaev and G. P. Sidyakin Khim. Prir. Soedin. 1983 650. 171 N. N. Sabri N. A. Abd El-Salam A. A. Seif El-Din and S. M. Khafagy Phytochemistry 1983 22 201. 172 J. Fayos A. Perales M. Pinar M. Rico and B. Rodriguez Phytochemistry 1983 22 1983. 173 M. Pinar B. Rodriguez M. Rico A. Perales and J. Fayos Phytochemistry 1983 22 987. 174 J. Oberti V. E. Sosa W. Herz P. J. Siva and U. L. Goedken J. Org.Chem. 1983 48 4038. 175 F. Bohlmann E. Tsankova and J. Jakupovic Phytochemistry 1983 22 1822. 176 G. M. Massane I. G. Collado F. A. Macias F. Bohlmann and J. Jakupovic Tetrahedron Lert. 1983 24 1641. 177 V. Castro F. Ciccio S. Alvarado F. Bohlmann G. Schmeda- Hirschmann and J. Jakupovic Liebigs Ann. Chem. 1983 974. 178 G. Willuhn P. M. Roettger and U. Matthiesen Planta Med. 1983 49 226. 179 G. Willuhn J. Kresken and D. Wendisch Planta Med. 1983,47 157. 180 S. Inayama K. Harimaya H. Hori T. Kawamata T. Ohkura 1. Miura and Y. Iitaka Heterocycles 1983 20 1501. 18 1 S. Gill W. Dembinska-Migas M. Sielinsak-Stasiek W. M. Daniewski and A. Wawraun Phytochemistry 1983 22 599. 182 J. Borges A. Bradley M. T. Manresa P. Vazquez and F. Rodriguez-Luis Phytochemistry 1983 22 782.183 R. Tressel K. H. Engel M. Kossa and H. Koeppler J. Agric. Food Chem. 1983 31 892. 184 R. Bos H. Hendriks J. Kloosterman and G. Sipma Phyto-chemistry 1983 22 1505. 185 H. Hikino Y. Hikino K. Agatsuma and T. Takemoto Chem. Pharm. Bull. 1968 16 1779. 186 J. Polonsky 2. Varon H. Jacquemin D. M. X. Donnelly and M. J. Meegan J. Chem. Soc. Perkin Trans. I 1980 2065. 187 J. Polonsky J. C. Beloeil T. Prange C. Pascard H. Jacquemin D. M. X.Donnelly and P. T. M. Kenny Tetrahedron 1983 39 2647. 188 R. Uegaki T. Fujimori S. Kubo and K. Kato Phytochemistry 1983 22 1193.

