摘要:

2 The Classical Prostaglandins and their Analogues 2.1 General Several review articles5-l0 have appeared in which the different synthetic strategies that lead to the classical prostaglandins i.e. those of the A B C D E F and J series are analysed in detail. The heyday for declaring new synthetic strategies is now over having petered out perhaps in the late 1970’s. However it has become apparent during the past few years that a number of former seemingly intransigent tactical problems are now on the verge of being solved. Moreover perhaps due to forthcoming problems of registration greater emphasis is now placed upon those chiral syntheses that lead to optically pure end-products. 2.2 Prostaglandin Intermediates During the past two decades a variety of ingenious synthetic approaches to substituted cyclopentenones have been reported.This is mainly because they are valuable precursors via a 1,4- conjugate addition reaction (see below) of the natural prosta- glandins E (PGE’s) and of the 11-deoxy-PGE series both of which possess potent anti-ulcer properties. Two new routes to the cyclopentenone (2) have been re- ported11.12 (Scheme 2). A common feature is the attack of a stabilized carbanion upon an electrophile to generate a keto- aldehyde of the type (I) which cyclizes when it is treated with a base. Workers at Syntex have reported13 that allylic hydroxylation of the enone (4) is best achieved by solvolysis of the bromide (5) with silver oxide (Scheme 3). The remaining and as yet unsolved problem with this-approach to the natural series of prostaglandins resides in the random nature of the initial free-radical bromination reaction.A simple multi-gram procedure for the direct selective allylic hydroxylation of (4) would be of enormous synthetic value. Two routes to the trione (6) (Scheme 4) which is another OH NATURAL PRODUCT REPORTS 1988 well-used intermediate in the conjugate-addition approach to prostaglandins have been described by Chadha and co-workers.14 Enzymic methods whereby one enantiomer in a racemic mixture is selectively transformed into an easily separable chiral product are becoming increasingly popular 153 16.41 especially since hydrolytic enzymes are comparatively easy to handle. Laumen and Schneider,15 for example have disclosed in their synthesis of the important chiral lactone (9) that the prochiral diacetate (7) could be enzymically hydrolysed to (8) on a multi-gram scale (Scheme 5).Russian chemists1’ have converted the lactone (9) via a regioselective Prins reaction into the precursor (10) of the Corey aldehyde. Their improvement lies mainly in the selective tritylation of the primary alcohol function since this overcomes the need for a selective Pfitzner-Moffat or chlorine-thioanisole oxidation which was necessary in the original (1976) Hungarian procedure. Collington and co-workersl* have adopted a similar approach in their synthesis of prostaglandin D,. Workers at Salford University and at Glaxo have publish- ed19 the full paper concerning the microbial reduction of the racemic ketone (1 1) (Scheme 6).By using actively fermenting baker’s yeast (Saccharomyces cerevisiae) they obtained a mixture of the chiral endo- and em-alcohols (12) and (13) respectively which could be readily separated either by distillation or by column chromatography. These compounds are chiral precursors of the tricyclic intermediate (14) and the versatile ketal-epoxide (1 5). The steric and electronic factors that affect the cleavage of epoxides of the type (15) with organometallic reagents have recently been investigated in some detail.,O Italian chemists have described21 an elegant approach to the hemi-acetal (20) which is a potential intermediate in the synthesis of prostaglandin FZa (Scheme 7).Base-induced cyclization of the readily available y-keto-ester (16) led directly to the cyclopentanedione (17) in 98% yield. Following its 0 0 (1) (2) (X=C0,Me or CH,OThp) vii ,viiir” Tos HC-I [CH2]$Thp I % [1>[CH2I2-7- To s I [CH 3 OThP 28 Br [CH 23 6:)\o NC NC (3) (Thp= tetrahydropyran -2 -yl) Reagents i OHC[CH,],CO,Me AmberlysP A-21 resin; ii pyridinium chlorochromate; iii Bu,SnH; iv acetone H’; v MeONa MeOH; vi NaH (3); vii H+; viii dihydropyran Scheme 2 420 -fiR HO (4) Br (5) ( R = CH,CH,OAc) Scheme 3 NATURAL PRODUCT REPORTS 1988-T. W. HART Br[CH2]pThpI*++) /, A H,C [CH2],C=C[CH2]PThp Reagents i HC=C[CH,],CH(OH)CH,; ii pyridinium chlorochromate; iii H,; iv (CO,Et), NaOEt ; v HCEC[CH,],CHO base; vi Hg2+ H,O; vii MeOH H+ Scheme 4 I I (7) (8) OH L-PhC,H,O (10) Reagents i porcine liver esterase [carboxylesterase] ;ii MeC(OEt), hydroquinone at 140 "C ; iii KOH MeOH; iv HCI; v toluene-p-sulphonic acid THF; vi [HCHO], HC0,H ;vii hydrolysis viii Ph,CCl pyridine ;ix 4-PhC,H9C(O)C1; x toluene-p-sulphonic acid HOAc Scheme 5 HO .-b-A bakers ' OR (14) (13) Scheme 6 EtOr I II I\ o@v o&v -@v H3C C0,Et CO Et CO Et 00 0 C02Et 0 0 0 uo U (16) (171 (18) (19) OMe C0,Et C0,Et Oez B*d (20) Reagents i LiNPr' (3 equivalents) at 20 "C; ii HOCH,CH,OH H+;iii H,SO, SO, CH,Cl,; iv MeOH BF Scheme 7 conversion into the bis-ketal (18)’ the ketal further from the ester group was then unmasked in quantitative yield with sulphuric acid and silica gel in methylene chloride.Thereafter (19) was transformed into (20) by using standard methodology. An interesting route to the key norbornanone intermediate (21) has been reported by Fickes and Glass22 (Scheme 8) and the utility of the norbornadiene route has been further extended by the Salford-Glaxo group,23 who have prepared the versatile aldehyde (25) in five steps from 7-t-butoxy-8,9,lO-trinorborna-diene (22) (Scheme 9). A key feature of their synthesis was the peracid-mediated oxidation of (23) to the cyclic enol ether (24). Many of the selective reducing and oxidizing agents that are now commercially available first found application in prosta- glandin chemistry.Similarly the polyhydroxylic nature of the prostaglandins not only accelerated the development but in many instances was the raison d’etre for many new alcohol- protecting groups. L~mbardo~~ has reported an improved procedure for the introduction of the t-butyldimethylsilyl (TBDMS) protecting group by using ethyldi-isopropylamine as base while the t-butylmethoxyphenylsilyl(TBMPS) group has been as having a remarkable lability to fluoride NATURAL PRODUCT REPORTS 1988 ion. By judicious choice of conditions it is now possible to remove either of these silyl groups from a protected molecule in the presence of the other. Ogawa and Shibasaki have demonstrated26 that diethylaluminium chloride removes a tetrahydropyranyl protecting group in the presence of a TBDMS group.A milder method for achieving this particular selective deprotection would be of great general value to synthetic organic chemists. The 13,14-didehydro-prostaglandins,while retaining most of the biological activity of their natural counterparts are not substrates for the ubiquitous metabolizing enzyme prosta- glandin 15-dehydrogenase. However isolation of the bio-logically active (1 59-epimer usually entrapped in a mixture with its chromatographically identical (1 5R)-epimer has been a perennial problem for medicinal chemists. Fried and 0-Yang have recently discoveredz7 that the stable diastereoisomeric complexes between these epimers and cobalt octacarbonyl are easily separated by chromatography (Scheme 10). The desired optically pure isomer is then regenerated by simple oxidation of the cobalt complex.In a complementary approach Midland and co-workers at the University of California have demon- strated2* that chiral acetylenic alcohols of the type (26) CI CH20Me MeOCH,-MeOCH + (OAC ’ -& Cl’ r3L ‘?1) 0 CL OThp Scheme 8 OSi Me But OSi Me But C5H11 (22) (23) vii,v +HO J I ButMe2Si0 6Si Me2B> Reagents i HCl Et,O; ii BrMgCrCCH(OSiMe,But)C,H,,; iii Bu,N+ F-; iv LiAlH,; v Bu‘Me2SiC1;vi CH,CO,H; vii H,Ot Scheme 9 HO HO. C02H C=C-CHC,H, f-Hd I Hd OH (co),co-co OH Reagents i Co,(CO), Et,O; ii Fe(NO,) or (NH,) [Ce(NO,),] Scheme 