ISSN:0265-0568    

DOI:10.1039/NP9850200147

出版商:RSC    

年代:1985

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 1983 and June 1984 (Continuing the coverage of the literature in Natural Product Reports 1984 Vol. 1 p. 181) 1 1.1 1.2 1.3 1.4 2 2.1 2.2 2.3 3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 4 4.1 4.2 4.3 4.4 5 5.1 5.2 5.3 6 6.1 6.2 7 7.1 7.2 7.3 7.4 8 Pyrrolidine and Piperidine Alkaloids Cocaine Phenanthroindolizidine Alkaloids Pyrrolizidine Alkaloids Quinolizidine Alkaloids Isoquinoline Alkaloids Benzylisoquinoline Alkaloids Colc hicine Tubulosine Metabolites Derived from Tryptophan Terpenoid Indole Alkaloids Triostin A and Echinomycin Penitrem A Roquefortine Oxaline and Echinulin Pyrrolnitrin Streptonigrin Ergot Alkaloids Metabolites Derived from Phenylalanine and Tyrosine Gliotoxin and Aranotins Tuberin Ilicicolin H Arphamenines Other Metabolites Derived from the Shikimate Pathway Ansamycins Phenazines Acridone Alkaloids P-Lactams General Penicillins and Cephalosporins Miscellaneous Metabolites Streptothricin F N eom yc ins Virginiamycin M Myxopyronin A References General reviews of earlier work that provide useful background material which is relevant to the present discussion appear in the Specialist Periodical Reports on ‘The Alkaloids” and on ‘Biosynthesis’,2 in Natural Product report^,^ and in two other v~lurnes.~~~ Appropriate reference is made to these reviews in the text.1 Pyrrolidine and Piperidine Alkaloids Full details of a study6 on the stereochemistry of oxidation of cadaverine to A’-piperideine by hog kidney diamine oxidase have been published,’ with the inclusion of results on the related diamines putrescine and agmatine. In each case it is the 1-pro+ proton which is removed in the enzyme-catalysed oxidation. These results which are in agreement with others,* are of relevance to the biosynthesis of piperidine and pyrrolidine alkaloids (cJref. 1 Vol. 13,pp. 1 and 5). Chirally deuteriated samples of the amines were used in this study and it is interesting to note that whilst cadaverine underwent oxidation without detectable isotope effect an intramolecular primary isotope effect (K,/KD = 4) was observed in the enzyme-catalysed oxidation of putrescine.’ The effect of varying the supplementation with auxins and with biosynthetic precursors on the production of nicotine anabasine and related alkaloids in cell cultures of Nicotiana tabacum has been noted.9 1.1 Cocaine Long-sought information on the biosynthesis of cocaine (2) (cf ref.3 p. 181)has been followed uplo by results which show that the tropinone (1) is an intact precursor for cocaine (2). Thus [9-3C,14C, 0-methyl-3H]-2-carbomethoxy-3-tropinone[as (l)] afforded cocaine without change in isotopic ratio and all of the tritium was still in the 0-methyl group.(Insufficient enrich- ment was obtained for 13C assay). 1.2 Phenanthroindolizidine Alkaloids Full details have been published’ on the biosynthesis of these alkaloids e.g. tylophorine (4) in Tylophora asthmatica via 2-phenacylpyrrolidines [as (3)](cf. ref. 1 Vol. 8 p. 6); (3)is the alkaloid nor-ruspolinone which has been isolated from another plant (Ruspolia hypercraterformis). * 1.3 Pyrrolizidine Alkaloids The base portion [as (7)] of pyrrolizidine alkaloids e.g. retrorsine (8) has been shown to derive from L-ornithine via 9 L-Ornithine I putrescine (5) and homospermidine (6) (cf. ref. 3 p. 182). Further confirmation of the role of putrescine as an intact source for the retronecine moiety (7) in (8) has been obtained in an experiment with [1,2-l 3C2]putrescine [as (5)I.I The 3C n.m.r.spectrum of the derived retronecine showed doublets (due to the expected 13C-13C coupling) for each of the carbon atoms and these doublets were of similar intensity. The way in which putrescine (5) is used to elaborate pyrrolizidine alkaloids has been probed by use of 2H-labelled precursors. Thus [1,4-' 4C2 2,3-2H4]putrescine (9) gave retror- sine (8)14 with specific incorporations of 3-5% of 14C.Analysis of the alkaloid by 2H n.m.r. spectroscopy showed it to be labelled as shown in (10); the extents of enrichment for each labelled site were similar. The results are consistent with the pattern of biosynthesis of pyrrolizidine alkaloids that has so far been established and show further that C-7 of (7) (which bears a hydroxy-group) does not become a keto-group when the oxygen atom is introduced or subsequently.[1,4-2H4]Putrescine (1 1) gave a sample of retrorsine that was labelled predominantly as shown in (14);14 labelling in the C-5a and C-8 positions was also observed as expected but this was five times less than for the other positions. A reasonable explanation is that mainly the homospermidine (12) is formed in the plant from deuteriated and unlabelled putrescine and that subsequent oxidation to give (13) which involves one of the two primary amino-groups occurs preferentially (because of a primary deuterium isotope effect) at the centre which does not contain deuterium. This then affords retronecine that is preferentially labelled as shown in (14).(For a similar observation see below). The labelled retrorsine (14) is of (S) configuration at C-9 which shows that this carbon is at some stage an aldehyde group (like C-8) and that it then undergoes stereospecific reduction the outcome being the expected stereochemistry for a normal coupled dehydrogenase enzyme system. (8) Putrescine (15) 'H -NATURAL PRODUCT REPORTS 1985 Two groups have reported similar interesting results for the incorporation of (1S)-[l-2H,]-and (1R)-[l-2H,]-putrescine into the retronecine fragment of pyrrolizidine alkaloids. The latter precursor was incorporated without loss of deuterium (as measured against 4C-labelled material that was fed alongside).Thus none of the transformations which convert putrescine into retronecine (17) involves loss of the 1-re proton in the diamine; labelling by deuterium was equally at positions 3-r~ 5-re 8 and 9-si. 5,1 (lS)-[1-*H,]Putrescine gave retronecine (1 7)that was labelled only at positions 3-si and 5-si. These sites were equally labelled,15.*6 but for each position at a value of 69% of that found for 14C (50% was expected).l6 This was attributed' tentatively to a primary deuterium isotope effect in the oxidation of putrescine which favours reaction at the unlabelled 1-si position and then an enhancement of deuterium label at the carbon that still bears the primary amino-group [ = C-3/C-5 of (17) which are equivalent via (16)l. (For a similar result again attributed to a primary deuterium isotope effect see above; see also ref.7). Scheme 1 shows the stereochemical conclusions to be drawn from the results. Results of a study of the biosynthesis of the necic acid components of trichodesmine (18) and of the closely related grantaline indicate that in common with several other neck a~ids,~,~ branched-chain amino acids are involved. This is illustrated in Scheme 2 for trichodesmic acid (19); the two halves of the molecule derive predominantly from different pairs of a-amino acids. ' 1.4 Quinolizidine Alkaloids Long-standing evidence4y5 arising from 4C-labelling studies indicates that quinolizidine alkaloids [exemplified by lupinine (22) and sparteine (26)] arise from lysine (20) by way of cadaverine (21).This has been nicely confirmed for lupinine using 3C-labelled lysine.l* DL-[4,5-' 3C2 6-14C]Lysine (20) (the I3C labels were in the same molecule) gave lupinine (22) that was labelled as shown; the labelling pattern was discernible (at low specific incorporation) from the doublets which flanked the natural-abundance singlets in the I3C n.m.r. spectrum (cf ref. 1 Vol. 13 p. 4and ref. 3 p. 182 for earlier applications of this approach in the study of the biosynthesis of plant alkaloids). The results provide clear confirmation of the earlier ones on the incorporation of lysine and the labelling pattern clearly shows that a symmetrical intermediate [cadaverine (21)] is involved in the biosynthesis of lupinine. [from si-face] H [from re-face] [attack from rP-farP1 ( J (17) Scheme 1 NATURAL PRODUCT REPORTS.1985-R. B. HERBERT MeAO,H MeA02H ke OH \ &/ Threonine Me NH (19) \ Me -0,H M e G 'COzH Leucine Me Isoleucine Scheme 2 qH2OH m 11 \ (24) The way in which cadaverine is used in the elaboration of lupinine (24) and sparteine (26) has been probed in experiments with [1-13C,l-arnino-1SN]cadaverine19-21 (the labels were in the same molecule) and with (1R)- and (1 S)-(l-'H,)cadaver-[ 1-l 3C l-amino-' SN]Cadaverine (23) when fed together with [1 ,5-14C,]cadaverine to Lupinus lureus plants gave a sample of lupinine (24)20,21 for which the I3Cn.m.r. spectrum showed equally enriched signals for C-4 C-6 C-10 and C-1 1 ; the level of enrichment that was obtained from the 3C data for each of the two separate C units [divided by a dotted line in structure (24)] corresponded to the 14C value.Crucially the presence of l3C-l5N coupling between C-6 and N-5 but its absence between C-4 and N-5 excludes an intermediate of C2" symmetry e.g. (25) such as is found in the biosynthesis of pyrrolizidine alkaloids (see Section 1.3). In further support of this hypothesis radioactive (25) was found to be an insignifi- cant precursor for lupinine and it could not be identified as being present in L. luteus by a trapping experiment in which L-[U-4C]lysine was used as a precursor. Examination19.20of [I-' 3C,l-arnino-1 SN]cadaverine (23) as a precursor for sparteine (26) in Lupinus luteus plants gave results which were similar and complementary to those that were obtained for lupinine (24).For sparteine (26) three separate molecules of cadaverine are used and intact incorpor- ation of 13C-15N was observed for C-2-N-1 and C-15-N-16 and for these only [see (26)]. Carbon atoms 6 10 11 and 17 appeared as enriched singlets in the 13C n.m.r. spectrum and similar levels of enrichment for each of these atoms and for C-2 and C-15 were observed. Again the 13C enrichment agreed with the 14C value. The results that are described here for lupinine (24) and sparteine (26) agree very well with the scheme (see Scheme 5 in ref. 1 Vol. 1 1 p. 8) that has been proposed for the biosynthesis of sparteine on the basis of important results that were obtained when enzyme preparations were used.23 It is to be noted that a diamine oxidase is apparently not involved in the formation of quinolizidine alkaloids nor much less securely is dl-piperi-deine (28) (cf.ref. 1 Vol. 1 1 p. 4; Vol. 12 p. 7). The stereochemistry that is associated with C-1 (= C-5) of cadaverine (27) when it is biotransformed into lupinine (29) has been investigated with (1R)-and (1s)-(1-*H,)cadaverine [as (27)].22 The conclusions are summarized in Scheme 3. The conclusions necessarily rely (in part) on the 3C-labelling studies that have just been discussed. The hypothetical pathway (Scheme 3) differs from the one just alluded to for ~parteine,~~ which may be simply adapted to account for the biosynthesis of lupinine.It is interesting to note however that the stereochemistry of the first step is the same as that which would be expected' of a diamine oxidase (see above). Clearly further work will help to decide what is the actual course of biosynthesis of lupinine and of sparteine but the stereochemi- cal information will in any case be valid. Certainly it helps to restrict the nature of possible intermediates; an intermediate such as (25) with C,, symmetry is independently excluded by rattack from 1 [from si face] Scheme 3 these results. It is worthwhile for the reader to compare Scheme 3 with Scheme 1. Some interesting conclusions have been made regarding the genes that are associated with the biosynthesis of quinolizidine alkaloids ;24 the conclusions are potentially of far-reaching significance.Quinolizidine alkaloids are widely distributed in the Fabaceae and are assumed to be specific to this plant family. However the induction of synthesis of quinolizidine alkaloids could be achieved in cell cultures of plants that are outside this family and which produce other alkaloids or no alkaloids at all. This indicates that these genes are not restricted to the Fabaceae but have a wide distribution. In these other species simply the genes are not expressed. The occurrence of an N-methyltransferase which transfers a methyl group from S-adenosylmethionine to cytisine has been observed in Laburnum anagyroides plants and in cell cultures of Laburnum alpinum and Cytisus canariensis.25 The patterns of quinolizidine alkaloids in cell cultures of ten species of the Fabaceae have been analysed and compared to the alkaloids that are present in the leaves of the respective plants.The cell cultures produced lupanine and related alkaloids.26 a-Pyridone alkaloids although produced by the leaves of some of the plants were not produced in cell cultures. 2 lsoquinoline Alkaloids 2.1 Benzylisoquinoline Alkaloids Norlaudanosoline (33) is a key intermediate in the biosynthesis of a large number of benzylisoquinoline alkaloid^.^.^ Evidence from several groups of workers had indicated that (33) is formed by condensation of dopamine (30) with 3,4-dihydroxy- phenylpyruvic acid (35) to give the amino acid (39) which upon decarboxylation and reduction affords norlaudanosoline (33) (cf ref.1 Vol. 13 p. 8 and refs. cited therein). Subsequently an enzyme (S)-norlaudanosoline synthase was isolated from several plant species which produce benzyliso- quinoline alkaloids and not from others which do not produce these alkaloids. Dopamine (30) is a substrate for the enzyme but 3,4-dihydroxyphenylpyruvic acid (35) is not. Instead 3,4- dihydroxyphenylacetaldehyde (31) was found to act as co- substrate with dopamine and (S)-norlaudanosoline (33) was ~btained.