10 NATURAL PRODUCT REPORTS 1988-T. W. HART (Scheme 11) can now be easily prepared from the corresponding of (28) with alkyl allylic or propargylic halides has not yet ketone by treatment with Alpine-BoraneB or NB-Enantranem.been achieved. This is due in part to the unreactivity of the Occasionally the stereochemistry of a hydroxyl group needs enolate that is generated but mainly to its propensity to to be inverted. To this end chemists at Teikyo University have isomerize under forcing conditions and so eliminate the 1 1-oxy developed29 an improved procedure for inverting secondary function regardless of the protecting group. However it appears alcohols viu the corresponding mesylates by heating with that after ten years and much concerted effort the groups at caesium acetate complexed with 18-crown-6 in refluxing Nagoya University and Teijin Ltd.are now close to a solution. benzene (Scheme 12). Entries into the D E and F series of prostaglandins have been achieved by trapping the enolate (28) with a suitably derivatized aldeh~de~l~~~ forming adducts such as (29) or nitro-~lefin,~~ (30) and (31). Removal of the unwanted nitro-group or alcohol 2.3 Syntheses of Prostaglandins function from (29) or (30) after each had been converted into The ‘three-component coupling process’ (Scheme 13)30 is a the thiobenzoate was accomplished with tributyltin hydride procedure in which the C(12)-C(13) bond is formed by an while dehydration of the 7-hydroxy-PGE1 derivative (3 1) led to initial conjugate addition reaction of an w-side-chain to an em-enones of the type (32) which exhibit potent inhibitory enone of the type (27) and the resulting enolate (28) is then activity on the growth of L1210 tumour cells in ~itr-0.~~ trapped in situ with an alkylating agent.By employing chiral In a highly imaginative approach Fuchs and other workers reagents this strategy becomes one of the most elegant and at Purdue University have completed35 a stereoselective economic routes for the synthesis of prostaglandins. Trapping synthesis of prostaglandin E, starting from racemic (33) HCECCHR HCECCR -& HCGCFHR 3 II I OH 0 bH ( 26) Reagents i Jones reagent ;ii (8-Alpine-BoraneB (B-isopinocampheyl-9-borabicyclo[3.3.llnonane) or NB-Enantrane@ (nopol benzyl ether-9- borabicyclo[3.3. llnonane adduct) Scheme 11 ?< .. dBZ OH oez I OAc Reagents i mesylation;ii CsOAc 18-crown-6 benzene Scheme 12 PGE methyl ester 6-keto-PGF1,.methyl ester (29) OH bPGE methyl ester R’d ( 27) 0 2 = ButMezSi ,.R = -CH=CH$HC,H, Reagents i H,C=C(NO,)[CH,],CO,Me; ii OHCC-C[CH,],CO,Me; iii OHC[CH,],CO,Me Scheme 13 NATURAL PRODUCT REPORTS 1988 2 R1 = SiMe2But R =-CH=CHCHC,H, OSi MeZBu' R3= -CH,CH&H[CHA,CO,Me Reagents i peracid; ii R'Li; iii ICH,CH=CH[CH,],CO,Me; iv BF; Et,O [HCHO] Scheme 14 .. (38) lXIi PGE. 0y C02Et MeOCH,O R (AP4c5H'1 lxiii Hd OH (37) Reagents i Li [Cu(CN)R]; ii Bu'OOH ~(O)(acac),]; iii CrO, pyridine; iv LiNPr', Et3SiC1; v Li(CNCu[CH,],OSiMe,) then KF at pH 7 EtOH; vi 0, PtO,; vii HF MeCN; viii L-Selectride@ (LiBHBu",); ix LiAlH,; x MeOCH,Cl NEtPr',; xi EtO,CCHN, CuSO,; xii Et,N+ F-;xiii lithium cis,cis,trans-perhydro-9b-boraphenalyl hydride THF Scheme 15 (Scheme 14).A key feature was their strategic deployment of diene monoepoxides. In their second route the epoxide moiety an exo-sulphone group to stabilize the carbanion in (34) so that of (36) was first converted into the cyclopropyl ether (38) by it could be alkylated in situ with an iodinated side-chain. reaction with ethoxycarbonylcarbene. Fluoride-ion-induced Following some manipulations of functional groups which ring-opening then yielded the ketone ester (39) which upon included a novel Polonovski-like method for the conversion of reductive cyclization produced the versatile prostaglandin a tertiary amine into a secondary amine prostaglandin E was precursor (40).obtained in an outstanding overall yield of 14%. Two elegant routes to prostaglandins of the E and F series starting from the same intermediate (36) (Scheme 15) have 2.4 Prostaglandin Analogues been described by Marino et aZ.45In their first approach to the In 1982 Nokami and co-workers at Okayama University prostaglandins E and FIa and to the bronchodilator 1 -hydroxy-discovered that the 'conjugate addition 'route to prostaglandins methyl-1 -decarboxyprostaglandin E (37). they exploited the could be accomplished by using sulphur-stabilized lithiated ability of cyanocuprates to effect a 1,4-addition with cyclic 1,3- carbanions. More recently36 they have prepared the 10-oxa- NATURAL PRODUCT REPORTS 1988-T.W. HART OH (42) Reagents i R'Li; ii R21 Scheme 16 &-CHZCH H ( R = [CHJ6C02Me 1 Scheme 17 Reagents :i H,CC(O)CH,CO,Et base; ii Me$,; iii CF,CO,H benzene; iv NaBH,(CN) ;v PhS(O)C(=CH,)C(O)C,H, ;vi (MeO),P. toluene heat; vii reduction Scheme 18 analogue (42) of prostaglandin E by trapping the lithiated number of elegant routes to the 1 1 -deoxy-prostaglandins using enolate (41) with a propargylic iodide (Scheme 16). Research this methodology (Scheme 17).38*39 groups led by Mel'nikova and Pivnitskii,' have demonstrated In a theme heavily laden with sulphur chemistry chemists at that the ability of these reagents to effect the 1,4- as opposed to Sheffield University40 have deployed sulphoxides to fabricate the 1,2-addition reaction increases with the oxidation state of the acyclic C(lFC(12) skeleton to cyclize it and finally to the sulphur.These workers have subsequently developed a attach the w-side-chain (Scheme 18). NATURAL PRODUCT REPORTS 1988 viii-xii i1 HO XVI ,xvii- Rdk l O R ROh:ZR C H,OR CH,OR RO Rd (45) ( R= Si Me2But) Reagents i porcine liver esterase; ii ClC(O)C(O)Cl ;iii NaBH ;iv toluene-p-sulphonic acid toluene heat ;v 0,; vi MeOH H+ ;vii ButOK ; viii NaBH,; ix KOH H,O THF; x B,H,; xi Bu‘Me,SiCl; xii LiNPr’,; xiii [Mo(O)(O,),(pyridine)(HMFT)J(‘MoOPH’) or 0 and (MeO),P; xiv LiAlH,; xv NaIO,; xvi MeSO,Cl pyridine; xvii Et,N Scheme 19 OH Reagents i NaOCI CH,Cl, Et,N Scheme 20 Reagents i see J. Am Chem. SOC.,1960 82 5339; ii Bu‘,AlH; iii Raney nickel; iv Rexyn 300@ [a mixed acid-base ion-exchange resin] Scheme 21 OCH MeOEt OH Methylenomycin A J/xii xiii 0.CO,H I OH OH (L8) Reagents i MeI KHCO, DMF; ii acetone cyanohydrin Na,CO, MeCN; iii NaBH,; iv EtOCH=CH,; v Bu’,AlH; vi Ph,P=CH[CH,],- C0,Na; vii CH,N,; viii Collins reagent; ix Bu,P=CHC(O)C,H,,; x NaBH,; xi HOAc H,O; xii NaOH H,O MeOH; xiii BF Scheme 22 exo-Methylene derivatives of the type (45) and (46)(Schemes 19 and 20) which were originally prepared via an enolate- trapping approach by Stork and Isobe in 1975 are valuable intermediates in the synthesis of prostaglandin analogues in which the a-side-chain is modified. Two new routes for their preparation have recently been described. In most elegant fashion Gais and co-worker~~~ have synthesized the versatile chiral building block (44)from meso-tetrahydrophthalic an-hydride via selective enzymic hydrolysis of the dimethyl ester (43) (Scheme 19).The conversion of (44) into the key prostaglandin intermediate (45) was cleverly achieved by using direct methodology. An intramolecular cycloaddition of a NATURAL PRODUCT REPORTS 1988-T. W. HART Pr'o2C \ --co2pr1 (49)C02Pr' C02 H 3-CSH 11 OH H L/ \ \r C02Pr' Reagents i BrCH,CH,CO,Et; ii HOCH,CH,OH; iii NaIO, OsO Scheme 23 HC=C-CH20H -L HC-C ,CH20H -*ii-iv ~~~cH2l,co2Me II c'coyo -co(co)3 R Q-[cH2l2co2Me (51) ( 50) Reagents i CO,(CO),; ii (50) HBF, Et,O CH,Cl,; iii heat in toluene; iv lithium alkynylcuprate Scheme 24 AcO [CH213C0 Me ++ 4-0 0 &c~C[CH2]3C02Me O (5L) (52 1 04 'I Q0 Scheme 25 Scheme 26 0 nitrile oxide is the key feature of Kozikowski and Stein's approach was further underlined by the subsequent synthesis of of the intermediate (46) (Scheme 20) and also of prostaglandins of both the 9-and the 1 1-deoxy series and of the Curran's approach43 to the precursor (47) of prostaglandin E isopropyl ester of sarkomycin.have ingeniously In a demonstration of the general utility of the Pauson- (Scheme 2 1). Meanwhile chemists at Sanky~~~ exploited the exo-methylene group of methylenomycin A in Khand reaction Pauson and Jaffer,' have prepared some 11-their synthesis of 10,ll -dimethyl-prostaglandin analogues of deoxy heteroaromatic analogues of the type (51) (Scheme the type (48) (Scheme 22).24). 8-methylprosta-An extremely clever route to cyclopentanoids in general and East German workers have pre~ared~~-~O to 11-deoxyprostaglandins in particular has been by glandin analogues of the C series (Scheme 26). Their key Yamamoto and co-workers at Nagoya University (Scheme 23). intermediate (54)was first synthesized in racemic form from The reaction between the dianion of di-isopropyl hex-3-the readily available 2-methylcyclopentane- 1,3-dione (52) and enedioate and ethyl P-bromopropionate led directly to the 2,3- then later in chiral form from optically active (53) as shown disubstituted cyclopentanone (49). The versatility of this in Scheme 25. '0 Ill -v "' 1 -""4" HO CH,F OJ OH (55) NATURAL PRODUCT REPORTS 1988 In a continuation of their studies on fluorinated prosta- glandins Grieco and Vedananda51 have reported an enantio- specific total synthesis of (55) (Scheme 27).The structure-activity relationships in a series of configura-tionally rigid aryl prostaglandins of the type (56) have been reported by Schaaf and co-w~rkers.~~.~~ Favara et aZ.54have prepared a series of interesting 13-aza- 14-0x0-analogues of the A, E, and Fznseries (Scheme 28). Two features of Corey and Shimoji's synthesis55 of the major human urinary metabolite (58) of prostaglandin D (Scheme 29) are the new methods for converting ketones into thioketals in the presence of acid- and base-sensitive groups and the selective conjugate reduction of a trans-enone system.Corey and his colleagues have also reported56 the total synthesis of C, prostanoids in the E and F series which are theoretically derived from the docosahexaenoic acid (DCHA) skeleton. Icosanoids that are based on DCHA are beginning to receive some considerable attention. It is thought that the cardiovascular-protective effects that are associated with a diet that includes a high proportion of fish may be due to a combination of DCHA (which is a strong competitive inhibitor of prostaglandin synthase) and icosapentaenoic acid (EPA) (which is the progenitor of the potentially less harmful 3-series of thromboxanes and the 5-series of leukotrienes). 3 The Thromboxanes and Endoperoxides Perhaps as much effort has been expended in the industrial search for a potent selective inhibitor or antagonist of thromboxane synthase as in the academic quest to be the first to prepare the unsubstituted nucleus of thromboxane A (TXA,).Up to the end of 1984 neither faction had been obviously successful. Two stable fluorinated derivatives (59) (Scheme 30) of the parent ring-system of thromboxane A have been prepared by Fried and co-w~rkers.~' The electron-withdrawing properties of the fluorine atoms stabilize the system such that its rate of hydrolysis is lo8 times lower than that of TXA,. A photochemical route to the seven-membered ring-system (60) has been reported by Carless and Fekarurhob~~~ (Scheme 3l) while the corresponding carbocyclic analogue (61) (Scheme 32) has been prepared59 via an interesting regioselective enamine reaction.Reagents i HBr; ii HOCH,CH,OH; iii LiNPr', MeS0,Cl; v KF diethylene glycol at 100 "C Scheme 27 0. (.56)X = 6-or p -OH Y = CH2 or 0 n= 1 or2 04 &02H OAc OAc HCHO; iv OAc Reagents i CIC0,Et; ii NaN,; iii benzene heat; iv ButOH ; v HO,CCH(OAc)CH,OC,H,F-p Ph,P(O)N,; vi KOH MeOH H,O; vii chromatography Scheme 28 NATURAL PRODUCT REPORTS 1988-T. W. HART ?4 I iii -vi i ,vii cr' S& wCH20SiPh2But ___) C02Me AH bS 0 ,OH Ls VilI (57) Reagents i Pr'N=C=NPr' Cl,CHCO,H (> 90%); ii HSCH,CH,SH Zn(OTf),; iii Bu',AIH; iv (57); v PhC(O)Cl pyridine; vi Bu,N+ F-; vii MeO,CCH,CH,C(O)CH,P(O)(OMe),; viii H,S K,CO, DMSO Bu,P hv;ix H,SO, MeOH; x NaOH MeOH; xi HgCl, CaCO Scheme 29 (59) ( R=C%OCH,Ph or R -R = -[CH2IL-) Scheme 30 hV 0 ___) ic / Scheme 31 0 + 0i'ii @o iii iv Br2CHCCHBr2 II -vi ii ( Thp- tetrahydropyran -2 -yl) Reagents i B(OEt), Zn; ii Zn/Cu couple; iii H, Pd; iv pyrrolidine ;v Br[CHJ,OThp; vi cF,S-dimethyl-S-phenylsulphoximine anion then aluminium amalgam; vii B,H, then H,O ;viii pyridinium chlorochromate ;ix (MeO),P(O)CHC(O)C,H, Na+; x H+ H,O; xi pyridinium dichromate DMF ;xii L-Selectridem (LiAlHBu'J Scheme 32 Chemists at SquibbGo have investigated in detail the biological properties associated with the furan derivatives (62) and (63) which were prepared as shown in Scheme 33.Routes to carbocyclic analogues remain popular owing to the potent biological activity that is retained by these systems.Chemists at Ono have reportedG1 a new route to (64) (CTA,) which is the carbocyclic analogue of TXA (Scheme 34). Following on from earlier studies Ansell and Caton and their collaboratorsG2 have synthesized the pinane analogue PTA (65) of thromboxane A (Scheme 35). In doing so they also developed a much needed yet simple method for establishing NATURAL PRODUCT REPORTS 1988 unambiguously the configuration of the hydroxyl group at C-15 of pro~tanoids.~~a parallel approach workers at In RocheG4 synthesized the twelve stereoisomeric analogues of PTA (Scheme 37) employing both enantiomers of myrtenol as the precursors of the intermediates (66) and (67) (Scheme 36).Chemists at Ono66-68 have used the intramolecular dis-placement of a mesylate group by a thiolate anion to prepare sulphur-containing ring analogues of the types (68) (Schemes 38 and 39) and (71) (Scheme 40).Of particular interest in their route to the dithia-analogue (71) is the preparation of (70) R2 (63) { R1= CH,CH=CH[CH&O,H Z Reagents i H, Pd ;ii Ph,P=CHOMe 7-ene; vii (MeO),P(O)~HC(O)C,H, R 2= CH=CHCH(OH)C5H1,} E ;iii H,O+ ; iv Ph,P=CH[CH,],CO,Na; v Htzner-Moffat oxidation ; vi 1,8-diazabicyclo[5.4.O]undec-Na+;viii NaBH Scheme 33 Jliii ix C0,H CO Me -&lo I OH Carbathromboxane A (64) Reagents i LiNPr', (9-ICH,CH=CH(Me)SiMe,; ii m-ClC,H,CO,H then HC0,H; iii KOH MeOH (aq.); iv Li liquid NH,; v Jones oxidation; vi bromination; vii LiBr Li,CO, DMF; viii OsO,; ix Pb(OAc), MeOH Scheme 34 Z 2E = CH2CH=CH[CH2]3C02H R =CH=CHFHC,H, OH Reagents i dihydropyran ;ii 9-borabicyclo[3.3.llnonane then CO and LiA1(OBut),H Scheme 35 Reagents i (EtO),CH ;ii 9-borabicyclo[3.3. llnonane then H,O, OH-Scheme 36 13 NATURAL PRODUCT REPORTS 1988-T. W. HART (67 1 -t) . mMHR R Z E = CH2CH=CH[CH2]3C02H R2= OH Scheme 37 II -VII I Me02C QCHO C02Me 0 QN SC (0)CH 3 C02H iviii,v C02Me MesO I I OH OAc (68) Reagents i butadiene SnC1,; ii NaBH,; iii; MeS0,Cl; iv NaCN; v KOH H,O; vi KI I,; vii 1,8-diazabicyclo[5.4.0]undec-7-ene; viii MeONa Scheme 38 OMes i ii ... xi -xiii xiv aR' ,b:l Ill-x -A ,-s R2 AcS'* Z E = CH,CH=CH [CH2],C02Me R2 = (68) Reagents i NaBH ; ii pyridinium chlorochromate ;iii N,CHCO,Et ;iv NaBH,; v chromatography ;vi Collins reagent; vii NaH PhSeCl ; viii H,O,; ix PrSH Pr',NEt; x NaCl H,O DMSO; xi MeC(0)SK; xii NaBH,; xiii MeS0,Cl; xiv MeONa at 55 "C; xv KOH H,O Scheme 39 (69) (701 \C02Me CO H I (d=CH,CH=CH [CH2].$02Me) z dH (71 1 Reagents i H,S NaOAc; ii ButOK HMPT Scheme 40 which was synthesized via a double Michael addition of hydrogen sulphide to the dienone (69).The key inter-mediate (72) which has been prepared by Kale and Clive69 from levoglucosan (Scheme 41) was used in their chiral approach to the oxathia-analogue (73). The nature of the catalytic site of thromboxane synthase has prompted Adams and Metcalf 70 at the Merrell Dow Research Institute to prepare the two PGH analogues (75) from (74) (Scheme 42).Both the oxime and the -diazo-ketone were moderately good non-time-dependent inhibitors of throm-boxane synthase. For the same reasons Corey and co-worker~~~ synthesized the pyridine prostaglandin analogue (76) (Scheme 43) which at concentrations that were theoretically sufficient to inhibit the biosynthesis of TXA in vitro attenuated but did not prevent arachidonic-acid-induced aggregation of platelets. An improved route to an 8-aza-analogue of an endoperoxide (Scheme 44)has been described by Blondet and M~rin.