~’ Further results give very convincing evidence about the status and properties of (S)-norlaudanosoline synthase.28 The enzyme which was obtained from cell suspension cultures of Escholtzia tenuifolia has been purified approximately forty-fold.Its molecular weight is apparently 15 500 Dalton. Evidence was obtained for the existence of four isoenzymes none of which catalyses the reaction of dopamine (30) with 3,4-dihydroxyphenylpyruvicacid (35) or with 4- hydroxyphenylpyruvic acid (36). The values of KMfor 3,4-dihydroxyphenylacetaldehyde(3 1) and for 4-hydroxyphenylacetaldehyde (32) as substrates for the synthase are almost identical which means that the enzyme is also responsible for the formation of demethylcoclaurine (34) which by way of coclaurine (41) is then a key precursor for a number of benzylisoquinoline alkaloid^.^^^ The products of the enzymic reaction are (S)-norlaudanoso- line (33) and (S)-demethylcoclaurine (34). No evidence could be obtained for the formation of the (R)-isomers.Where the (R)-isomers are needed for subsequent biosynthesis of alkaloids it is suggested that they arise by isomerization of an (S)precursor. It has been noted consistently that whereas tyrosine (37) affords both the isoquinoline and benzyl halves of a benzyliso- quinoline skeleton dopa (38) provides only the isoquinoline moiety. This is now understandable in terms of the above findings ; rather than deriving the 3,4-dihydroxyphenylacetal-dehyde (31) from (35) [which is the transamination product of dopa (38)] there must be a different pathway from tyrosine (37). Discussion of the above findings may be followed rather nicely by noting the results that were obtained in a study of the alkaloids of Stephania glabr~.~~ The results of careful experi- NATURAL PRODUCT REPORTS 1985 R/ dCHO i HOW (33) R = OH (31) R = OH (34) R = H (32) R = H (35) R = OH (37) R = H (36) R = H (38) R = OH (39) Me0 \ (43) R = H (42) (44) R = Me MeOm (45) (46) ments show that the tetrahydroprotoberberine alkaloids ste- pholidine (43) corydalmine (44) capaurine (49 and corynoxi- dine (46) are stereospecifically biosynthesized from (5’)-reticuline (40) and from this precursor only.On the other hand the bisbenzylisoquinoline alkaloids cycleanine (47)* and desmethylcycleanine (48)* and the proaporphine alkaloid pronuciferine (49) are derived specifically and independently from (R)-N-methylcoclaurine (42); stepharine (50) is derived from coclaurine (41).The presence of both reticuline (40) and N-methylcoclaurine (42) in S. glabra was confirmed. The quaternary protoberberine derivatives in the plant were shown to be formed by dehydrogenation of the corresponding tetrahydroprotoberberines. The results are all in accord with what has been deduced previ~usly~~~ about the biosynthesis of these alkaloid types. The tetrahydroprotoberberine skeleton is formed from (S)-reticuline (40) by a ring-closure reaction in which the N-methyl group of (40) becomes C-8 the ‘berberine bridge’ in the * There seems to be some confusion about the absolute stereochemistryof these alkaloids. NATURAL PRODUCT REPORTS 1985-R. B. HERBERT pR 0 R (49) R = Me (50) R = H (47)' R = Me (48) R = H c%oMe OMe OMe -,OMe OMe (53) (54) Scheme 4 OMe (56) R' = H R2 = OH (55) (57) R' = OH R2 = H Me (51).475 tetrahydroprotoberberine (S)-scoulerine A cell-free system from cell cultures of Macleaya microcarpa had been shown to catalyse the conversion of (40) into (51).30 The berberine-bridge enzyme has been isolated from cell cultures of Berberis beaniana and purified to h~mogeneity.~ The enzyme is inhibited by u-phenanthroline and reducing agents such as dithioerythritol.It does not need added pyridine nucleotides for catalytic activity. (S)-[N-methyl-3H3]Reticuline [as (40)] was converted into (9-scoulerine (51) with loss of one third of the tritium (curiously no isotope effect was observed). One mole of oxygen was taken up and one mole of hydrogen peroxide was released.The enzyme is specific for the (S)-isomer of reticuline and neither the (R)-nor the (S)-N-oxide is a substrate. (S)-Protosinomenine acted as a substrate [145% of (40)] as did laudanosoline [20% of (40)]. Orientaline iso-orientaline laudanidine and laudanosine would not act as substrates. Another enzyme was found to occur in a number of plant cell cultures especially those strains of species of the genus Berberis which produce considerable amounts of pr~toberberines.~~ It catalyses the conversion of a tetrahydroprotoberberine e.g. (52) into a protoberberine [as (54)]. On the one hand the enzyme is specific for tetrahydroprotoberberines of the (S) configuration [as (52)] whilst on the other hand the aromatic substitution pattern on rings A and D [see (52)] only quantitatively affects the catalytic activity.1.5 Mole of oxygen is consumed and 1 mole of hydrogen peroxide and water is produced for each mole of substrate that is oxidized. In the presence of NaBD the enzyme does not oxidize canadine (52) (59) Me0 OMe M OH (62) (63) to berberine (54) but the canadine that was re-isolated contained a deuterium atom at C-14. The fact that 13,14-di- dehydrocanadine [as (52)] and some other compounds were not substrates indicates that the oxidation proceeds via (53) as shown in Scheme 4. The berberine relative jatrorrhizine (55) when compared to reticuline (40) and scoulerine (Sl) has the 'wrong' methylation pattern. Res~lts~~?~ of experiments with cell cultures of Berberis species have shown that jatrorrhizine (55) is formed via (9-reticuline (40) and berberine (54) i.e.the transfer of a methyl group occurs from one oxygen [at C-6 in (40)] to another [at C-2 in (55)] by way of a methylenedioxy-group. This is an observation which has not previously been noted. Curiously again no isotope effect was observed for the loss of a proton from a methyl group [as in (40)].34 The cis N-methyl salts (56)and (57) of the 13-hydroxytetrahy- droprotoberberines epiophiocarpine and ophiocarpine respec- tively are converted into a benzindanoazepine (60) via a protopine derivative (58) and then via (59) in callus cultures of Corydalis species.35 The methyl salt with a trans ring-junction which corresponds in structure to (56) was not metabolized.A further end-product of metabolism was the spiro-compound (61).36A 13C label on the N-methyl group of (56) was retained in the 0-methyl group of (61)35-another unusual migration of a methyl group. It has been shown that the isoquinoline (62) (labelled with tritium) is specifically a precursor for cularine (63) in Corydalis claviculata; stylopine and protopine that were isolated in this NATURAL PRODUCT REPORTS 1985 Me0Me0 Me "9:zrqNMe \ __3 ___ E:zMq:Ac \ Me0'OH Me0 P' H MeOQAMeI f -NMe Me0 \ "q<;e Me0 \ Me0 Me0 Me0 WOH Me0 O U (67) R' = H R? = Me (68) R' = Me R' = H experiment were appropriately ina~tive.~' This unusual base (62) is a natural constituent of C.clu~iculutu.~~ A most interesting development involving cells of Pupuver somnqerum has been reported.39 Cells from cell cultures have been immobilized in calcium alginate where they continued to live and to be biologically active for six months. These immobilized cells very efficiently (higher than with cell-suspension cultures) converted codeinone into codeine. Work in relation to the production of alkaloids in cell cultures of Pupuuer br~cteutum,~~ and Es-Dioscoreophyllum cummin~ii,~ choltziu culijomicu4' has been described. 2.2 Colchicine It is known that colchicine (66) is biosynthesized via the phenethylisoquinoline (64) and the dienone (65).4.5 In an attempt to gain insight into the fascinating steps that are involved in this sequence particularly (65) + (66) the methyl- substituted phenethylisoquinolines (67) and (68) were tested (in labelled form) as precursors for colchicine and for related alkaloids in Colchicum a~tumnule.~~ None of the alkaloids was labelled by the precursors.It was further shown in a dilution experiment that cyclization of (67) to give 13-methyl-0- methylandrocymbine (69) also did not occur. The results indicate that at least one of the late enzymic steps in the 0 1 OMe conversion of autumnaline (64) into these tropolone alkaloids e.g. '(66) is highly sensitive to structural change close to the nitrogen atom. 2.3 Tubulosine The ipecac alkaloid cephaeline (70) is known to arise from deacetylisoipecoside (7 1) in Alungium lumurckii (CJ ref.1 Vol. 10 p. 18). Alungium Iumurckii also produces tubulosine (74) which apparently has a structure that is related to those of the ipecac bases. A plausible biosynthetic route to (74) is via deacetylisoipecoside (71) and (72) which could condense with tryptamine leading to (74). In this route the stereochemical detail of the precursor (71) is preserved. An alternative route however because of the tryptamine unit is one which is related to that of the terpenoid indole alkaloids and notably involves strictosidine (76) but there are stereochemical difficulties associated with the conversion of (76) into (74). An excellent specific incorporation of [3-'T]deacetyliso- ipecoside [as (71)] into tubulosine (74) and an insignificant incorporation of similarly labelled strictosidine (76) plus vincoside validates the first of these two pathways (Scheme 5).44 Further results have established the sequence as tyrosine (37) + dopamine -t (71) + deoxytubulosine (73) + tubulosine (74) which is analogous to the route leading to cephaeline (70).Derived from Tryptophan 3.1 TeWnoid hdole Alkaloids Secologanin (75) is a key terpenoid intermediate in the biosynthesis of these alkaloids. A review on the biosynthesis and synthesis of this monoterpene and related compounds has been published,45 as has a survey of the biosynthesis of terpenoid indole alkaloids which includes a discussion of structural relationships within the group.46 Me0 Meomb (73) R = H (74) R = OH Scheme 5 NATURAL PRODUCT REPORTS 1985-R.B. HERBERT Elegant work with enzyme preparations has revealed the detail of the biosynthesis of heteroyohimbine alkaloids e.g. ajmalicine (81) (cf. ref. 1 Vol. 11 p. 17). The pathway is illustrated in Scheme 6. Examination of the mechanisms of the various steps shows that one proton is taken up in the sequence from strictosidine (76) to cathenamine (79) and then a hydride ion and a proton are added to the intermediate cathenamine (79) to give ajmalicine (81). This has been confirmed47 by carrying out the enzyme-catalysed conversion of (76) into (79) in D20; the cathenamine (79) that was formed was reduced in situ with sodium borohydride to give tetrahydroalstonine (82).This contained two deuterium atoms one at C-18 and one at C- 20 (introduced during chemical reduction). The same incorpor- ation of deuterium was observed if NADPH in D20 was used when ajmalicine (8 I) 19-epi-ajmalicine (83) and tetrahydro- alstonine (82) were the products. Carrying out the reaction with NADP*H gave samples of the three alkaloids in which a single deuterium atom was stereospecifically located in the 21a- position. Geissoschizine (78) is at a shunt to the pathway which affords (8 1)-(83). Mechanistic considerations indicate that the conversion of (78) via (77)/(79) into (81)-(83) should result in the incorporation of one deuterium atom from NADP2H. Incubation of (78) with NADP+/NADP2H did indeed give this result; the deuterium atom was also in the 21a- position.These results obtained with crude enzyme prepara- tions from Catharanthus roseus tissue cultures thus nicely corroborate earlier evidence. Further work4* has been published on PNA esterase which is an enzyme that catalyses the conversion of polyneuridine aldehyde (84) into the acid (85) (cf. ref. 3 p. 185). The enzyme shows very high substrate specificity for (84). The acid (85) undergoes spontaneous decarboxylation to give 16-epi-vellosi- H‘cs..OG Ic MeOzC \ [-Tryptamine (75) mine (86) which is seen as a key intermediate leading on the one hand to ajmaline-type alkaloids (see below) and on the other to sarpagine-type alkaloids as shown in Scheme 7. For the formation of the latter group 16-epi-vellosimine (86) undergoes spontaneous inversion of configuration at C-16 to give vellosimine (87) which is converted into lo-deoxysarpa- gine (88) in a NADPH-dependent reaction that is catalysed by vellosimine reductase (cf.ref.3 p. 185). Further work has been published on this red~ctase,~~ which was isolated from RauwolJia serpentina and purified. Acceptable substrates were generally found to be terpenoid indole alkaloids of the sarpagine group with vellosimine (87) showing the lowest value of KMand the highest v,,,; it has an absolute requirement for NADPH (v,, = 0 for NADH). The reductase was found exclusively (but widely) in cultures from plants of the Apocynaceae. The product of the reaction 1 0-deoxysarpagine (88) was shown to be a very efficient precursor (86% incorporation!) for sarpagine (89) in a cell suspension culture of R .serpentina. An enzyme vinorine synthase has been isolated from cell cultures of RauwolJiaserpent in^.