~~ Antagonistic properties are often conferred upon those prostaglandins which are substituted at C- 13 with an oxygen or a nitrogen heteroatom.For this reason presumably the analogues (77),72 (78),73 and (79),74 have recently been prepared. Corey and co-worker~~~ have suggested that the preferential formation of the exo,exo-endoperoxide (81) (Scheme 45) during the homolytic demercuration of the 1,2-dioxoiane (80) in the presence of oxygen is due to a sterically unfavoured endo,endo-disrotatory pathway because of the 2-geometry of the 12-13 double-bond. Chemists at Procter and Gamble76 NATURAL PRODUCT REPORTS. 1988 have demonstrated that hydroperoxides of the type (82) (Scheme 46) undergo a kinetically controlled radical autoxida- tion to yield cis cyclic species of the type (83). It becomes apparent therefore that one of the main functions of the enzyme prostaglandin cyclo-oxygenase is to ensure the correct trans alignment of the two side-chains 4 The Clavulones Hybridalactone the Dicranenones and the Levuglandins 4.1 The Clavulones The clavulones I and I1 [(84) and (87) respectively ;see Schemes 47 and 481 are potent anti-inflammatory agents possessing inhibitory activity against cultured L1210 leukaemia cells.77 They were isolated independently in 1982 from the Okinawan soft coral Clavularia viridis (Quoy et Gaimard) by Kikuchi et ul.and Kobayashi et ul. who have recently disco~ered~~.~~ new members of this family of compounds. Some 20-acetoxy- derivatives have been detected by other workers.so It is unclear at present (because of the unusual substitution pattern of this group of compounds possessing as it does an aberrant hydroxyl function at C-4) whether the clavulones are derived from 8- HPETE or 9-HPETE.81.102 The first racemic synthesis of clavulone I (84) was reported by Corey and Mehrotras2 (Scheme 47).Starting from D-mannitol and the optically active cyclo- pentenone (86) Yamada and co-~orkers~~ have synthesized chiral clavulone I1 (87) (Scheme 48). 1 Z E (73) { R = CH2CH=CH [CH,],C02Me R2=CH=CHCH(OBz)C5H1,} Scheme 41 i,iid [CH&OSi Me2Buf 4 0 2CO,HH 0G C ! j H 1 1 (7L) L 6si Me,B u iii ,iv OH I OH ( 75 a 1 R = NOH (75b)R=N2 Reagents i HC0,H; ii esterification; iii ButOK C5H110N0 ButOH; iv pyridinium tosylate EtOH; v chloramine T (sodium salt of N-chlorotoluene-p-sulphonamide) Scheme 42 VI -xi \ OThp OH (76) Reagents i LiNPr',; ii DMF; iii (MeO),P(0)~HC(O)C5Hll Na'; iv NaBH,; v dihydropyran; vi ButLi; vii CuCN; viii H,C=C=C(I)- [CH,],CO Me; ix toluene-p-sulphonic acid MeOH; x H, Pd; xi NaOH Scheme 43 NATURAL PRODUCT REPORTS 1988-T.W. HART ii\ Q + LCF3-Q CO Et NC C0,Et CN I I OH Scheme 44 CO,H OH OH ON0 11105 (77) SKll -lLL(78) (79) HR q3 HO + qHgcL{%c5H, OOH H 0‘ OH CSH 11 C,H,,CH=CH C,H,,CH=CH (81) (80) Z [ R= CH2CH=CH[CH2’],C0,Me or CH(OMe1 I Scheme 45 R’ (82) (83) OOH 1 (R = [CHJLC02Me R2=C5Hll) J Scheme 46 A’ HO OAc A/ vi-viii Clavulone I (84) Reagents i 0,,hv Rose Bengal; ii NaBH,; iii pyridinium dichromate; iv H, Lindlar catalyst; iv ButMe,SiOTf 2,6-lutidine; vi LiNPr’, then (Z)-OHCCH=CHCH(OSiMe,But)CH~CHzCOzMe; vii Bu,Nf F- Ac,O 4-dimethylaminopyridine ;viii chromatography Scheme 47 C0,Me I-IV ,B z l o ~ o H v-x D-Mannitol _t_j v ““‘Q OAc OAc 0 (85) U 0 HO (86) (87) Reagents i LiAlH,; ii ButMe,SiC1; iii Ac,O pyridine; iv Bu,N+ F-; v pyridinium chlorochromate 3 A molecular sieve; vi Jones reagent; vii CH,N,; viii H, Pd/C; ix ClC(O)C(O)Cl DMSO then Et,N; x Ph,P=CHCHO; xi LiNPr’, then (85);xii Ac,O pyridine Scheme 48 4.2 Hybridalactone Hybridalactone (89) (Scheme 49) first isolated from the red alga Laurenciu hybrida is a putative metabolite of icosapenta- enoic acid via a 12-lipoxygenase path~ay.~~,~~ Corey et al.have confirmed its structure by X-ray analysiss4 and also by total synthesiss5 (Scheme 49). 4.3 The Dicranenones The dicranenones a series of prostaglandin-like fatty acids of the type (90) and (91) were isolated recently from the mosses Dicranum scoparium and Dicranum japonicum.87 These cyclo- pentenoids are putative metabolites of 9-HPETE. 4.4 The Levuglandins The two aldehydes levuglandin D (LGD,) and levuglandin E (Scheme 50) were isolated in a combined yield of approximately 20 YOas solvent-induced decomposition pro- ducts of prostaglandin H,.88It is quite likely that they will be detected in vivo and thus establish another branch of the arachidonic acid cascade although they do undergo a facile dehydration to the corresponding anhydro-derivatives (92) and (93) which will (as in the case of PGA,) make them difficult to detect owing to their conjugation with such endogenous thiols as glutathione.5 Prostacyclins Carbacyclins and their Analogues 5.1 General Prostacyclin (prostaglandin I,) is one of the most potent anti- aggregatory and vasodilatory substances known to Man. Since its discovery and the elucidation of its structure in the late NATURAL PRODUCT REPORTS 1988 1970's the search for an orally active stable prostacyclin analogue possessing either anti-platelet or antihypertensive properties coupled with a measure of that intangible quality termed 'cytoprotection ' has continued unabated. 5.2 Prostaglandins I and I A highly imaginative approach to prostacyclin de novo has recently been reported by workers at Salford University and Glax~.*~ The aldol reaction between the aldehyde (25) which is a key prostaglandin intermediate (see Section 2.2) and cyclopentanone furnished the two threo-adducts (94) and (95) respectively (Scheme 5 1).Following iodolactonization both were separately converted into PGI via a sequence that involved a regiospecific Baeyer-Villiger reaction and a stereo- specific dehydromesylation step. A remarkably facile synthesis of PGI has been accom-plishedgovia the intramolecular oxymercuration of the acetyl- enic alcohol (96) (Scheme 52) which was obtained30 by using the enolate-trapping approach (see above). The unusual biological properties of the metabolites of icosapentaenoic acid [20 :5(03)] are the centre of much interest which will no doubt be further stimulated by the first direct evidence for the formation of PGI in vivo in Man.91 5.3 Enol Ether Analogues of Prostacyclin The therapeutic potential of prostacyclin in the treatment of a variety of cardiovascular disease states is severely limited by the metabolic instability of its enol ether function.Therefore because retention of spatial pattern of the oxygenated functional groups is necessary for maximum activity analogues that possess an acid-stable (a-enol ether group have always been a logical and justifiable target for the medicinal chemist. Chemists at Chinoing2 have recently prepared the 4-0x0- WOTs + $H L Et iii-v H /O -7 C=CH I Et it Et Reagents i BuLi; ii Bu,N+ F-; iii L-Selectride@ (LiBHBu"); iv ButOOH [v(O)(acac)]; v ButMe,SiOTf; vi BuLi CuCN HMPA; vii (88); viii H, Lindlar catalyst; ix pyridinium dichromate; x NaHSO,; xi lactonization Scheme 49 C =C[CHJ,C02H L 0' 0- Dicranenone A (90) Dicranenone B (91) NATURAL PRODUCT REPORTS 1988-T.W. HART I OH PGH 4 4 HJ4-=47C02H H C,Hl C5H11 0 OH 0 OH LGE LGD J. .1 C0,H MeL7 COzH H Me C5Hll Me%-0 0 (93) (92) Scheme 50 ButMe2Si0 (95) OHC -H PGI 2 6H HO (25) (94) Reagents i KI, Na,CO ; ii 2,4,4,6-tetrabromocyclohexa-2,5-dienone ; iii Bu,SnH ; iv rn-ClC,H,CO,H ; v K,CO, MeOH ; vi MeSO,Cl Et,N; vii HOAc H,O THF ; viii 1,8-diazabicyclo[5.4.0]undec-7-ene;ix NaOH Scheme 51 Me0 0,.IZCECCCH&O2Me I ,iI +-b PGI C5H 11 Rd OR R0' OR ( 96) ( R= Si Me2Buf 1 Reagents i (CF,CO,),Hg Et,N; ii NaOH NaBH Scheme 52 NATURAL PRODUCT REPORTS 1988 0 OH Hd I OH H0’ I 6H Yi’ ( 971 ?4 (98) Reagents i piperidine HOAc (98) benzene ; ii rn-ClC,H,CO,H ; iii DMF heat ; iv (100) ; v BrCH,CO,Et CH,N,; viii HF MeCN HO +; OH (103a) R1 = C5H, or cyclohexyl Rz= H (103b) R’= C,H, R2=Me X.0 or derivative (102) (Scheme 53) in modest overall yield by Knoevenagel condensation of the lactol (97) with the sulphide (98). In an alternative approach Nokami and converted the lactone (99) directly into the ketone enol ether (101) by reaction with the dianion (100).Unfortunately however alkylation followed by decarboxylation masking of the protecting groups afforded mainly the unwanted (a-isomer the desired (2)-enone (102) being formed in only very low yield. I 6H ONa I Li CH,C=CHCO,Me (1 00) K,CO,; vi NaOH ; vii Scheme 53 Some important structure-activity relationships have been reported by chemists at Grunenthal,’ who have synthesized a series of prostacyclin and carbacyclin analogues (103). Of the compounds in which the upper side-chain was replaced by a variety of carboxyphenylene derivatives only the rneta-substituted compounds possessed high activity. The most interesting of their compounds was CG 4305 (103a; R1 = cyclohexyl R2 = H X = CH,) which being the first potent crystalline prostacyclin analogue has undergone much detailed X-ray analysis.ss Schaaf and co-worker~~~~ 53 have also published some structure-activity relationships for their more rigid prostacyclin analogues.A novel intramolecular Mitsunobu reaction which also opens up a new general route to benzopyrans has been CH developedg5for the synthesis of the aromatic analogue (104) (Scheme 54). Enol ethers are by definition electron-rich entities. Electron-withdrawing substituents at C-4 C-5 C-7 or C-10 of PGI greatly stabilize the molecule towards hydrolysis by acids. Two approaches to 7-substituted derivatives have recently been Whereas the hydroxy-and acetoxy-compounds co-workersg3 (105; R1= H) and (106) (Scheme 55) displayed only weak prostacyclin-like activity the 7P-fluoro-analogue (107) was a most potent mimic of PGI, with a half-life of greater than 1 and un-month at pH 7.4.The key step in Raduchel’s synthesis” of the acid-stable anti-aggregatory imino-ether (109) (Scheme 56) was the cyclization of (108) by using a double-inversion technique. NATURAL PRODUCT REPORTS 1988-T. W. HART kH2 Thpd R ThpO''R b*OThp \ = {wc5H11 Thp=tetrahydropyran -I OThp Scheme 54 Me0 O? QR2 R'O' R'O R'O Me0 J Me0 MeO, b [R! S IMe26u' 1 ?%OAc T' ~ H0' C5H11 '5h11 8L OH Rld OR' H 0' 1 (106) (105) (107) 6H =SiMe2But or Ac R2=kc5Hi3 1 t)R' Reagents i PhSCl; ii rn-ClC,H,CO,H; iii Et,NH Scheme 55 B u Me2Si0 Et 0 Thpd ","I) cc, HO 1 OH (109) 0 3iif CLR T hpO' Reagents i Et,N CICO,But; ii H,N[CH,],CO,Et; iii Bu,N+ F-; iv MeS0,CI; v HOAc; vi LiBr Scheme 56 Bromohydrin derivatives of the type (1 10) (Scheme 57) because they can be easily converted in situ into either a tricyclic intermediate or an epoxide intermediate are valuable pre- cursors of many 13-heterosubstituted analogues such as (1 i1).99 Nickolson and VorbruggenlOO have prepared the furan analogue (112) of prostacyclin (Scheme 58) by a necessarily circuitous route because the more obvious cyclization of a 6- keto-PGE derivative could not be achieved.5.4 Carbacyclins Replacement of the oxygen atom of the enol ether moiety of prostacyclin by a methylene group affords (a-carbacyclins which although being approximately one-third to one-tenth as active are physiologically much more stable.Skuballa and Vorbruggen have recently annotatedlOl their Me0 Me0 OH Reagents i PhCH,NHMe NATURAL PRODUCT REPORTS 1988 three approaches to the orally active vasodilator and anti- aggregatory agent Iloprost (ZK 36374) (1 15) (Scheme 59). All three approaches start from the optically active commercially available 'Corey lactone' (1 13). Their first approach (Scheme 59) provided the intermediate (1 14) in eleven steps while their more favoured second approach (Scheme 60) utilized a neat one-pot procedure for the conversion of (116) into (1 17) involving a base-catalysed rearrangement which has also been described by Mongelli and co-~orkers.~~~ Their third route (Scheme 61) employed a protocol that had previously been reported by Bestmann et al.lo5 in which the keto-acid (1 18) after cyclodehydration to the unsaturated ketone (1 19) was reduced with triethylammonium formate in the presence of a palladium catalyst. Ueno and co-workers106 have used an analogous keto-ester (120) in their synthesis of (122) by cyclization of the aldehyde (121) with Wilkinson's catalyst (Scheme 62). Me H­ 6 O -+ I NCH,Ph6 Med OMe (14;R=Me) Scheme 57 ?4 . .. I -Ill iv-vii C02Me R Thpd + '-Hzp* , I ThpO ThpO J viii iii H218O2 = Me02C[CH2] I ix,x &I5 r, 3 ff-H, OH OH Thpd4 R Thpd R i I (112) ( R=CH20SiMe2But Thp = tetrahydropyran -2 -yl 1 Reagents i (Me,Si),NLi; ii PhSeC1; iii H,O,; iv NaBH, PhSeSePh; v Bui,AIH; vi Ph,P=CH[CH,],CO,Li; vii CH,N,; viii I, NaHCO ;ix 1,8-diazabicycl0[5.4.0]undec-7-ene; x MgSO, benzene heat Scheme 58 NATURAL PRODUCT REPORTS 1988-T.W. HART -0: I i -iii IV J iii v ) vi-ix aR Th p0' T hpd Thpd (11 31 J x xi HOml 2 fc. R Hd ( R 2 CH20CH2Ph (114) Iloprost ( 115) Reagents i Bu',AlH; ii Ph,P=CH,; iii TosC1 pyridine; iv KNO, DMSO; v CH,(CO,Et), ButOK; vi LiCl DMSO at 160 "C; vii OsO, NaIO ; viii Jones oxidation ;ix CH,N ;x ButOK; xi 1,4-diazabicyclo[2.2.2]octane Scheme 59 C02Et C02Et 4 d -Et Ow VII-IX CH20R -a rv v VI -PhCb PhCd H0' CH20R 0 CH,OR Hd QHp QCH20H I1 II (116) ( 117 1 0 ( R = Si Me2But) Reagents i LiCH,CO,Et ; ii toluene-p-sulphonic acid ; iii K,CO, MeOH ; iv Collins reagent; v 1,5-diazabicyclo[4.3.0]non-5-ene; vi NaBH ;vii 1,4-diazabicyclo[2.2.2]octane,PhMe H,O; viii PhC(0)Cl; ix HOAc H,O THF Scheme 60 VI -Lc_) R R Thpd Thpd Thpd ThpO' (118) (119) (R = CHtOBzl Thp = tetrahydropyran-2-yl) Reagents i KOH MeOH; ii citric acid; iii Jones oxidation; iv Ph,P=C=C=NPh EtOAc heat; v toluene EtOH heat; vi Et,NH+ HC0,- Pd/C toluene at 70 "C Scheme 61 ,-C02Me H2C -CHO VI -lX 'CH20Thpj ThpO' ThpO 'CH20Thp A Thpd CH20Thp Bz0 (120) (1211 (122) Reagents i K,CO, MeOH; ii dihydropyran; iii KOH; iv CH,N,; v CrO, pyridine; vi PhMeS(O)=NMe MeMgBr; vii aluminium amalgam; viii LiAIH,; ix CrO, pyridine; x [RhCl(PPh,),] CH,Cl, at 40"C for 20 hours Scheme 62 Chemists at E.Merck'O' have disclosed that the 13-thiacarba-cyclin analogue EMD 46335 (Scheme 63) is an orally active antihypertensive agent. The reaction of the bromohydrin (1 23) with the optically pure thiol (124) prepared from (+)-L-mandelic acid afforded the cyclobutanone (125) ; this after ring-expansion with diazomethane provided their desired intermediate (126) in 30% overall yield from (123). A common feature of most syntheses of carbacyclin is the problem of the generation of isomers by the final Wittig reaction since the two isomeric (2)-and (E)-olefins are often difficult to separate while nearly all the biological activity resides with the latter.In their elegant synthesis of racemic carbacyclin (128) (Scheme 64) workers at Sankyolo8 partially overcame the problem of separation of isomers when they readily isolated the ($)-isomer of (127) and then obtained the upper side-chain stereospecifically by a dehydrative decarboxylation reaction. 0 h 0b NATURAL PRODUCT REPORTS 1988 Shibasaki and co-workers at Sagami,120in a most elegant and practical solution to this troublesome problem discovered that 1,4-hydrogenation of 1,3-dienes of the type (148) (Scheme 72) specifically formed carbacyclins that possess the desired E configuration (see below). Two syntheses of the carbacyclin analogue of PGI:,have been reported.log.'lo A fascinating result discovered by chemists at Sankyo,"" was that the enol ether (130) (Scheme 65) when treated with phenylsulphenyl chloride afforded only the one isomer (1 31).This was stereospecifically converted into the desired (1 5s)-15-hydroxy-derivative by using standard method-ology. carbacyclins that contain heteroatoms at positions 11 and 12 been (Schemes 66,67 and 68) although little is known regarding their biological activity. 