^^ It catalyses the conversion in the presence of acetyl-CoA of 16-epi-vellosimine (86) into vinorine (91). It has thus been established that there is a biosynthetic link between polyneuridine-type [as (84)] and ajmaline-type alkaloids and that there is a clear relationship between the latter group and the sarpagine-type alkaloids. The enzyme acts on substrates which have an endo-aldehyde at C-16 (this configuration is geometrically essential for ring-closure); no reaction occurs if the substrate also has an ester group at C-16 and not surprisingly if the indolic nitrogen is methylated.The acetyl-CoA is of course necessary in this enzymic conversion to drive the reaction forward beyond the unstable intermediate (90) as is the case in a similar chemical OH MeO,C? OH (77) (81) 19P-H 2w-H (79) lw-H (82) 19P-H 20a-H (80) 19~~-H (83) 19~t-H 2w-H Scheme 6 NATURAL PRODUCT REPORTS 1985 - PNA esterase (84) H 0-p' Y NADPH IAcSCoA (88) R = H C(89) R = OH Scheme 7 OAc QH ?H (94) (95) (92) R = H (93) R = galactosyl conversion of an alkaloid of type (90) into one of type (91). Evidence relating to biosynthesis beyond alkaloids of the vinorine type has .been obtained using a crude enzyme preparation from cell cultures of Rauwolfia ~erpentina.~ The preparation was found to transform vomilenine (92) into ajmaline (95) in the presence of both NADPH and S-adenosylmethionine.In the absence of S-adenosylmethionine (94) was obtained; incubation of (94) with enzyme and S-adenosylmethionine afforded (95). In the reaction of (92) to give (99 appropriately two deuterium atoms were incorpor- ated if NADP*H was the cofactor. Overall an esterase one or two reductases and a methyltransferase are involved. It is an open question at this stage as to when the hydroxy-group at C-21 is actually introduced during the biosynthesis of ajmaline in vivo. Raucaffricine (93) has been isolated as the major alkaloid of cell suspension cultures of Rauwolfia serpentina.52 It is converted into its aglycon vomilenine (92) by a newly discovered enzyme raucaffricine glycosidase.The dialdehyde (96) and related geraniol/nerol derivatives that are oxygenated at C-1 and C-10 have been identified as intermediates in the biosynthesis of terpenoid indole alkaloids e.g. vindolineS3(cf ref. 1 Vol. 13 p. 14). Work by others has confirmed these findings for vindoline and for secologanin (96) 2E/2Z (97) (98) (75).s4 Furthermore evidence was obtained that geraniol/nerol derivatives that are oxygenated at C-1 C-9 and C-10 are not involved in contrast to other work which indicates that they are.s5 Iridodial (97) is also a good precursor for (75) and for vindoline. Thus oxygenation at C-10 occurs apparently after the formation of the five-membered ring that is found in loganin (98).s4Loganin is of course the pivotal intermediate leading to secologanin (75) and these indole alkaloids.46 An alkaloid guettardine of structure (99) has been isolateds6 from plants that produce Cinchona alkaloids.The natural occurrence of an alkaloid with such a structure suggests for the biosynthesis of Cinchona alkaloids that the P-carboline system of corynantheine may be cleaved before the quinucli- dine ring is formed (cf. refs. 4 5 and 46). The conversion of anhydrovinblastine into vinblastine by a cell-free homogenate of a cell-line of Catharanthus roseus that NATURAL PRODUCT REPORTS 1985-R. B. HERBERT 100) does not produce vinblastine or related bisindole alkaloids has been noted.57 A detailed discussion of one group’s work in relation to the use of different cell-lines of C.roseus to study the production and biosynthesis of terpenoid indole alkaloids has appeared.s8 Two novel dimeric indole alkaloids voafrine A and voafrine B have been isolated from cell suspension cultures of Voacanga africanaS9 and their medium-dependent formation has been studied. Further work has been published on cell suspension cultures of Catharanthus roseus.60 3.2 Triostin A and Echinomycin The carbon skeleton of the quinoxaline residues (100) in the otherwise peptidic antibiotics triostin A and echinomycin has been shown to derive from tryptophan (by studying the incorporation of DL-[ben~ene-ring-U-’~C]tryptophan).~~ New results using SN-labelled medium and 14N-labelled precursor show that N-1 and N-4 of the quinoxaline rings (100) of triostin A derive from the indole ring and from the amino-group of tryptophan respectively in cultures of Streptomyces triostini- CUS.~~ The 5N n.m.r.spectrum of the sample of triostin A that was obtained showed a virtually complete reduction in the signal for N-1 but about 50% reduction in the signal for N-4. The conclusions then rest on the fact that the indole nitrogen atom will only interchange slowly with the 15N pool in the organism whereas the amino-nitrogen atom is expected to undergo normal rapid exchange. This is an interesting way of studying nitrogen metabolism which may be applicable in other cases; it avoids the need to synthesize complex precursors that contain 15N.The effect of phosphate and of various amino acids on the production of echinomycin in Streptomyces echinatus has been reported.63A number of nitrogen-containing heterocyclic acids has been examined for their suitability as substrates in S. echinatus leading to the production of novel analogues of ec hinomycin. 64 3.3 Penitrem A Further details have been published65 of an ongoing study of the biosynthesis of penitrem A (101) (cf. ref. 1 Vol. 13 p. 20; Vol. 11 p. 20). The results were principally obtained by using samples of acetate and of mevalonate that were labelled with 2H and I3C. It is apparent that (101) is formed from tryptophan geranylgeranyl pyrophosphate and two isopen- tenyl pyrophosphate units.The initial stages of the pathway including a rearrangement step are apparently similar to those that have been proposed for pa~paline~~,~~ (cf. Scheme 10 and p. 23 in ref. 1 Vol. 11) and pa~illine.~~ 3.4 Roquefortine Oxaline and Echinulin The efficient incorporation of (2S)-[ring-2-14C]histidineand of (2S)-[3-I4C]tryptophan into roquefortine (1 03) in cultures of Penicillium roqueforti confirms the origins of this metabolite as being from tryptophan and histidine68 (cf. ref. 1 Vol. 10 p. 25). For other earlier work on roquefortine see ref. 1 Vol. 13 p. 20 and Vol. 11 p. 22. The incorporation of (2RS)-[3-14C 2-3H]tryptophan [as (102)] into roquefortine occurred with substantial loss of tritium. This can be ascribed to a combination of two factors uiz.(i) the conversion of (2R)-tryptophan into (2s)-tryptophan [and equilibration in uiuo of (2s)-tryptophan by transamina- tion] via indolepyruvic acid with concomitant loss of tritium from C-2 and (ii) exchange of 3H at C-16 in (103) with lH of the medium. Thus the incorporation of [I SN]tryptophan into (103) with substantial loss of I5N label would be expected.68 (2RS)-[indole-2-’3C 2-l SN]Tryptophan [as (102)] {admixed with (2RS)-[benzene-ring-U-l “C] t ryp top han to provide an independent measure of dilution} was efficiently incorporated into roquefortine (103). The I3C n.m.r. spectrum of the metabolite showed an enhanced natural-abundance singlet for C-6 (I3C-l4N; 64% loss of 15N) as well as a doublet due to one- bond 3C-15N coupling.A similar experiment with oxaline (105) in Penicillium oxalicum gave exactly similar results i.e. an enhanced natural-abundance singlet for C-2 (l 3C-14N) and a doublet (l3C-I5N) in the 13C n.m.r. spectrum; there was a 37% loss of IsN label. Most importantly these results show the way in which the tryptophan skeleton is arranged in these two metabolites. Roquefortine (103) and oxaline (105) co-occur in Penicillium oxalicum; this taken together with the above findings suggests that oxaline derives from roquefortine. This was confirmed by showing that [benzene-ring-U-I4C,6-l 3C 5-I 5N]roquefortine [as (103)] was efficiently incorporated into oxaline (105). Unfortunately the dilution was too great for the I3C-l5N coupling that is associated with C-2 and N-14 to be observed in the 13C n.m.r.spectrum. A plausible mechanism for the conversion of (103) into (105) is shown in Scheme 8. It is supported by the isolation of 16- hydroxyroquefortine (1 04) together with roquefortine from cultures of Penicillium crustosum. A notable structural feature in (103) and (105) is the ‘reversed’ prenyl residue at C- 14 and C-3 respectively. Echinulin (107) also contains a ‘reversed’ prenyl residue in this case at C-2. The overall stereochemistry that is associated with the conversion of C-3 of mevalonic acid (106) into the carbon atom of (107) which bears the two diastereotopic methyl groups has been examined.69 [Me-2H3]Mevalonic acid lactone [as (106)] gave labelled echinulin when fed to cultures of Aspergillus amstelodami.Degradation afforded a sample of labelled 2,2-dimethylbutan- 1-01 (108). The enantiotopic methyl groups of racemic 2-[2H3]methyl-2-methylbutan-l-ol can be distinguished in the *H n.m.r. spectrum by use of a chiral shift reagent.’O In this way it was revealed that most of the 2Hlabel (89%)was present in the 2-pro-S methyl group.69 Thus this methyl group is derived from the 3-methyl group of mevalonate (106). It is to be noted that the diastereotopic methyl groups of the reversed prenyl residue in roquefortine (103) are both derivable (in a ratio of 2 :1) from the 3-methyl group of mevalonate7I (cf. ref. 1 Vol. 13 p. 20). 3.5 Pyrrolnitrin Several bromo-analogues of pyrrolnitrin (1 10) and related compounds have been isolated from cultures of a mutant strain of Pseudomonas aure~faciens.’~ A tentative pathway has been proposed for the bromo-compounds that includes (109).Good evidence exists however that the corresponding chloro-compound is not an intermediate in the biosynthesis of pyrrolnitrin (at least when it is formed from the L-isomer of 172 NATURAL PRODUCT REPORTS 1985 Oxaline (1 05) Scheme 8 0 CHO QLJQJcl CI H (1 11) trypt~phan).~~ The late stages of the biosynthesis of (1 10) have been affirmed and evidence is presented that chlorination may occur as an early step7* (cf. ref. 1 Vol. 12 p. 18). 3.6 Streptonigrin Analysis of the 13C n.m.r. spectrum of a sample of streptonigrin (1 13) that was obtained after feeding [U-l 3C]glucose (1 1 1) to Streptomyes jlocculus established that this metabolite was formed from the intact units that are shown with heavy bonding in (1 13) (cf ref.1 Vol. 13 p. 18). The labelling pattern in rings c and D was consistent with the known derivation of these rings from tryptophan uiu the shikimate path~ay.~ The C unit here is D-erythrose 4-phosphate (1 12). Results of new experiments on streptonigrin (1 13) using cultures of S. jlocculus show that all three of the C units (heavy bonding) in (1 13) derive from intact erythrose units.74 Both [1-I4C]- and [4- 4C]-~-erythrose were good precursors for streptonigrin whereas [l-14C]-~-thre~~e was poorly utilized. Furthermore [1-13C]-~-erythrosegave a sample of (113) for which the I3C n.m.r.spectrum showed enrichment of C-9’ (1 .Ox),C-6’ (1. l%) and C-8 (0.6%) and of these carbon atoms only; significantly no enrichment was observed of C-12’ C-4 or C-5. The pattern is consistent with the labelling that occurred from glucose (1 1I) and it is clear that the intermediate which affords ring A is formed along the shikimate pathway. It remains to be discovered what this intermediate actually is and how the third C unit is employed in linking ring A to the rest of (1 13). HOTMe Me Me (ii) I $ J 0-LQCO2H Br H 1 OMe (1 13) Me (I 1.1) (iii) T Mc Enzymes (i) S-adenosylmethionine methyltransferase; (ii) a-ketoglutarate transaminase; (iii) glutamate transaminase Scheme 9 Rings c and D in streptonigrin (1 13) are formed from 3- methyltryptophan (1 14) (cf ref.1 Vol. 10 p. 23). Enzyme activities which catalyse the conversion of tryptophan into 3- methyltryptophan by two different routes (Scheme 9) have been demonstrated in cell-free extracts of S.~occulus.7s~7~’ The product from the reaction that is catalysed by tryptophan C-methyltransferase was deduced to be (2S 3R)-3-methyl- tryptophan. NATURAL PRODUCT REPORTS. 1985-R. B. HERBERT 3.7 Ergot Alkaloids The purification from Claviceps purpurea of ergopeptine synthetase which is a multi-enzyme complex that synthesizes peptidic ergot alkaloids has been described along with some of its proper tie^.^^ Work on the immobilization of C.purpurea cells in different matrices has been rep~rted.’~ With a view to using microbial means to prepare lysergic acid amides from agroclavine (1 13 the substrate specificity of agroclavine hydroxylase from Claviceps fusiforrnis has been in~estigated.~~ This enzyme normally converts agroclavine (1 15) into elymoclavine (1 16).From the eighteen analogues of (1 15) that were examined it was concluded that for hydroxyla- tion to occur the 8-9 double-bond and a tertiary N-6 must be present. The enzyme was tolerant of variations associated with the pyrrole moiety in (1 15). 