4 4 iii iv Hd CI QR HO (1261 EM0 L6335 HSa I 6; \ -sa) I OH OH (1241 Reagents i (124) ;ii CH,N ;iii Ph,P=CH[CH,],CO,K; iv p-benzamidophenol dicyclohexylcarbodi-imide Scheme 63 VII-x ,VllI Hov XI XI1 ,G O 2 H n CHO CHO C,H 11 Hd I QCH0 Thpd 6Thp (127) Hd I OH (1281 Reagents i LiNPr', ClC(O)[CH,],CO,Me; ii NaBH, MeOH; iii NaOH; iv acetylation; v 0,; vi piperidine HCI Zn(OAc),; vii Horner-Wittig reaction; viii dihydropyran ;ix NaBH ; x HOAc then chromatography of isomers; xi K,CO, MeOH; xii KOH H,O; xiii dimethylformamide dimethyl acetal CHCI ;xiv HOAc H,O; xv KOH then H30+ Scheme 64 NATURAL PRODUCT REPORTS 1988-T.W. HART HO Q 2-+ Hd OH Thpd OH Reagents i Ph,P=CHOMe ;ii PhSCl K,CO, PhMe ;iii Ph,P=CHCH,CH=CHEt ; iv m-ClC,H,CO,H ; v (MeO),P Scheme 65 HO IX-XIII I-IV v-viii CO Et ___) -Y -Q-yc”Hll C0,Et 0 OH OH Reagents i (MeO),P(O)CH,CO,Me NaH; ii H, Pd/C; iii NaH; iv NaCl DMSO H,O at 150 “C; v CH(0Me),; vi MeLi; vii H,C=CHC(O)C,H,,; viii NaBH, EtOH at -20 “C; ix Ac,O; x N-bromosuccinimide NaHCO, THF H,O; xi K.,CO, MeOH ;xii toluene-p- sulphonic acid acetone ;xiii Ph,P=CH[CH,],CO,K Scheme 66 ..I -Vl v I 0 OH Reagents i NaIO,; ii LiNPr’, OHCCH2k(OCH,CH,b)C,H,,; iii B,H,; iv HOAc H,O; v H,SO, H,O; vi HOCH,CH,OH H+; vii NaBH,; viii H,O+; ix Ph,P=CH[CH,],CO,Na Scheme 67 . ... 1-111 IV,V ___) w ‘%1 J aCH2C02Me I I OH Reagents i NaBH, aq. THF ; ii Jones oxidation ; iii ketalization ; iv Bu’,AlH ; v Ph,P=CHCO,Me xylene reflux; vi standard methodology Scheme 68 NATURAL PRODUCT REPORTS 1988 HO "Oh P (1321 (133) "2ER' iii Jiv -QR2 I I ThpO Thpd ThpO ThpO (134) (135) 4 CO Me CHO k-co2Me v,vI -a- IV R2 vii viii 0 ThpO' ThpO' Th p0 (136) ix ,vJx i 8 I H0' OH (1331 Reagents i Zn CH,Br, TiCI,; ii thexylborane then H,O,; iii I, NaHCO,; iv 1,8-diazabicyclo[5.4.0]undec-7-ene; v HOAc H,O; vi SO, pyridine; vii TiCl, Zn THF; viii MeSO,Cl Et,N; ix NaI (CF,CO),O; x NaOH H,O THF Scheme 69 In their second approach Ikegami and co-w~rkers~"iso-5.5 Isocarbacyclins merized the known readily available exo-enone (137) (Scheme The initial discovery by Bundy and Baldwin114that the nitrilo-70) into its endo-isomer (138) by employing a rhodium catalyst.PGF, derivative (132) was equipotent with BGI as an inhibitor Deoxygenation of (138) without scrambling of the double-of the aggregation of platelets prompted the synthesis of the bond was accomplished by protodesilylation of the silane (139) corresponding compound isocarbacyclin (133) which quite [which was prepared by conjugate addition of trimethylsilyl surprisingly was found to be a more potent mimic of PGI than anion to the enone (138) followed by reduction mesylation carbacyclin itself.. and finally dehydromesylation]. In their first approach to isocarbacyclin (133) Ikegami and In their third approach"* the Corey lactone (141) (Scheme co-workers115 at Teikyo University constructed the desired 7 1) was cleverly converted by using their alcohol-inversion intermediate (136) via an intramolecular pinacol-coupling re-protocol (Scheme 12) into the dimesylate (142). After cycliza-action. In a later paper116it was revealed that the reduction of tion to the key intermediate (143) isocarbacyclin was formed in (134) to (135) is best achieved by using thexylborane rather most economical fashion via an aldol condensation and a than 9-borabicyclo[3.3.llnonane (Scheme 69). Claisen rearrangement. NATURAL PRODUCT REPORTS 1988-T. W. HART R’O’ R’O Me vii-ix f-Meo- R10’2:,vI R1:Si Me26ut I Reagents i LiNEt, Et,O; ii cuprate; iii LiNPr’, OHC[CH,],CO,Me; iv MeSO,Cl Et,N; v 1,8-diazabicyclo[5.4.0]undec-7-ene;vi RhCl;3H,O K,CO, EtOH at 70 “C; vii Bu,N+ F-; viii dihydropyran; ix Me,SiSiMe, Bu,N+ F- HMPA; x NaBH, CeCl, MeOH; xi (CF,SO,),O pyridine; xii HOAc H,O; xiii NaOH H,O MeOH then H,O+ Scheme 70 ?4 i -iii ___) Thpd (141) Thpd 0 PhOCS. II xi f-Thpd ZR f 133) ( R=CH20SiPh2But1 Reagents i LiAlH ;ii MeS0,Cl; iii CsOAc 18-crown-6; iv K,CO, MeOH; v MeS(O)CH,SMe BuLi; vi N-bromosuccinimide CaCO, aq.MeCN ;vii OHC[CH,],CO,Me; viii dehydration ;ix NaBH, CeCl * 7H,O MeOH ;x PhOC(S)Cl MeCN ;xi Bu,SnH azobisisobutyronitrile benzene Scheme 71 NATURAL PRODUCT REPORTS 1988 OHC. U C0,Me # Rid-R2 R' 01 ThpO (145) (144) li 4r214c02H ff-'I R'O' QR 2 I Hi OH (133) (147) r=icH22cozMe V t R' 0'QR2 R'O' IlL8) Reagents i toluene at 180 "C; ii H, Pd/C; iii MeSO,CI Et,N; iv 1,8-diazabicyclo[5.4.0]undec-7-ene, at 120 "C; v H, acetone [Cr(CO),- (PhCO,Me)] 70 atm at 120 "C for 5 hours Scheme 72 C,H0 I-I11 v vi 04 ... H2trrCHO ThpO' R ThpO' R OI (119) Thpd vii "0i-C"O X VI I1 ,IX vii (1 33) -QR -3-8' Th p0 R QR a R Q Thpd Th pd Thpd (151) (150) ( R=CH20SiMe2Buf1 Reagents i Bui,AIH ; ii Ph,P=CH ; iii pyridinium chlorochromate NaOAc; iv Zn CH,Br, TiC1,; v di-isoamylborane then H,O,; vi.ClC(O)C(O)Cl DMSO CH,Cl, then Et,N ; vii benzene (PhCHJ2NH2+ CF,CO,- heat ; viii Ph,P=CH[CH,],CO,K ; ix CH,N ; x H, Pd/C Scheme 73 A Corey lactone (144) (Scheme 72) was also used as the trans double-bond followed by dehydration afforded the starting point for the synthesis of isocarbacyclins by Ogawa silylated intermediate (147). It is important to note the flexibility Following the conversion of (144) into the of this approach since it has also been used120 to prepare and Shiba~aki."~ aldehyde (145) an intramolecular ene reaction furnished the stereospecifically carbacyclins that possess the desired E two isomeric alcohols of the type (146).Hydrogenation of the configuration (see above). NATURAL PRODUCT REPORTS 1988-T. W. HART [CH 1 CO2Me + 22 v-VII (133) Q R2 R'OI Reagents i Zn CH,Br, TiCl,; ii 9-borabicyclo[3.3.1]nonane,then H,O,; iii Swern oxidation; iv standard methodology (see below); v H, modified Wilkinson's catalyst; vi H,O HOAc; vii NaOH Scheme 74 0 H204 Mes0..4 6-P XIV,VIII ,xv XI -xiit IX ,x Cope 0 C02Me 0 Thpd (157) Thpd (156) ( R = [CH&OCH2Ph) Reagents i PhCH,O[CH,],MgBr ; ii toluene-p-sulphonic acid benzene heat; iii m-ClC,H,CO,H; iv BF .Et,O; v NaBH,; vi TosC1; vii KO, 18-crown-6; viii MeSO,Cl Et,N; ix 1,8-diazabicycl0[5.4.O]undec-7-ene; x MeOC(O)OMe NaH ; xi HCO,H conc.H,SO ; xii NaBH, EtOH; xiii dihydropyran; xiv K,CO, MeOH; xv PhSeNa EtOH at 70 "C then H202 Scheme 75 Following on from this work Sodeoka and Shibasaki121 have reported one of the most versatile high-yielding syntheses of chiral isocarbacyclin (Scheme 73). The regioselectivity of both the intramolecular aldol reaction of the dialdehyde (149) and the hydrogenation of the diene (1 51) are important features of their work. In an alternative approach to dialdehydes of the type (149) using a fully elaborated o-side-chain Shibasaki and co-workers122 prepared the ketone (152) in five steps from furfural (Scheme 74). An improved modified Wilkinson's catalyst namely that formed from chlorodicyclo-octene-rhodium(1) and phenyldipiperidylphosphine,was used for the regioselective hydrogenation of the em-double-bond in (154).In their elegant synthesis of isocarbacyclin (133) Koyama and K~jima,',~ at Sankyo first converted the readily available monoketal (155) (Scheme 75) into the tricyclic entity (156). Regioselective cleavage of the latter (using formic acid) followed by hydrolysis and dehydration of the formate ester furnished the desired olefin (157) which was thereafter elaborated by using standard methodology. NATURAL PRODUCT REPORTS. 1988 i-iii 0 + a4+Pl1 i I PhC H OC H,O bCH20CH2Ph P hCH ,OCH,O bCH20CH2Ph (159 1 I HO OH Reagents i m-CIC,H,CO,H ; ii (MeO),P; iii PhCH,OCH,CI ; iv N-bromosuccinimide H,O DMSO ; v pyridinium chlorochromate ; vi H,NC(S)[CH,],CO,Me; vii Ph,P EtO,CN=NCO,Et THF ;viii toluene-p-sulphonic acid; ix NaOH H,O MeOH Scheme 76 5.6 Nitrilo-analogues Bradbury and Walker124 have synthesized the thiazole analogue (160) (Scheme 76) via the regioselective cleavage of epoxy- cyclopentene with thioallyl anion.The desired thiazole ring was cleverly fabricated by condensing the bromo-ketone (159) with methyl 6-amino-6-thioxohexanoate,using diethyl azodicar- boxylate methodology. An improved route to azaprostacyclins of the type (164) and (165) (Scheme 77) has been described by workers at Hoechst.lZ6 The readily available chloro-lactone (1 6 I) after conversion into the corresponding acetal-ester (1 62) was transformed (via azide displacement and hydrogenation) into the lactam (163).This was subsequently converted into HOE 892 (1 64) which is equipotent with PGI as an inhibitor of aggregation of platelets but is approximately one-tenth as active as a vasodilator. 