4 Metabolites Derived from Phenylalanine and Tyrosine 4.1 Gliotoxin and Aranotins Gliotoxin (1 19) is biosynthesized via the cyclodipeptide (1 17) in Gliocladium deliquescens (cf ref. 1 Vol.10 p. 27). The unnatural precursor (1 18) has been found to give (1 20) as one of three products.80 Examination of this structure indicates that in the normal biosynthesis of gliotoxin (1 19) substitution by sulphur can occur before N-methylation or modification of the aromatic ring. The cyclodipeptide (121) is a key precursor in the biosynthe- sis of bisdethiobis(methy1thio)acetylaranotin (124) in Aspergil- lus terreus (cf:ref. 1 Vol. 12 p. 28). The compound (122) which is related to (1 20) has been isolated from A. terreus.81 The same conclusion as was drawn for the biosynthesis of gliotoxin about the timing of substitution by sulphur may be made for the biosynthesis of (124). Furthermore (123) which was ssFthe- sized from [4-3H]phenylalanine and [3SS]sulphur has been shown to be a precursor for (124) but a change in the isotope ratio indicates that there is not quite an intact incorporation.4.2 Tuberin Tuberin (1 25) is a metabolite of Streptomyces amakusaensis. Its structure bears at least a superficial resemblance to the intriguing bisisocyanide (1 26). With the exception of the isocyanide functions this metabolite like another isocyanide is known to originate from tyrosine with loss of the carboxyl group. The origins of the isocyanide functions in each case remain a mystery (cf ref. 3 p. 188). Tuberin (125) also derives from tyrosine with loss of the carboxyl carbon.82 Curiously even though high incorporations of tyrosine were observed some degradation of the precursor occurred with subsequent incorporation of label probably via the C pool.Neither [2-I4C]tyramine [as (I 27)] nor [2-3H]octopamine (128) served as a precursor of tuberin. DL-[2-I4c 3’,5’JH2]- threo-3-hydroxytyrosine [as (1 29)] gave labelled tuberin but the metabolite contained only 14C label which was found to be almost equally divided between the N-formyl and the 0-methyl group. This suggested that an enzyme-mediated reverse aldol reaction was occurring on the (129) that was fed to the organism giving [2-I4C]glycine [as (13O)l; this then served as a Cl source via tetrahydrofolate metab~lism.~~ This hypothesis was supported when it was shown that [2-14C]glycine was a good precursor for tuberin (125) and that there was almost equal labelling of the two C units.82 [I4C]Formate failed to act as an exogenous C source for (125) but [Me-14C]methionine served as an efficient precursor for the 0-methyl group of (125) as expected.These findings on the failure of (127) (128) and (129) to act as precursors for tuberin (1 25) indicate that hydroxylation at C- 3 of tyrosine or a derivative is not involved as the means by which the double-bond in (125) is introduced. Ph HN (1 17) R = CHtOH (115) R = H (118) R = CH2CH3 (116) R = OH (121) X = H (122) X = SMe +-(127) R = H (1 26) (128) R = OH 4.3 Ilicicolin H Results of experiments with 3C-labelled acetate and methion- ine and with * 5N-and 14C-labelled phenylalanine indicate that ilicicolin H (1 3 1) is biosynthesized by Cylindrocladiurn ilicicola as shown in Scheme Whilst the results with I3C-labelled acetate and methionine and with [I 5N]phenylalanine are unambiguous the only test for the manner of incorporation of the carbon skeleton of phenylalanine was a simple incorpora- tion of L-[ U-14C]phenylalanine.The rearrangement mecha- nism (Scheme 10) for the phenylalanine moiety in (131) follows from a detailed study of the biosynthesis of tenellin (132).85 4.4 Arphamenines Simple measurement of the incorporation of ~-[U-’~C]argin- ine of [1-“TI- and [2-I4C]-acetate (positive incorporation) of DL-[1-I4C]arginine and of L-[methyl-14C]methionine(negative incorporation) into arphamenine A (1 33) and arphamenine B (134) has in part established their origins.86 ~-[U-’T]Phenyl- alanine served as a precursor for arphamenine A (1 33) but not for arphamenine B (1 34) the opposite result being obtained with ~-[U-l~C]tyrosine.These results complete the identifica- tion of the origins of the two metabolites and indicate that (133) is not a precursor for (134). The incorporation of acetate was substantiated by using [I 3C]acetate as a precursor appropriate labelling of the relevant carbon atoms was observed through I3C n.m.r. analysis. NATURAL PRODUCT REPORTS 1985 COlH -I-H02C (o)m-&e ~ ~ 0 [Me UIMethionine GH2 Me Phenylaianine 1 Me (131) Scheme 10 5.3 Acridone Alkaloids Results of further experiments relating to the biosynthesis of HoQ+L+yy rutacridone (137) in cell suspension cultures of Ruta graveolens have been reported 89,90 (cf.ref. 3 p. 190). Thus methionine 5 Other Metabolites Derived from the Shiki-mate Pathway 5.1 Ansamycins 3-Amino-5-hydroxybenzoic acid (135) is a key precursor in the biosynthesis of a number of antibiotics e.g. actamycin (cf. ref. 3 p. 188 and refs. cited therein). The effect of analogues of (135) on the production of antibiotics by a species of the genus Streptomyces which normally produces actamycin has been noted.87Whilst the production of actamycin was enhanced by the presence of added (135) the addition of the 4-chloro- 6-chloro- N-methyl- and 0-methyl-analogues of (135) not only gave no analogues of actamycin but also led to less antibiotic being produced by the cultures (cf. ref.3 p. 188). 5.2 Phenazines The metabolism of several phenazines in Pseudomonas aureofa-ciens has been examined.88Hydroxylation and decarboxylation of phenazine-1-carboxylic acid was observed. H*NYNH NH NH I T-H2NyNH I c02 [YH,], H ,N-CH-+-CH+-C I II H02C Arginine '0 Tk2 has been shown to be specifically the source of the N-methyl group of (137) and N-methylanthranilic acid has been identified as a biosynthetic intermediate following anthranilic acid ;N-methyl-[carbo~yl-~~C]anthranilic acid [as (136)] was an efficient precursor for rutacridone (137) and it could be isolated in radioactive form from the cultures after feeding them with labelled anthranilic acid.89Cell-free extracts of cultures of Ruta gruveolens have been obtained which convert anthranilic acid into N-methylanthranilic acid (1 36).90This N-methyltransfer-ase activity was missing from cultures of plants which do not produce acridone alkaloids.6 j3-Lactams 6.1 General The biosynthesis of p-lactam antibiotics has been surveyed in a three-part work on the chemistry and biology of these most important of natural product^.^' 6*2 and CephalosPOrins It is well established that the penicillins e.g. isopenicillin N (142) are formed via the ACV tripeptide (138). Recent results R I 0 'iH2 +-Phenylalanine or Tyrosine H-C02 H I (133) R = H (134) R = OH k02H (138) R' = RZ = Me (139) R1 = Me R2 = H (137) (140) Rl = Me R2 = 2H (141) RI = 2H R2 = Me NATURAL PRODUCT REPORTS 1985-R.B. HERBERT with modified tripeptides indicate which of the two ring- closure reactions that occur in this transformation happens first. It had previously been reported that the tripeptide (1 39) gave (143) on incubation with a cell-free extract of Cephalosporium acremonium (cf ref. 1 Vol. 13 p. 35). Incubation of (1 39) with a highly purified sample of the single enzyme isopenicillin N synthetase in the presence of FeSO, dithiothreitol ascorbic acid catalase and oxygen gave (143) as before but now a second product (146) was also obtained; the products were formed in a ratio of 3 :1 re~pectively.~~ Purification of the enzyme had removed ring-expansion activity so that the normal conversion of penam into cepham could not occur.The results are accommodated by a pathway (Scheme 11) in which (145) is formed with further reaction yielding either (143) or (1 46). The two diastereotopic tripeptides (140) and (141) if they were separately incubated with purified isopenicillin N synthetase and cofactors (see above) gave the same product namely (144).93 This result was interpreted as further evidence for a cyclization mechanism in which an intermediate is formed with a radical at the atom which becomes C-2 in (144). Curiously no loss of deuterium was observed i.e. no P-lactam product that contained lH at C-2 was obtained. Incubation of the modified and tritiated tripeptide (147) with purified synthetase and cofactors (see above) resulted in inactivation of the enzyme and release of tritium as tritiated water the extent of release of tritium corresponding to the concentration of enzyme in the reaction mixture.94 The substitution of tritiated tripeptide by 14C-labelled material as the substrate and the inclusion of sodium borotritiide (which was shown not to affect the activity of the enzyme) in the incubation mixture gave (147) that was tritiated at C-3 of the cysteinyl moiety.This was interpreted as indicating that (147) underwent cyclization to give (148) which inhibited the enzyme; reduction of (148) then opened the ring again. Other interpretations are possible including the one whereby the thioaldehyde equivalent (149) is formed as the enzyme inhibitor. In support of the work of others (cf ref.3 p. 190) it has been found that (1 50) is not converted into isopenicillin N (142) by a cell-free preparation of Cephalosporium acremoni~m.~~ Nor is the corresponding thiol. An attractive mechanism for forming the P-lactam ring in isopenicillin N (142) has been proposed which involves the hydroxamic acid (1 5 1). This compound has been synthesized but it fails to give p-lactams on incubation with an enzyme system derived from cells of C. a~remonium.~~ Indeed it acts as an inhibitor for the conversion of (138) into (142). The ACV tripeptide analogue (1 52) has been converted into the corresponding isopenicillin analogue by an enzyme preparation from cells of Cephalosporium acremoni~m.~' The yield was comparable to that which was obtained for the transformation of (1 38) into (142).Possible mechanisms for the formation of p-lactams in viuo have been adduced/supported on the basis of the results that were obtained in chemical experiment^.^^ The purification of isopenicillin N synthetase isolated from Cephalosporium acremonium has been reported.99 A cell-free preparation from a P-lactam-negative mutant of C. acremonium has been found to convert a-aminoadipic acid cysteine and valine into the tripeptide (1 38) and also into &(L-a-aminoadi- poy1)-L-cysteine.loo A variety of inorganic and organic sources of nitrogen have been tested for their regulatory effect on the production of p-lactam antibiotics by C. acremonium.lol L-Asparagine and L-arginine were the best sources of nitrogen.Enzyme activities that are associated with the production of penicillins G and V have been isolated from Penicillium chrysogenum; they have been purified and characterized.Io2 Partial purification of the enzymes which catalyse the ring- expansion of penicillin N that gives deacetoxycephalosporin C and the subsequent hydroxylation that gives deacetylcephalo- sporin C has been achieved.lo3 The two enzyme activities could not be separated. k02H (142) R' = R2 = Me (143) R' = Me R2 = H (144) R1= Me R2 = 2H 1 I I C02H (143) 602H (145) (1 46) Scheme 11 S-Enzyme + 602H k02H (149) \ H I C02H (152) (153) X = H (154) X = OH (155) X = OMe The 01-and P-sulphoxides of penicillin N have been tested as intermediates in the ring-expansion of penicillin N which affords deacetoxycephalosporin C.O4 Neither sulphoxide acted as a substrate for the synthetase. The finding with the p-sulphoxide agrees with earlier results. O5 Cephamycin C which is produced by Streptomyces clauuli- gerus has the methoxycephalosporin C structure (155) (cf ref. I Vol. 10 p. 29). It has been shown using an extract of S. clavuligerus,that entry of the methoxy-group in cephamycin C (1 55) is a two-step process; 7a-hydroxycephalosporin C (1 54) is an intermediate.lo6 The enzyme preparation catalysed the NATURAL PRODUCT REPORTS 1985 H NAC02 H H I H N?CO2 H Arginine (1 58) Ht; H Ct HU 1 fNH 0 i2H (PLP = pyridoxal phosphate) Scheme 13 hydroxylation of (153) to give (154); the same preparation would convert (1 54) into (1 55).The stereochemistry that is associated with the two methyl groups of the valine residue in (138) during the formation of cephalosporin C (1 53) has been examined,’ O7 using samples of valine in which the methyl groups are chirally labelled (C1H2H3H). The experiments were carried out with washed cells of Cephalosporium acremonium. The method of analysis was by 3H n.m.r. with and without proton decoupling. What was known about the incorporation of valine at the outset of this work is shown in Scheme 12. The si-methyl group of valine [with the (R) or the (S) configuration] on incorporation into cephalosporin C (157) (i.e. into C-3’) gave the complementary results that were expected ; the conclusion was drawn that stereospecific (> 70%) hydroxylation of this carbon atom had occurred.An unexpected set of results was obtained for the re-methyl group however. It was apparent that regardless of whether this methyl group was of the (R) or the (S)configuration the same two species [CPDaT and CctDPT at C-2 in (157)] were generated in a similar (approximately 2 1) ratio. No proton-bearing species were apparent indicating that there is a large deuterium isotope effect. The results indicate that an inter- mediate that is associated with the re-methyl group of (156) is generated during ring-expansion with the same stereoche- mistry regardless of the configuration of the re-methyl group in the precursor.lo7 7 Miscellaneous Metabolites 7.1 Streptothricin F It has been demonstrated (with some elegance) that the streptolidine moiety [as (159)l of streptothricin F (160) is formed from an intact molecule of arginine (1 58) (cf.ref.1 Vol. 13 p. 31). Full details of the work and of that with [ 3C]acetate have been published.lo8 The results include those that were obtained with four arginine samples labelled with I3C and lSN which unambiguously established the way in which the arginine molecule is used to construct (1 59); two of these results are new. Arginine (1 58) labelled with deuterium at C-2 and/or C-3 gave samples of streptothricin F which were in each case devoid of deuterium. This shows that C-3 of (158) is at some stage a keto-group and this leads to a modification of the pathway that had previously been proposed to that which is shown in Scheme 13.That there is complete loss of deuterium from C-2 is surprising since the (2s) configuration of the starting arginine is retained in the metabolite and nitrogen is not lost from C-2. It is suggested that deuterium may be lost from C-2 in a pyridoxal-catalysed reaction with arginine which involves the introduction of a hydroxy-group at C-3. The mechanism and stereochemistry of the conversion of a-lysine (161) into P-lysine (162) in species of the genera Clostridium and Streptomyces [as part of the streptothricin molecule (1 60)] have been investigated with complementary results (cf ref. 1 Vol. 13 p. 33). Full details of the work on streptothricin have been published and there are additional experiments using labelled materials from the Clostridium investigation.lo9 The results are the same as before in the conversion of (161) into (162) the 3-pro-R proton of a-lysine is transferred to C-2 and the 3-pro-S proton is retained at C-3 of (162); inversion of configuration occurs at both C-3 and C-2; migration of nitrogen is intramolecular.A new result is that migration of hydrogen from C-3 to C-2 is substantially or completely intermolecular. The high degree of incorporation of P-lysine into streptothricin F (160) that was observed indicates that (162) is probably an intermediate in the biosynthesis of (1 60). 7.2 Neomycins It has been shown that neamine (164) is an efficient and specific precursor for the neomycins (165) and (166) in Streptomyces fradiae where only negligible incorporation of NATURAL PRODUCT REPORTS 1985-R.B. HERBERT 6 H2NACO2H A Glycine 163) R' = OH [MeIMethionine / ((164) R' = NH2 I NH2 Neomycin B (165) R1 = NH2 R2 = H R3= CH2NH2 Neomycin C (166) R' = NH, R2 = CH2NH2 R3 = H 0 OH paromanine (163) was observed.' lo It is clear therefore that the 6'-amino-group is not introduced at a late stage of biosynthesis. 7.3 Virginiarnycin MI The origins of virginiamycin MI (167) which is produced by Streptomyes uirginiue have been revealed in a detailed study principally conducted with 3C-labelled precursors. l Most notable are the origins of the oxazoie ring from serine and the methyl group C-33 from a fragmented acetate unit.It appears from the evidence that has been obtained including the clever use of [3-' 3C]serine as a 'delayed' source of [2-I3C]acetate that this methyl group is introduced at a late stage of biosynthesis. Both C-10 and C-22 were labelled by [l-I3C]glycine the latter as a result of normal conversion into serine and then incorporation into the oxazole ring (cf. Section 7.4). 7.4 Myxopyronin A Myxopyronin A (168) is a metabolite that is produced by the gliding bacterium Myxococcusfu/uus.The biosynthesis of (1 68) has been investigated with [ 3C]acetate with [Me-'3C]meth-ionine and with glycine that was labelled with 3C and ISN. The results are shown in (168). The origin of the methyl group (C-21) from C-2 of acetate is to be noted (cJ Section 7.3).The origin of C-13 is not clear. 8 References 1 R. B. Herbert in 'The Alkaloids' ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society/The Royal Society of Chemistry London 1971. Vol. I ; 1973-1975 Vols. 3-5; ibid. ed. M. F. Grundon 1976-1983 Vols. 6-13; J. Staunton ibid. 1972 Vol. 2. 2 E. Leete in 'Biosynthesis' ed. T. A. Geissman (Specialist Periodical Reports) The Chemical Society/The Royal Society of Chemistry London 1972 Vol. 1 ; 1973 Vol. 2; 1975 Vol. 3; ibid. ed. J. D. Bu'Lock 1976 Vol. 4; 1977 Vol. 5; 1980 Vol. 6; ibid.,ed. R. B. Herbert and T. J. Simpson 1983 Vol. 7. H J V' v Serine A [MelMethionine 3 R. B. Herbert Nat. Prod. Rep. 1984 1 181. 4 R.B. Herbert in "Rodd's Chemistry of Carbon Compounds" ed. S. Coffey Elsevier Amsterdam 1980,2ndedn. Vol. IV Part L p. 291. 5 R. B. Herbert 'The Biosynthesis of Secondary Metabolites' Chapman and Hall London 1981. 6 J. C. Richards and I. D. Spenser J. Am. Chem. Soc. 1978 100 7402. 7' J. C. Richards and I. D. Spenser Tetrahedron 1983 39 3549. 8 A. R. Battersby J. Staunton and M. C. Summers J. Chem. Soc. Perkin Trans. I 1976 1052; ibid. 1979 45; H. J. Gerdes and E. Leistner Phytochemistry 1979 18 771 ;A. R. Battersby M.Nicoletti J. Staunton and R. Vleggaar J. Chem. Soc.,Perkin Trans. I 1980,43; A. R. Battersby J. Staunton and J. Tippett ihici. 1982 455. 9 G. B. Lockwood and A. K. Essa Plant Cell Rep. 1984 3 109. 10 E. Leete J. Am.Chem. Soc. 1983 105 6727. II R. B. Herbert F. B. Jackson. and I. T. Nicolson J. Chem. Soc. Perkin Trans. I 1984 825. 12 F. Roessler D. Ganzinger S. Johne E. Schopp and M. Hesse Hell.. Chim. Acta 1978 61 1200. 13 D. J. Robins J. Chem. Res. (S) 1983 326. 14 J. Rana and D. J. Robins J. Chtwi. Soc. Chem. Commun. 1983 1222. 15 J. Rana and D. J. Robins J. Chem. Soc. Chem. Commun. 1984 517. 16 G. Grue-Srarensen and I. D. Spenser J.Am. Chem. Soc. 1983,105 7401. 17 J. A. Devlin and D. J. Robins J. Chem.Six.,Perkin Trans. I 1984 1329. 18 J. Rana and D. J. Robins J. Chem. Res. (S). 1984 164. 19 J. Rana and D. J. Robins J. Chem. Soc. Chem. Commun. 1983 1335. 20 W. M. Golebiewski and I. D. Spenser J. Chem. Soc. Chem. Commun. 1983 I 509.21 J. Rana and D. J. Robins J. Chem. Soc.. Chem. Commun. 1984 81. 22 W. M. Golebiewski and 1. D. Spenser J. Am. Chem. Soc. 1984 106,1441. 23 M. Wink T. Hartmann and H.-M. Schiebel Z. Naturjbrsch. Sect. C 1979 34 704; M. Wink and T. Hartmann FEBS LRtt. 1979 101 343; M. Wink T. Hartmann and L. Witte 2.Naturjorsch. Sect. C 1980. 35 93. 24 M. Wink and L. Witte FEBS Lett. 1983 159 196. 25 M. Wink Planta 1984 161 339. 26 M. Wink L. Witte T. Hartmann C. Theuring and V. Volz Planta Med. 1983 48 253. 27 M. Ruffer H. El-Shagi N. Nagakura and M. H. Zenk FEBS Lett. 1981 129 5. 28 H.-M. Schumacher M. Riiffer N. Nagakura and M. H. Zenk Planta Med. 1983 48 212. 29 D. S. Bhakuni S. Gupta and S. Jain Tetrahedro? !983,39,4003.30 E. Rink and H. Bohm FEBS Lett. 1975 49 396; Biochem. Physiol. Pfianzm 1975 168 69. 31 P. Steffens N. Nagakura and M. H. Zenk Tetrahedron Lett. 1984 25 951. 32 M. Amann N. Nagakura and M. H. Zenk Tetrahedron Lett. 1984 25 953. 33 C. W. W. Beecher and W. J. Kelleher Tetrahedron Lett. 1983,24 469. 34 M. Ruffer 0. Ekundayo N. Nagakura and M. H. Zenk Tetrahedron Lett. 1983 24 2643. 35 K. Iwasa A. Tomii and N. Takao Heterocycles 1984 22 33. 36 K. Iwasa A. Tomii and N. Takao Heterocycles 1984 22 1343. 37 G. Blaschke and G. Scriba Tetrahedron Lett. 1983 24 5855. 38 G. Blaschke and G. Scriba Z. Naturforsch. Sect. C 1983,38,670. 39 T. Furuya T. Yoshikawa and M. Taira Phytochemistry 1984,23 999. 40 T. M. Kutchan S. Ayabe R. J. Krueger E.M. Coscia and C. J. Coscia Plant Cell Rep. 1983 2 281. 41 T. Furuya T. Yoshikawa and H. Kiyohara Phyto-chemistry 1983 22 167 1. 42 J. Berlin E. Forche V. Wray J. Hammer and W. Hosel Z. Naturfbrsch. Sect. C 1983 38 346. 43 A. R. Battersby E. McDonald and A. V. Stachulski J. Chem. Soc. Perkin Trans. 1 1983 3053. 44 D. S. Bhakuni S. Jain and R. Chaturvedi J. Chem. Soc. Perkin Trans. I 1983 1949. 45 L.-F. Tietze Angew. Chem. Int. Ed. Engl. 1983 22 828. 46 R. B. Herbert in ‘Indoles Part 4 The Monoterpenoid Indole Alkaloids’ ed. J. E. Saxton (Vol. 25 in the series ‘The Chemistry of Heterocyclic Compounds’ ed. A. Weissberger and E. C. Taylor) Wiley-Interscience New York 1983 p. 1. 47 J. Stockigt T. Hemscheidt G. Hofle P. Heinstein and V.Formacek Biochemistry 1983 22 3448. 48 A. Pfitzner and J. Stockigt Planta Med. 1983 48 221. 49 A. Pfitzner B. Krausch and J. Stijckigt Tetrahedron 1984 40 1691. 50 A. Pfitzner and J. Stockigt Tetrahedron Lett. 1983 24 5197. 51 J. Stockigt A. Pfitzner and P. J. Keller Tetrahedron Lett. 1983 24 2485. 52 H. Schiibel and J. Stockigt Plant Cell Rep. 1984 3 72. 53 A. R. Battersby M. Thompson K.-H. Gliisenkamp and L.-F. Tietze Chem. Ber. 1981 114 3430. 54 S. Uesato S. Matsuda and H. Inouye Chem. Pharm. Bull. 1984 32 1671. 55 J. Balsevich and W. G. W. Kurz Planta Med. 1983 49 79. 56 M. H. Brillanceau C. Kan-Fan S. K. Kan and H.-P. Husson Tetrahedron Lett. 1984 25 2767. 57 W. R. McLauchlin M. Hasan R. L. Baxter and A. I. Scott Tetrahedron 1983 39 3777.58 J. P. Kutney B. Aweryn L. S. L. Choi T. Honda P. Kolodziejczyk N. G. Lewis T. Sato S. K. Sleigh K. L. Stuart B. R. Worth W. G. W. Kurz K. B. Chatson and F. Constabel Tetrahedron 1983 39 3781. 59 J. Stockigt K.-H. Pawelka T. Tanahashi B. Danieli and W. E. Hull Heltl. Chim. Acra 1983 66 2525. 60 J. M. Merillon J. C. Chenieux and M. Rideau Planta Med. 1983 47 169; D. Neumann G. Krauss M. Hieke and D. Groger ibid. 1983 48 20. 61 T. Yoshida and K. Katagiri Biochemistry 1969 8 2645. 62 D. G. Reid D. M. Doddrell D. H. Williams and K. R. Fox Biochim. Biophys. Acta 1984 798 11 1. 63 J. V. Formica and M. J. Waring Antimicroh. Agents Chemother. 1983 24 735. 64 D. Gauvreau and M. J. Waring Can. J. Microbiol. 1984,30,439.65 A. E. de Jesus C. P. Gorst-Allman P. S. Steyn F. R. van Heerden R. Vleggaar P. L. Wessels and W. E. Hull J. Chem. Soc. Perkin Trans. I 1983 1863. 66 W. Acklin F. Weibel and D. Arigoni Chimia 1977 31 63. 67 Y. Yamazaki in ‘The Biosynthesis of Mycotoxins’ ed. P. S. Steyn Academic Press New York 1980 p. 210. 68 P. S. Steyn and R. Vleggaar J. Chem. SOC. Chem. Commun. 1983 560. NATURAL PRODUCT REPORTS 1985 69 D. M. Harrison and P. Quinn J. Chem. Soc. Chem. Commun. 1983 879. 70 D. M. Harrison and P. Quinn Tetrahedron Lett. 1983 24 831. 71 C. P. Gorst-Allman P. S. Steyn and R. Vleggaar J. Chem. Soc. Chem. Commun. 1982 652. 72 K.-H. van Pee 0.Salcher P. Fischer M. Bokel and F. Lingens J. Antihiot. 1983 36 1735. 73 C. J.Chang H. G. Floss D. J. Hook J. A. Mabe P. E. Manni L. L. Martin K. Schriider and T. L. Shieh J. Antibiot. 1981,34,555. 74 W. J. Gerwick S. J. Could and H. Fonouni Tetrahedron Lett. 1983 24,5445. 75 M. K. Speedie and D. L. Hartley J. Antibiot. 1984 37 159. 76 D. L. Hartley and M. K. Speedie Biochem. J. 1984 220 309. 77 W. Maier D. Erge and D. Groger FEMS Microbiol. Lett. 1983 20 233. 78 B. Kopp and H. J. Rehm Eur. J. Appl. Microbiol. Biotechnol. 1983 18 257. 79 R. Sieben U. Philippi and E. Eich J. Nut. Prod. 1984,47 433. 80 G. W. Kirby W. Losel P. S. Rao D. J. Robins M. A. Sefton and R. R. Talekar J. Chem. Soc. Chem. Commun. 1983 810. 81 G. W. Kirby D. J. Robins and W. M. Stark J. Chem. Soc. Chem. Commun. 1983 812. 82 R. B. Herbert and J.Mann J. Chem. Soc. Chem. Commun. 1983 1008. 83 D. W. Young in ‘Chemistry and Biology of Pteridines’ ed. J. A. Blair Walter de Gruyter and Co. Berlin 1983 p. 321. 84 M. Tanabe and S. Urano Tetrahedron 1983 39 3569. 85 A. G. McInnes D. G. Smith J. A. Walter L. C. Vining and J. L. C. Wright J. Chem. Soc. Chem. Commun. 1974 282; J. L. C. Wright L. C. Vining A. G. McInnes D. G. Smith and J. A. Walter Can. J. Biochem. 1977 55 678; E. Leete N. Kowanko R. A. Newmark L. C. Vining A. G. McInnes and J. L. C. Wright Tetrahedron Lett. 1975 4103. 86 S. Ohuchi A. Okuyama H. Naganawa T. Aoyagi and H. Umezawa J. Antibiot. 1984 37 518. 87 A. M. Becker A. J. Herlt G. L. Hilton J. J. Kibby and R. W. Rickards J. Antibiot. 1983 36 1323. 88 A.Romer and E. Lange Z. Naturforsch. Sect. C 1983 38 539. 89 A. Baumert I. N. Kuzovkina M. Hieke and D. Groger Planta Med. 1983 48 142. 90 A. Baumert M. Hieke and D. Groger Planta Med. 1983,48,258. 91 S. W. Queener and N. Neuss in ‘Chemistry and Biology of p-lactam Antibiotics’ ed. R. B. Morin and M. Gorman Academic Press New York 1982 Vol. 3 p. 1. 92 J. E. Baldwin E. P. Abraham R. M. Adlington B. Chakravarti A. E. Derome J. A. Murphy L. D. Field N. B. Green H.-H. Ting and J. J. Usher J. Chem. Soc. Chem. Commun. 1983 1317. 93 J. E. Baldwin E. P. Abraham R. M. Adlington J. A. Murphy N. B. Green H.-H. Ting and J. J. Usher J. Chem. SOC. Chem. Commun. 1983 1319. 94 J. E. Baldwin E. P. Abraham C. G. Lovel and H.-H. Ting J. Chem. Soc. Chem. Commun.1984 902. 95 S. K. Chung R. Shankaranarayan and A. I. Scott Tetrahedron Lett. 1983 24 2941. 96 R. L. Baxter G. A. Thomson and A. I. Scott J. Chem.Soc. Chem. Commun. 1984 32. 97 J. E. Shields C. S. Campbell S. W. Queener D. C. Duckworth and N. Neuss Heltl. Chim. Acta 1984 67 870. 98 C. J. Easton J. Chem. SOC. Chem. Commun. 1983 1349; C. J. Easton and N. J. Bowman ibid.,p. 1193; A. J. Beckwith and C. J. Easton Tetrahedron 1983 39 3995. 99 I. J. Hollander Y.-Q. Shen J. Hein A. L. Demain and S. Wolfe Science 1984,224,610; J. Kupka Y.-Q. Shen S. Wolfe and A. L. Demain Can. J. Microbiol. 1983 29 488. 100 R. M. Adlington J. E. Baldwin M. Lopez-Nieto J. A. Murphy and N. Patel Biochem. J. 1983 213 573. 101 Y.-Q. Shen J. Heim N. A. Solomon S.Wolfe and A. L. Demain J. Antibiot. 1984 37 503. 102 R. G. Kogekar and V. N. Deshpande Indian J. Biochem. Biophys. 1983 20 208. 103 A. Scheidegger M. T. Kiienzi and J. Nuesch J. Antibiot. 1984 37 522. 104 S. Kukolja S. W. Queener R. D. Miller D. C. Duckworth D. E. Dorman L. L. Huckstep and N. Neuss Heft.. Chim. Acta 1984 67 876. 105 J. E. Baldwin M. Jung P. Singh T.Wan,S. Haber,S. Herchen J. Kitchin A. L. Demain N. A. Hunt M. Kohsaka T. Konomi and M. Yoshida Philos. Trans. R. SOC. London Ser. B 1980 289 169. 106 J. D. Hood A. Elson M. L. Gilpin and A. G. Brown J. Chem. Soc. Chem. Commun. 1983 1187. NATURAL PRODUCT REPORTS 1985 107 E. Abraham C.-P. Pang R. L. White D. H. G. Crout M. Lutstorf P. J. Morgan and A.E. Derome J. Chem. Soc.. Chem. Commun. 1983 723. 108 K. J. Martinkus C.-H. Tann and S. J. Gould Tetruhedron 1983 39 3493. 109 T. K. Thiruvengadam S. J. Gould D. J. Aberhart and H.-J. Lin J. Am. Chem. Soc. 1983 105 5470. I10 J.-R. Fang C. J. Pearce and K. L. Rinehart Jr. J.Antihiot. 1984 37 77. 111 D. G. I. Kingston M. X. Kolpak J. W. LeFevre and I. Borup-Grochtmann J. Am. Chem. Soc. 1983,105,5106;J. W. LeFevre T. E. Glass M. X. Kolpak and D. G. I. Kingston J. Not. Prod. 1983 46 475. 112 W. Kohl H. Irschik H. Reichenbach and G. Hofle Liehigs Ann. Chem. 1984 1088.