5.7 Miscellaneous The 10-oxa-analogue (166) of PGI (Scheme 78) was prepared1,’ from D-ribofuranose but was inactive on platelets. Chemists at SyntexlZs have prepared the chiral oximino- derivative (169) (Scheme 79) which is four times more potent than PGE as an inhibitor of ADP-induced aggregation of platelets. The racemic epoxide (167) when cleaved to introduce the chiral acetylenic side-chain afforded two ring diastereo- isomers of the type (168) which were easily separated by using Fried’s dicobalt octacarbonyl technique,’ (see above). 6 The Leukotrienes 6.1 General The leukotrienes arise by metabolism of arachidonic acid to 5-HPETE through the arachidonate 5-lipoxygenase pathway and are considered to be potent mediators of many allergic and inflammatory disease states.Most of the strategies that have been employed in their synthesis can be classified into three distinct groups. Thus the many convergent routes that begin with simple racemic starting materials usually exploit an asymmetric reaction (such as a Sharpless epoxidation) to introduce chirality into the system while the chiral-pool approach dips immediately into the natural fund of simple carbohydrates for its synthetic building blocks whereas the biomimetic route starts from arachidonic acid itself. 6.2 Leukotriene Intermediates Corey and Wright12g have improved upon an earlier procedure for the purification of both arachidonic acid and docosa- hexaenoic acid (DCHA) from impure commercially available samples (Scheme 80).Iodolactonization of the crude ara- NATURAL PRODUCT REPORTS 1988-T. W. HART CI H.4 iv ii -HO Qc Hd (161) (162) (163) / I I HO OH HOE 892 (164) X = S (165) X = 0 or NH Reagents i ClC(O)C(O)Cl; ii H, Pd/C; iii H+ MeOH; iv NaN, DMSO Scheme 77 (-1 -D -Ribose OH (166) Scheme 78 0-CH ,CO ,H 6H bH (168) 169) Reagents i Me,AIC~CCH(OSiMe,But)C,H,,; ii Co,(CO),; iii separation of isomers by chromatography ; iv oxidation ; v HOAc H,O ; vi H,NOCH,CO,H Scheme 79 CO SiMe I impure AA -Iiii ( AA = arachidonic acid ) pure AA Reagents i iodolactonization ;ii Me,SiCl NaI MeCN; iii hydrolysis Scheme 80 NATURAL PRODUCT REPORTS 1988 - I -Ill (172) (173) Reagents i LiCH=CHCH=CHOEt; ii MeSO,CI Et,N; iii pH 7 Scheme 81 ... I II 111 IV HC ECC,H, * ( EtOIZCH HCEC-CH I OH lv 0 CO 2Et C-vii -ix vi -Gco2'" \xi V /-2 OMe LTA methyl ester (175) Reagents i BuLi BrCH,CH(OEt),; ii H, Pd/BaSO,; iii HO,CCO,H aqueous acetone; iv BuLi HC-CH; v MeC(OEt),; vi A1,0, benzene reflux for 1 hour; vii LiAlH,; viii PBr,; ix (EtO),P; x NaH 15-crown-5; xi (172) Scheme 82 HO OH -V -vn (177 1 (176 1 Reagents i Na,CO, H,O, then HCl ;ii Me,C(OMe), toluene-p-sulphonic acid then NH,OH ;iii Bu',AlH Scheme 83 chidonic acid mixture results in the formation of (170).After purification this was converted into the desired (a-olefin (1 71) by treatment with trimethylsilyl iodide. Co-ordination of the latter with the lactone moiety is it is thought followed by the release of iodide ion which then regenerates the (a-olefin by a concerted anti-periplanar attack. This ingenious protocol works well for arachidonic acid because it is the only component of the original mixture that is capable of undergoing iodo- lactonization. The that the red alga Porphyridium cruentum is a potentially valuable source of arachidonic acid with cost estimates of less than El per gram is bound to stimulate interest in the biomimetic approach. An improved simple method for the synthesis of the LTA precursor (173) by four-carbon homologation of the chiral synthon (172) (Scheme 31) has been devised by Corey and Albright.131 Syntheses of the C synthons methyl (5S,6S)-5,6-epoxy-6- formylhexanoate and methyl (5S,6S)-5,6-epoxy-7-hydroxy-heptanoate have been described.13 6.3 The Synthesis of Leukotrienes A C D and E Routes that lead to LTC, LTD, and LTE invariably proceed by way of LTA and are therefore included in this section. The stereoselective synthesis of the methyl ester (175) of LTA has been reported133 in which the unusual alumina-promoted re- arrangement of (174) features as the key step (Scheme 82). The full paper describing the enantiospecific synthesis of LTA (and hence of LTC, LTD, and LTE,) from D-isoascorbic acid via the versatile intermediate (176) (Scheme 83) has been published by workers at Hoffmann-La Roche.Syntheses of leukotrienes C and D have been described.lZ5 NATURAL PRODUCT REPORTS 1988 OX0 OHC ,I .. yC02 Me %I -I OC Ph II 0 '0 H \ii (186 1 = ~ ButPhZSiO C5H 11 OH Reagents i BrMg[CH,],CH=CH,; ii BrCH,C=CH Zn Et,O Scheme 86 :G" _. -Et (193 1 H-YY ... 111 (192) I LTB Reagents i BuLi; ii HMPT; iii Pr'OK Pr'OH Scheme 87 a basic starting material Italian chemists13' have prepared the two LTB precursors (188) and (190) (Scheme 86) from a common chiral synthon. The threo-isomer (1 89) was readily prepared from (1 86) by a Reformatsky-type reaction but unfortunately the Grignard reaction with (1 86) afforded a 60:40 mixture of (187) and its epimer.Wittig coupling of the two synthons (191) and (192) to form the epoxy-lactone (193) (Scheme 87) enabled Corey and co- workers138 to accomplish the first total synthesis of LTB,. Intriguingly the latter possesses only about 5 % of the activity of LTB for the chemotaxis and aggregation of leukocytes. 7 The HETEs DiHETES and Other Related Compounds 7.1 The Lipotrienes The first total stereospecific synthesis of lipotriene A from 2-deoxy-D-ribose (194) (Scheme 88) was achieved by the Merck Frosst group.'." A similar approach14' was also used in their synthesis (Scheme 89) of (1 1 S,12S,5Z,7E,9E,142)-1 1,12-epoxy-icosa-5,7,9,14-tetraenoic acid (1 96).Corey et have reported a novel route to LTA which involves condensation of the lithio-derivative (1 97) (Scheme 90) NATURAL PRODUCT REPORTS 1988 [CH ,l,CO,Me .. -I I1 Lipotriene A methyl ester (200) (AA = arachidonic acid 1 Reagents:i MeS0,Cl; ii 1,8-diazabicyclo[5.4.O]undec-7-ene Scheme 91 COzMe I OOH H 15 -HPETE methyl ester I ii I H H (200) Reagents i 2,6-lutidine (CF,CO),O; ii K,CO, MeOH ;iii Et,N MeS0,Cl; iv 1,8-diazabicyclo[5.4.O]undec-7-ene Scheme 92 0 t CH l3 CO Me [ CH 1,CO zMe OHC C5H11 (2011 b\, 0 CH 1,CO Me 0‘--‘SHl1 iii -vi ICH,1 C0 H -c/ =v=l CH 1,CO ,H (202) Reagents i PPh,; ii NaBH,; iii EtMgBr; iv I,; v disiamylborane; vi LiNPr’,; vii BuLi; viii CH,N,; ix H, Lindlar catalyst Scheme 93 with the chiral epoxy-aldehyde (198).The resulting mixture of diene (203) and the iodide (204) was best achieved by way of diastereoisomers of type (1 99) undergoes a stereospecific a novel tetrabutylammonium cuprate. This new reagent also elimination to yield LTA methyl ester in an outstanding yield effects the conjugate addition reaction with substituted cyclo- of 90 YO.By using this protocol lipotriene A methyl ester (200) hexenones although in this particular instance the desired has been successfully prepared from arachidonic acid (Scheme tetraenone (208) was most easily prepared by coupling the 91) and more recently from 15-HPETE14 (Scheme 92). Gilman vinylcopper derivative of (206) with the ynone (207).7.2 12-HPETE and 12-HETE 7.3 8-HETE and 9-HETE The two pairs of diastereoisomers (201) and (202) (Scheme 93) In a further development of their work on the rhodium-acetate- both of which are putative metabolites of (1251-12-HPETE catalysed addition reactions of diazocarbonyl compounds to have been synthesized by Corey et 146 furans Rokach and Adams14* have accomplished the first total A most efficient three-component synthesis of racemic 12- racemic synthesis of the chemotactic agents 8-HETE and 9- HETE (Scheme 94) has been devised by Corey and co-HETE (Scheme 95). worker^.'