ISSN:0265-0568    

DOI:10.1039/NP9850200163

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Pyrrolidine Piperidine and Pyridine Alkaloids A. R. Pinder Department of Chemistry Clemson University Clemson South Carolina 2963I USA Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of the literature in Natural Product Reports 1984 Vol. 1 p. 225) 1 Pyrrole and Pyrrolidine Alkaloids n-nonanoyl chloride Jo give 2-n-nonanoylpyrrole. This was 1.1 Sceletium Alkaloids subjected to Wolff-Kishner reduction then formylated by the 1.2 Spiropyrrolidine Alkaloids Vilsmsier-Haack method.* Funebrine is a pyrrole of novel 1.3 Bispyrrolidine Alkaloids structure (3) which occurs in the flowers of the Mexican tree 2 Piperidine Alkaloids Quararibea funebris (Llave) Vischer. Its structure has been 2.1 . Spiropiperidine Alkaloids settled by single-crystal X-ray diffraction analy~is.~ Several 2.2 Bispiperidine Alkaloids additional pyrrolidides have been isolated from species of the 3 Pyridine Alkaloids genus Achillea and their structures (4)revealed by spectroscopic 3.1 Nicotine Alkaloids study.6 Trichonine (5) which is an alkaloid of Piper trichosta- 3.2 Bispyridine Alkaloids chyon has been synthesized by application of a new diene 4 References synthesis (Scheme 2);' the elimination step (iii) is catalysed smoothly by molybdenum hexacarbonyl in the presence of N,O-bistrimethylsilylacetamide.The fourth volume of an encyclopaedia of alkaloids has appeared; it includes some bases in this group.' A review on the chromatography of alkaloids likewise covers many members of the family.* 1 Pyrrole and Pyrrolidine Alkaloids (3) Pyrrole has emerged as a structural feature in the alkaloid field.The pyrrole-2-carbaldehyde (1) is present in flue-cured to- bacco; it has been synthesized from L-leucine methyl ester hydrochloride as outlined in Scheme 1.3 In the last step R--0 t. racemization was prevented by exposure to a limited amount of base or by using trimethylsilyl iodide. 5-n-Nonylpyrrole-2- (4)a; R = Me[CH,],[CHLCH], carbaldehyde (2) has been isolated from a soft coral-sponge association. Its structure has been determined spectroscopi- b; R = Me[CH ,]?CH=kHC=C[CH2],[CHLCH] cally and confirmed by synthesis from pyrrole which was c; R = Me[CH?]2[CrC]2[CH2],[CH&H] converted into a Grignard reagent and then treated with d;R = MeCHCICH[C==C],[CH,],[CH~CH1 +NH Cl-l-3 I 2 QCHO /c qN>CH0 LC0,Me i ii ~ __j iii COIMe C0,Me CO,H Reagents i,1,4-dichloro-l,4-dimethoxybutane, Amberlyst A-21 resin at 0 "C; ii CH(OMe), TiCl,; iii Me,SiI or NaOH MeOH (I .2 equiv.) Scheme 1 + Me[CH2], '' Me[CH,I,,-C0,Me (5)[(E,E):(E,Z)12 11 = Reagents i piperidine MeCN ; ii Ac,O 4-dimethylaminopyridine; iii Mo(CO), 0,N-bistrimethylsilylacetamide,toluene; iv Me2A 1N , CH,Cl, for 48 hours Scheme 2 Manicoline B which occurs in the root bark of Dufacia guianensis (Engl.) 0.Ktze has been shown by X-ray diffraction analysis to be an equimolecular mixture of diastereoisomers represented by (6).* (-)-4-Hydroxypyrrolidin-2-one which occurs in the toadstool Amanita muscaria has been synthesized by a simple route which shows that it has the S configuration and not the R as assigned tentatively earlier.9 Vochysine is a pyrrolidinoflavan (7) found in the fruit of Vochysia guianensis (Aubl.) Poir.Its structure was arrived at by spectral and chemical study and confirmed by synthesis by the addition of 5,4'-dihydroxy-7-methoxyflavanto 1-pyrroline. 1.1 ScefefhnAlkaloids Two new syntheses of (+)-mesembrine have been reported. In the first the previously synthesized cyclobutanone (8) was oxidized by alkaline hydrogen peroxide to the lactone (9) which was in turn oxidized to ketone (10) by pyridinium chlorochromate. Refluxing (1 0) in ethanolic methylamine afforded the cis-octahydroindolone (1 l) which had earlier been transformed into (+)-mesembrine (12).l The second synthesis begins with 1-methyl-2-pyrrolidone (Scheme 3).The indolen- ine (13) is deaminated by nitrous acid to the hemiacetal (14) which on acetylation affords (15) possessing the mesembrane skeleton. 1.2 Spiropyrrolidine Alkaloids A total synthesis of (+)-polyzonimine (16) which is an alkaloidal insect repellent that is produced by the millipede Pofyzonium rosalbum has been published (Scheme 4). l4 Step vii involves a [2,3] sigmatropic rearrangement of an ammo- nium ylide that is derived from the quaternary ammonium benzenesulphonate. 1.3 Bispyrrolidine Alkaloids Hypercratine is a new alkaloid of the roots of Ruspofia hypercruterijbrmis M.R.;chemical and spectroscopic investiga- tions point to the bispyrrolidine structure (1 7). 2 Piperidine Alkaloids A review of the synthesis of 2,6-disubstituted piperidines includes a section on alkaloids of this type. A new piperidide (18) has been found in the underground parts of Achiffea figusticu,6 and has been formulated on spectroscopic evidence. An investigation into the human metabolism of pepper alkaloids has revealed that piperine is transformed into 5-(3,4- dihydroxypheny1)valeric acid piperidide (19) and its 4'-hydroxy-derivative (20) by most subjects but about 15% of the population produce 5-(3,4-dihydroxyphenyl)penta-2,4-dienoic acid piperidide (21).17 It has been established that wisanine (22) is a trans,trans-diene.I* The fruits of Piper fongum L.contain two new piperidides (23) and (24) named piperonaline and piperundecalidine respectively. The structure of piplar- tine (= piperolongumine) has been unequivocally settled as (25) by A'-ray-crystallographic analysis and by its synthesis in- volving the reaction between trans-3,4,5-trimethoxycinnamic anhydride and 5,6-dihydro-2( 1H)-pyrid~ne.~~ Earlier synthetic studies have been extended to enantiospeci- fic syntheses of (+)-and (-)-coniine via the intermediate oxazolopiperidine (26) which has also been converted in a similar fashion into (+)-and (-)-pinidhe (Scheme 5).21 A potentially general synthetic route to 2,6-disubstituted piperi- dine alkaloids has been devised; it involves a consideration of the stereochemistry of formation of A3-piperidines and their alumina-catalysed isomerization to A4-isomers.* * Racemic a-conhydrine is readily obtained by intramolecular regio- and stereo-specific ring-cleavage of the trans-azido-epoxide (27) (Scheme 6); (&)-P-conhydrine is similarly obtained from the cis-isomer (28).23 Another stereoselective synthesis of the NATURAL PRODUCT REPORTS 1985 CON H7 OH I-NK& Me0 WOH \ ,/ CH ,CON H 2 HN3 (7) OMe 0ALOH (9) H OMe OMe I 0 0 Me 0 0 Me OMe OMe Me H Me (12) Reagents i lithium N-cyclohexyl-N-isopropylamide, at -78"C then 4-bromoveratrole at 10°C;ii Bui,AIH then NaOH; iii methyl vinyl ketone Scheme 3 83 N Me H Me H racemic a-base is outlined in Scheme 7.24A new stereospecific synthesis of (+)-solenopsin A is outlined in Scheme 8; details are not yet available.25 The preferred conformations of a number of Sedum alkaloids in solution have been revealed by high-resolution IH and I3C n.m.r.spectroscopy.26 Six flavon- oid alkaloids of a novel type have been isolated from the leaves and fruit of Buchenazia macrophyllu and the seeds of B. capitata (Combretaceae). They are typified by buchenavianine (29) and their structures have been established by spectroscopic NATURAL PRODUCT REPORTS 1985-A. R. PINDER \/ 6O -+CO& A \OCH P h PhS0,-%NO2 xit xtv -fl (16) Reagents i NaH (EtO)lPOCH,COIEt DME reflux for 15 hours; ii polyphosphoric acid on silica gel CH,CIz; iii LiAIH,-AICl, diethyl ether at 0 "C for 1 hour; iv PBr, py at r.t.; v L-benzyloxyprolinol KzC03 DMSO for 15 hours at r.t.; vi PhS03CH2CN (3 equiv.) MeCN at 25-60 "C for 24 hours; vii KOBu' THF DMSO at -78 "C for 24 hours then CuS0,.5H20 EtOH for 10minutes; viii MeN02 KOH MeOH at r.t.for 1 hour; ix MeS02CI Et3N at r.t. for 1.5 hours; x NaBH, MeOH at 0-25 "C; xi O, CH2C1, PrOH at -78 "C then Me$ at -78 "C; xii (CH,OH), HC(OEt), toluene-p-sulphonic acid at 25 "C for 0.5 hour; xiii 3H2 Pt EtOH; xiv 10% HCl THF at 25 "C for 10 hours Scheme 4 0 (24) means.*' Various physicochemical studies on the cyclophane- type lythraceous alkaloids have been described. They indicate that in these bases there is a mobile equilibrium involving rotation about the C-C bond between the two benzene rings and a reversal (flip) of the piperidine ring.28 Full details of an earlier reported total synthesis of the racemic form of the monoterpene alkaloid tecomanine have been published.29 (-)-Mearsine is a unique isoquinuclidine alkaloid occurring in the Queensland plant Peripentadenia mearsii (C.T. White) L. S. Smith; X-ray crystallographic study allows its formulation as (30).30 2.1 Spiropiperidine Alkaloids The total synthesis of (+)-nitramhe (31) has been announced (Scheme 9).31The histrionicotoxin group continues to attract (20) R = OH 0 0 (25) attention. A new synthesis of (+)-depentylperhydrohistrioni-cotoxin has been reported32 and a new route to (*)-perhydrohistrionicotoxin has emerged (Scheme lo) the penul- timate product having been earlier converted into the lactam (32) which is a key intermediate in a reported synthesis of the target molecule.33 2.2 Bispiperidine Alkaloids Kopsirachine is found in the leaves of Kopsia dasyrachis Ridl. Its structure (33) settled by spectral and chemical investiga- tion represents a new type composed of a catechin and two skytanthine units.34 3 Pyridine Alkaloids Some synthetic studies in the area of simple pyridine alkaloids such as ricinidine and nudiflorine have been described.35 Two 184 NATURAL PRODUCT REPORTS 1985 RZ R'PoH R' \ R2 I R' NH2 (+)-Norephedrine (R' = Me R2 = Ph) or (-)-Phenylglycinol (R' = Ph R2 = H) (-)-(R)-Coniine (R = H) ii (-)-(2R,6S)-Dihydropinidine(R = R' R' ki "'0° -H V prY3=R (+)-(S)-Coniine (R = H) (+)-(2S,6R)-Dihydropinidine (R = Reagents i glutaric dialdehyde at pH 3.0; ii KCN at pH 3.0; iii AgBF, THF Pr"MgBr at 0 "C for 1 minute; iv NaBH, EtOH at 25-80 "C for 15 hours; v 70% H,SO, for 18 hours (for R' = Me R2 = Ph) or H2 Pd/C MeOH HCl for 15 hours (for R' = Ph RZ= H); vi LiNPrI2 THF at -78 "C Pr"Br for 3 hours Scheme 5 Iv (k)-0-Conhydrine (4 )-or-Conhydrine Reagents i LiAIH, diglyme; ii TsCI py at 0 "C; iii NaN3 DMSO at r.t.; iv m-chloroperoxybenzoic acid CH2C12 at 0 "C; v Ph3P THF H,O; vi toluene reflux for 30 hours Scheme 6 0 (+_)-or-Conhydrine Reagents i anodic 2-methoxylation; ii Ph,PCI AcOH; iii LiNPrl,; iv EtCHO; v heat; vi H2 (20 atm) PtO, AcOH for 7 hour; vii -OH Scheme 7 NATURAL PRODUCT REPORTS 1985-A.R. PINDER further syntheses of anibine have been reported. In one the dilithium salt of ethyl acetoacetate is condensed with ethyl -H CN nicotinate to generate a diketo-ester which is then elaborated COz( I PhCHzOzCN as shown in Scheme 11.36 In the other a ketene dithioacetal is SMe involved (Scheme 12).37Dinklageine (34) is a new type of monoterpenoid alkaloid ; its structure has been clarified by spectral analysis and confirmed along with its absolute stereochemistry by its synthesis from loganin (Scheme 13). It occurs in the leaves of Strychnos dinkfugei Gilg.38 n Me0 ? AN-".. c,I H23-n H (_+)-SolenopsinA CN Reagents i S=C' ; ii three steps 'SMe Scheme 8 iv v I 0-2.5 1 (separated by preparative g.c.) I viii H Reagents i EtAlCl, PhH at 25 "C for 20 hours; ii Na2C03 HzO heat; iii Pb(OAc), py at 25 "C for 2 hours; iv oximation; v NaBH3CN at pH 3; vi HCHO Na,SO (anhydrous) toluene at 0 "C vii reflux for 24 hours; viii Hz Pd EtOH Scheme 9 vC02Me C02Me C02Me -gBun -cJ;rMe -qBun +Bun NHCOCC13 NHCOCC13 0 OH iv v / 0 (32) (Thp = tetrahydropyran-2-yl) Reagents i 85-95 "C argon for 65 hours; ii HCI MeOH at 60 "C; iii NaBH, MeOH AcOH HzO at -20 "C; iv dihydropyran H+; v methoxycarbonylation ; vi 5% methanolic HCI heat Scheme 10 186 NATURAL PRODUCT REPORTS 1985 A high-field n.m.r.spectroscopic study of sesbanimide has confirmed its structure and stereochemistry ; in solution a solvent-dependent equilibrium exists between the cyclic OH hemiacetal and the y-hydroxy-ketone structure.39 Studies directed towards the synthesis of the alkaloid have been described.40 3.1 Nicotine Alkaloids A review of recent studies (conformational analysis chemical reactivity and theoretical modelling) in the chemistry of U nicotine and its congeners has a~peared.~' Both myosmine and (33) pseudo-oxynicotine exist in aqueous solution as equilibrium Reagents i 2 equiv.of LiNPr',; ii ethyl nicotinate TMEDA; iii heat at 150°C in vacuo; iv CH2N2 Scheme 11 SMe OMe $+ (MeS),C=C(CO,Me) - .-+ Anibine Reagents i KOH in DMSO; ii NaOMe heat; iii polyphosphoric acid at 100°C for 5 hours Scheme 12 OH ,OAc OAc ,OH OAc VI t- 'YH d 6 OH OH (34) Reagents i P-glucosidase at pH 6 at 37 "C for 2 hours; ii Ac20 py at r.t.for 48 hours; iii AcOH H,O at 80 "C for 10 hours; iv pyridinium chlorochromate CH,CI, at r.t. for 16 hours; v tyramine MeOH vi HCI MeOH heat for 1 hour Scheme 13 oNH2+irJ -S0,Me J. 0 .1 0 Nornicotyrine Reagents i C5H ,ONO AcOH at 75 "C; ii PBr, CHCI,; iii NaOH HzO dioxan Scheme 14 NATURAL PRODUCT REPORTS 1985-A. R. PINDER H (35) mixtures as a consequence of ring-chain tautomerism ; the systems have been investigated by ‘H and by 13C n.m.r. spectro~copy.~~ A new synthesis of nornicotyrine has been described (Scheme 14).43 Studies on the organometallic methylation of nicotine and its py-N-oxide have been continued .44 3.2 Bispyridine Alkaloids A new alkaloid isolated from the wood of Broussonetiu zeylundica has been shown on spectroscopic evidence to be 3,4’-dihydroxy-2,3’-bipyridine (35).45 4 References 1 J.S. Glasby ‘Encyclopaedia of the Alkaloids,’ ed. Vol. 4 Plenum Press New York 1983. 2 ‘Chromatography of Alkaloids’ (Journal of’ Chromatography Library Vol. 23A) Part A Thin Layer Chromatography A. B. Svendsen and R. Verpoorte Elsevier Amsterdam 1983. 3 T. H. Chan and S. D. Lee J. Org. Chem. 1983 48 3059. 4 B. F. Bowden P. S. Clezy J. C. Coll B. N. Ravi and D. M. Tapiolas Austr. J. Chem. 1984 37 227. 5 R. F. Raffauf T. M. Zennie K. D. Onan and P. W. Le Quesne J. Org. Chem. 1984 49 2714. 6 H. Greger C. Zdero and F. Bohlmann Phytochemistry 1984 23 1503.7 B. M. Trost M. Lautens and B. Peterson Tetrahedron Lett. 1983 24 4525. 8 J. Polonsky T. Prange C. Pascard H. Jacquemin and A. Fournet Tetrahedron Lett. 1984 25 2359. 9 E. Santaniello R. Casati and F. Milani J. Chem. Res. (S) 1984 132. 10 G. Baudouin F. Tillequin M. Koch M. Vuilhorgne J.-Y. Lallemand and H. Jacquemin J. Nut. Prod. 1983 46 681. 11 P. W. Jeffs R. Redfearn and J. Wolfram J. Org. Chem. 1983,48 3861. 12 K. S. Kochhar and H. W. Pinnick Tetrahedron Lett. 1983 24 4785. 13 J. Levy and F. Sigaut Tetrahedron Lett. 1983 24 4983. 14 T. Sugahara Y. Komatsu and S. Takano Heterocycles 1984 21 551 ; J. Chem. Soc. Chem. Commun. 1984 214. 15 G. Neukomm F. Roessler S. Johne and M. Hesse Planta Med. 1983 48 246.16 V. Baliah R. Jeyaraman and L. Chandrasekaran Chem. Rev. 1983 83 379. 17 C. Holzel and G. Spiteller Liehigs Ann. Chem. 1984 1319. 18 S. K. Okwute J. I. Okogun and D. A. Okorie Tetrahedron 1984 40,2541. 19 W. Tabuneng H. Bando and T. Amiya Chem. Pharm. Bull. 1983 31 3562. 20 P. M. Boll J. Hansen 0.Simonsen and N. Thorup Tetrahedron 1984 40,171. 21 L. Guerrier J. Royer D. S. Grierson and H.-P. Husson J. Am. Chem. Soc. 1983 105 7754. 22 M. Bonin J. R. Romero D. S. Grierson and H.-P. Husson J. Org. Chem. 1984 49 2392. 23 S. Pilard and M. Vaultier Tetrahedron Lett. 1984 25 1555. 24 T. Shono Y. Matsumura and T. Kanazawa Tetrahedron Lett. 1983 24 4577. 25 M. Ogawa and M. Natsume Heterocycles 1984 21 769. 26 B. Colau C.Hootelt and D. Tourwe Tetrahedron 1984 40,2171. 27 A. Ahond A. Fournet C. Moretti E. Philogene C. Poupat 0. Thoison and P. Potier Bull. SOC. Chim. Fr. Part 2 1984 41. 28 K. Fuji T. Yamada E. Fujita K. Kuriyama T. Iwata M. Shiro and H. Nakai Chem. Pharm. Bull. 1984 32 55; K. Fuji T. Yamada E. Fujita H. Nakai and M. Shiro ibid.,p. 63; K. Fuji T. Yamada and E. Fujita ibid. p. 70. 29 T. Imanishi N. Yagi and M. Hanaoka Chem. Pharm. Bull. 1983 31 1243. 30 G. B. Robertson U. Tooptakong J. A. Lamberton Y. Geewan-anda P. Gunawardana and I. R. C. Bick Tetrahedron Lett. 1984 25 2695. 31 B. B. Snider and C. P. Cartaya-Marin J. Org. Chem. 1984 49 1688. 32 W. Carruthers and S. A. Cumming J. Chem. Soc. Perkin Trans. I 1983 2383. 33 T.Ikuba H. Minakata Y. Mitsui K. Hayashi T. Taga and Y. Inubushi Chem. Pharm. Bull. 1982 30 2840; T. Ibuka H. Minakata M. Hashimoto L. E. Overman and R. L. Freerks Heterocycles 1984 22 485. 34 K. Homberger and M. Hesse Helv. Chim. Acta 1984 67 237. 35 J. Becher T. Johansen and M. A. Michael J. Heterocycl. Chem. 1984 21 41. 36 N. S. Narasimhan and R. Ammanamanchi J. Org. Chem. 1983 48 3945. 37 Y. Tominaga Y.Matsuda and G. Kobayashi Chem. Pharm. Bull. 1984 32 1665. 38 A. L. Skaltsounis S. Michel F. Tillequin and M. Koch Tetrahedron Lett. 1984 25 2783. 39 C. P. Gorst-Allman P. S. Steyn R. Vleggaar and N. Grobbelaar J. Chem. Soc. Perkin Trans. I 1984 1311. 40 M. J. Wanner G.-J. Koomen and U. K. Pandit. Heterocycles 1984 22 1483; G.W. J. Fleet and T. K. M. Shing J. Chem. Soc. Chem. Commun. 1984,835; K. Tomioka and K. Koga Tetrahedron Lett. 1984 25 1599. 41 J. I. Seeman Heterocycles 1984 22 165. 42 S. Brandange and B. Rodriguez Acta Chem. Scand. Ser. B 1983 37 643; S. Brandgnge L. Lindblom A. Pilotti and B. Rodriguez ibid. p. 617. 43 S. Saeki T. Hayashi and M. Hamana Heterocjdrs 1984 22 545. 44 J. I. Seeman H. V. Secor C. R. Howe C. G. Chandarian and L. W. Morgan J. Org. Chem. 1983 48 4899. 45 A. A. L. Gunatilaka M. U. S. Sultanbawa S. Surendrakumar and R. Somanathan Phytochemistry 1983 22 2847.

ISSN:0265-0568    

DOI:10.1039/NP9850200181

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Book Reviews Dictionary of Organic Compounds (Fifth Edition) First and Second Supplements ed. J. Buckingham; 1983 and 1984; Chapman and Hall London/Methuen Inc. New York/Methuen Publications Toronto; [First Supplement] xi + 796 pp; f 110; ISBN 0-412-17010-8; [Second Supplement] xi + 803 pp; f 110; ISBN 0-412-17020-5 The Dictionary of Organic Compounds (Heilbron) is a valuable compendium which has withstood the test of time since it was first published in 1934. It provides in an easily accessible form some useful references to the literature concerning many of the more important organic compounds together with source and physical data. The fifth edition of the Dictionary of Organic Compounds was published in October 1982 with entries covering the literature up to 198 1.Of the approximately 50 000 entries covering about 150000 compounds about 12 000 concerned natural products. As with the previous edition which was published in 1965 a series of annual supplements are being produced. Two covering 1982 and 1983 respectively have so far appeared. The entries in these supplements are of two types -some updating and replacing earlier entries whilst others are completely new. The first supplement contains 4300 entries and the second over 3000 entries. These contain information on the source of the compound related com-pounds structure physical data and literature references including those to spectroscopic data. Each supplement contains name molecular formula and CAS Registry Number indexes. These indexes are cumulative thus allowing access to entries in all of these supplements via the indexes in the most recent volume.In a dictionary of this type selection must inevitably reflect some arbitrariness on the part of the editors. There are a number of criteria by which these supplements could be judged. For example how representative is the selection of items and how generally useful are they? How easy are the supplements to use and how apposite and accessible are the literature references? A natural product chemist may well judge these in the light of different personal prejudices compared to a physical organic chemist. In terms of the coverage of natural products that of terpenoids and steroids is on the whole good. The formulae are accurately drawn.However some of the literature references are not always the most useful or the most recent. For example quite a lot of interest in 1982 centred on the trichothecene anguidine (diacetoxyscirpenol) as a possible tumour inhibitor. It was possible to locate this compound easily through the index under anguidin (no ‘e’) but the latest literature reference was 1976. Since this compound is one of the more readily accessible trichothecenes it was utilized in synthetic work in 1980-1982 (references in Tetrahedron Lett. J. Am. Chem. Soc. and J. Org. Chern.) there was a structure- activity study reported (J. Med. Chern.) in 1982 and also a review (Heterocycles)and chapters in a book (1983). For clarity the entries are often grouped under the least highly hydroxylat- ed or least substituted member of a series and hence the use of the index is an important aspect in tracing a compound in the supplements.Oxygen heterocyclic natural products are another area that are well covered. However alkaloids are rather more sparsely covered. There are entries for many of the compounds in the arachidonic acid cascade such as the leukotrienes prostacyclins thromboxanes and the HPETE derivatives. Carbohydrates and peptide hormones are also covered. The literature references are on the whole accurate although I did find one to J. Chem. Soc. Perkin Trans. I 1966 which rather predates the renaming of Section C of J. Chem. Soc. as Perkin Trans. 1. The synthetic aspects of natural product chemistry seemed to be rather less well served -partly because many reagents are organometallic and will presumably be covered in a separate dictionary.For example the first review of 1981 in Synthesis concerned the use of diethyl azodicarboxylate in the synthesis of natural products but there is no entry for this reagent in either of the supplements or in the main dictionary. Eschenmo- ser’s salt [dimethyl(methylene)ammonium iodide] which has had several useful synthetic applications was another missing example from both the dictionary and the supplements. Nevertheless the natural product chemist will find these supplements an invaluable adjuct to the main Dictionary of Organic Compounds in a departmental reference library. Not only do they maintain the high standard of presentation of the Dictionary of Organic Compounds but more important they keep it up-to-date.J. R. Hanson The Chemistry of Natural Products ed. R. H. Thomson; 1985; Blackie Glasgow and London; xii + 467 pp; f46.00; ISBN 0-216-91595-3 [Distributed in the USA by Chapman and Hall in association with Methuen Inc. New York; ISBN 0-412-00551-41 If nowhere else the reviews in Natural Product Reports attest to how much work is being done on the chemistry of natural products. So my first reaction on picking up this book was to wonder how many volumes there were in the series. But no this is a single-volume work covering progress on the chemistry of natural products over the past ten years. As to be expected the approach then is to highlight the main areas of progress and this is done in 467 pages.By choice the emphasis is on structure chemistry and synthesis but the emphasis varies quite markedly from chapter to chapter. Deliberately very little on biosynthesis is included although again there are variations in how much is dealt with in individual chapters. A broad survey of carbohydrates (J. A. Brimacombe) constitutes the first chapter. This is made up of a clear account of the application of protecting groups in synthesis a comprehensive review of the fashionable use of monosacchar- ides as ‘chiral templates’ for the elaboration of other natural products and surveys of the synthesis of oligosaccharide chains of glycoconjugates and the structure determination of poly- saccharides.The second chapter (E. J. Thomas) deals with aliphatic compounds and has a very heavy emphasis on synthesis. The syntheses outlined appear in attractive schemes with listed reagents which make instructive reading. There is provided a feast of different syntheses drawn from those of various antibiotics pheromones leukotrienes prostaglandins insect pheromones and marine natural products. A description of the origins and structures of interesting new aromatic compounds with some syntheses constitute Chapter 3 (T. J. Simpson). There is welcome inclusion of some biosynthe- tic information but in any case the rich variety of different structures provided are there for biosynthetic and synthetic speculation by the reader. Chapter 4 (J.R. Hanson) is concerned with a well-balanced overview of progress in all aspects of the study of terpenoids. Chapter 5 (B. E. Marples) is about the reactions of steroids (which includes an interesting section on rearrangement reactions) and the partial and total synthesis of steroids (which includes biomimetic syntheses). An entertaining and scholarly account under the heading of peptides forms the next chapter (B. W. Bycroft and A. A. Higton) which includes amino-acids atypical peptides (also including modified peptides like the P-lactam antibiotics) and typical peptides and proteins. Useful biochemical background is provided. A fascinating collection of new alkaloid structures organized along biosynthetic lines largely constitutes the next chapter (I.R. C. Bick). A nicely representative review on the very important nucleosides nucleotides and nucleic acids with NATURAL PRODUCT REPORTS. 1985 heavy emphasis on synthesis forms Chapter 8 (J. B. Hobbs). A very readable review on porphyrins (A. H. Jackson) which is useful to the general and specialist reader forms the last chapter. The index appears to work satisfactorily and each chapter has a good collection of references. The book is very well illustrated and produced. Sadly the price will exclude the private purchaser. There is much interesting chemistry in this collection of reviews. They certainly make informative and interesting reading. The accounts are by design not comprehensive. For comprehensive reviews one must look elsewhere (e.g.Natural Product Reports!). The book appears to be aimed very much at the specialist chemist with little concession to the non-specialist. I am sorry that in general I shall not easily be able to recommend the book for even advanced undergraduate reading. However the editor and his team are to be congratulated on producing a book which succeeds in presenting highlights from a decade of research in natural product chemistry. R. B. Herbert Phytochemical Methods -A Guide to Modern Techniques of Plant Analysis (2nd edition) J. B. Harborne; 1984; Chapman and Hail London and New York; xii + 288 pp; f17.50; ISBN 0-412-25550-2 Phytochemistry is concerned with the identification of the wide range of compounds which occur in plants. The subject deals not only with their structure and biosynthesis but also with their distribution and biological role.Central to these studies are the various methods which are used for the separation purification and identification of the constituents of plants. It is the object of this book to provide an introduction to the current methodology for the separation and identification of known plant constituents. It does not aim to provide a critical review of structural methods in natural product chemistry. This is the second edition of a succes_sful and authoritative book which was first published in 1973. In the intervening years there have been a number of advances in chromatogra- phic techniques such as the application of high-pressure liquid chromatography and in spectroscopic techniques particularly in n.m.r.spectroscopy. Hence there is a need for a new edition. The book like its predecessor takes the form of a laboratory manual with many useful experimental procedures described in sufficient detail that they can be followed without further recourse to the literature. This is particularly true of the many chromatographic systems that are described. The first introductory chapter is devoted to a general description of various separation techniques and characteriza- tion methods. A new feature is a useful flow diagram of a general procedure for extracting constituents from fresh plant tissue. With a rapidly developing subject some statements inevitably become dated -for example that h.p.1.c.has yet to prove itself for separation on a preparative scale. The necessarily brief treatment of the underlying physical basis of spectroscopic techniques could lead to misunderstandings e.g. that ions are accelerated by the magnetic field in a mass spectrometer. In the section on the criteria for phytochemical identification there is no mention of optical rotation. However the situation does arise particularly in the terpenoid area that enantiomers may occur. Nevertheless this chapter is very useful in terms of the methods of approach that it outlines. The second chapter is a substantial treatment of plant phenols -an area with which the author has considerable first- hand experience. Here chromatographic methods of separation and ultraviolet methods of detection are thoroughly covered and some helpful experimental details are given.A new section has been included on the tannins. The third chapter on the terpenoids has been updated in several aspects -for example with reference to the methods for handling the gibberellins and the carotenoids. The next chapter is devoted to the detection of organic acids and lipids. The omission of some plant acids such as tiglic and angelic acids presumably because of the pressure of space is nevertheless a pity particularly because these are often found as esters of other natural products. The terpenoid chemist may for example be seeking methods of separating and identifying the constituents of a hydrolysate of terpenoid esters. The fifth chapter deals with nitrogen compounds and includes sections not only on the determina- tion of alkaloids but also on plant amino-acids cyanogenic glycosides purines pyrimidines and chlorophyll.Chapters on sugars and finally macromolecules complete the book. There are a number of modifications to both chapters including some additional experiments on the isolation of nucleic acids from plants. Two appendices list recommended t.1.c. systems for the major classes of natural product and some addresses of suppliers of apparatus and chemicals. Each chapter has a useful and up-to-date list of general references and supplementary material giving an introduction to the specialist literature. The book is well-indexed and each chapter is clearly divided into subsections so that individual groups of compounds may be readily traced. The book is relatively free from trivial typographical errors although a few do exist -for example on page 24 a missing ‘minus’ sign makes nonsense of the relationship between T and 6; on page 41 orcinol is described as 6-methylresorcinol although the formula is correctly given on page 40;and thirdly a very curious formula is given for diosgenin on page 125. In conclusion this book can be highly recommended as a laboratory manual and as an introductory guide to all who become involved in the isolation chromatographic separation and identification of substances from plants. J. R. Hanson

ISSN:0265-0568    

DOI:10.1039/NP9850200189

出版商:RSC    

年代:1985

数据来源: RSC