^' The formation of (205) by coupling between the NATURAL PRODUCT REPORTS 1988-T. W. HART 35 I Bu,Sn /=v=\Li XT c . I3C!O> o-/ (2031 (2041 (205) X = SnBu3 (206) X = Li ..... II Ill 1 ( 207 1 (2 1-12 -HETE (208) Reagents i Bug” [Cu(CN),]-; ii BuLi CuBr.Me,S; iii (207); iv NaBH,; v NaHSO, aqueous DME Scheme 94 ~C~C[CH213C02Me + LiC E C [CH 13C(OMe)3 -HO 1. I -111 t.. .). r 1 C=C[CH213 C02Me C5H, -c==-co2H CHO (2)-8 -HETE C=C CH*C =C C 5H 11 J (2)-9 -HETE Reagents i Jones oxidation; ii ClC(O)C(O)Cl; iii CH,N,; iv furan [Rh(OAc),], for 2 hours at 20 “C; v rearranges on standing Scheme 95 NATURAL PRODUCT REPORTS 1988 ICH I3CO2Me Ph3P Bu Ph,S i0. CHO -=vy[CH,I ,CO ,Me + OSiPh Bu' w I (2091 bSiPh ,But (210) threo I OH OH OSiPhzBut OSi Ph,Bu I I I I I u l 'SH1.1 H 2 1 3 CO,H (5SJ12S) -5,12 -DiHETE (LTB,l(211) Scheme 96 CEC-SiMe ... Br I I1 'SHl1 ______) + w ic =CH \ C GCH =c WC""" I OSiMe But OSiMe,Bu' -,AMezBu+ Br [CH213CO Me I,CO,H iv -v; I (213) I OH 5 15 -DiHETE \+==C&l \ 'OSiMeBu' Reagents i [Pd(PPh,),] PrNH, CuI benzene at 25 "C; ii AgNO, KCN EtOH H,O; iii (213) [Pd(PPh,),] PrNH, CuI benzene at 25 "C; iv H, Lindlar catalyst; v HF pyridine; vi LiOH THF H,O Scheme 97 7.4 5-HETE and LTB Chemists at Merck Frosst have p~epared~",'~~ both 5-HETE and its arachidonate 12-lipoxygenase metabolite LTB (211) [(5S,12s)-5,12-DiHETE] from the common intermediate (209) (Scheme 96). LTB, which is isomeric with its more abundant isomer LTB, is found in human leukocytes and exhibits weak chemotactic activity although its biological function is unclear.It is interesting to note that while Wittig reactions of allylic phosphoranes normally form the (Z)-olefin in this instance the (@-isomer predominates over the (9-isomer in a 3 1 ratio. The greater rate of decomposition of the threo-betaine (210) over its erythro counterpart is thought to be responsible for this result. A series of (8S,15s)-and (8R,5s)-diastereoisomers I of 8,l 5-LTB4 and 8,l 5-LTBX have been similarly prepared from arabinose by the same group of ~0rkers.l~' 7.5 5,15-DiHETE and 8,15-DiHETE Nicolaou and Webber have synthesi~ed'~~ 5,15-DiHETE (Scheme 97) and 8,ISDiHETE (Scheme 98) by using an elegant methodology which is heavily based on the palladium-catalysed coupling of silylated acetylenes with vinyl bromides.7.6 The Lipoxins When Serhan Hamberg and Samuel~son'~~ incubated 15-HPETE (214) with human leukocytes in the presence of the calcium ionophore A23I87 they isolated two major highly NATURAL PRODUCT REPORTS 1988-T. W. HART OThp OThD 111 -v . .. ~ iiAILOH C I i SiMe3 SiMe OH OH I I I OH 6 Si Me But 8 15 -DiHETE Reagents i Bu',AlH ;ii Me,SiC-CCH=PPh,; iii pyridinium chlorochromate ; iv Ph,P=CH[CH,],CO,Na ;v CH,N,; vi (2 13) [see Scheme 971 [Pd(PPh,),] PrNH, CuI benzene at 25 "C;vii H, Lindlar catalyst; viii HF pyridine; ix LiOH THF H,O Scheme 98 OH Arachidonic acid I OH LX -A (215) I I OOH OH (15s)-15 -HPE TE (2141 OH LX -B (216) Scheme 99 polar fractions A and B both of which contained a conjugated Some doubt remains over the absolute stereochemistry of the tetraenetriol system and which are are now generally referred to vicinal alcohol functions and over the geometry of the double- as the lipoxins (lipoxygenase interaction products).Lipoxin A bond in lipoxin B (LX-B) (216) although the initial analysis by (LX-A) (2 15) (Scheme 99) possesses some very interesting the workers at Karolinska did allow a tentative assignment of biological properties such as the ability to inhibit natural killer the two structures (215) and (216) for LX-A and LX-B cells and to initiate the release of superoxide ion. The biological respectively . significance of these findings will no doubt be revealed in future Chemists at Merck Frosst1j4 have proposed a possible publications.pathway for the conversion of 15-HPETE into LX-A and LX- NATURAL PRODUCT REPORTS 1988 [CH,l ,CO,H I OH (218 1 \ LX-A (2151 L X-B (216) I bOH OH I 5 15 -DiHPETE (2171 (219) Scheme 100 [ CH ,l,CO ,Et OHC 1 I OH OH (2211 Scheme 101 F[CH I ,CO ,Me I - v [ C H 1,CO ,Me + CO Me I 1 I I OH 6H OH (2221 (2231 (2241 Reagents i ~(O)(acac),],Bu'OOH Scheme 102 B from 5J5-DiHPETE (217) (Scheme 100). They considered that the latter could undergo enzymatic rearrangement in similar fashion to that observed for the formation of LTA from 5-HPETE7to form the polyene epoxides (218) and (219) which could then be hydrolysed enzymatically to LX-A and LX-B respectively.To support this theory they synthesized (220) (Scheme 101) from 2-deoxy-~-riboseand D-arabinose exploiting much of their earlier methodology. Upon hydrolysis in vitro (220) furnished (221) as the major component; this as its methyl ester displayed similar spectroscopic properties to those that had been published by the workers at Karolinska for LX-A. 7.7 The Epoxygenase Pathway In 1981 it was demonstrated that arachidonic acid is converted by enzymes of the cytochrome P-450 class into a series of biologically active regioisomeric cis-epoxyicosatetraenoic acids (EETs). This discovery opened up new vistas for connoisseurs of the arachidonic acid cascade since these epoxides should also be substrates for the many endogenous glutathione transferases that abound.Corey's group along with that of Falck and Capdevila have been responsible for most of the original synthetic work. Members of the latter group have recently prepared155-156 a variety of EETs as well as their putative hydrolysis and oxidation products as illustrated in Schemes 102 103 and 104. Allylic epoxidation of methyl (15s)-15-hydroxyicosatetra-enoate (222) afforded a 1:2.3 ratio of (223) to (224). After saponification (223) could be converted into the (14S,15s)-14,15-DiHETE (226) or rearranged to (225). trans-( 14R 15R)-14,15-EET (228) was formed in 57 % yield from (224) by its mesylation followed by reduction with sodium borohydride. The synthesis of (14R,15s)-14,15-EET (231) and (14S,I5R)- NATURAL PRODUCT REPORTS 1988-T.W. HART 39 C5H11 C,H1 1 i bH OH (223) (225) I Ill \ -CH2l3CO2 H wc5H1 0 (228) (226) Reagents i NaOH; ii (Me,Si),NLi; iii NaBH, DMSO; iv MeS0,Cl; v NaBH Scheme 103 CO ,Me \\ I 0 (233) 4 0 0 iii -v . .. I I1 (226) (2291 (231) 0 111 -v OMe -0 C5H11 C0,Me wc5H11 0 (234) Reagents i 2-thiopyridyl chloroformate ;ii toluene at 115 "C ; iii mesylation ;iv saponification ;v CH,N Scheme 104 NATURAL PRODUCT REPORTS 1988 Arachidonic acid (236) X = H ,OH (237) X = 0 . .. I II R (238) R = CH,OH (239) R = C02H Reagents i 10 YOHC10,; ii Pb(OAc) Scheme 105 ETYA (240) 14,15-EET (232) was best achieved from (226) which was converted into an equimolar (yet easily separable) mixture of the lactones (229) and (230) respectively.Sequential mesyl- ation saponification and re-esterification afforded the desired EETs (231) and (232) which are known to be precursors of the isomeric EETs (233) and (234) respectively. A variety of lipoxygenase-type (Z,E)-dienols and w(w -1) oxidation products have now been isolated although the nature and composition of these metabolites is much dependent upon the biological origin of the enzyme system. When arachidonic acid is incubated with the cytochrome P-450 from pig kidney cortex microsomes the major products that can be isolated are 19- and 20-hydroxyicosatetraenoic acids and their oxidation products.Because the o-oxidation pathway repre- sents a possible route for detoxifying the products of the arachidonic acid cascade,lo3 the putative metabolites of the type (236) (237) (238) and (239) (Scheme 105) which have been prepared by Falck and co-w~rkers,'~' are of great biological interest. 8 Inhibitors of Arachidonate Lipoxygenases Some twenty years ago Blain and Shearer1j8 reported that icosa- 5,8,1 I 16tetraynoic acid (240) (ETYA) inhibits soybean arachi- donate 15-lipoxygenase. More recently following the discovery of the corresponding mammalian pathways a variety of acetylenic analogues have been prepared in a world-wide attempt to discover selective inhibitors of arachidonate 5-lipoxygenase. Corey and Eckrich'j9 have opened up a new route to 5,6-di-dehydroarachidonic acid (242) (Scheme 106) by way of a re- iterative coupling technique.Their method introduces a most interesting synthetic tactic for the preparation of (a-olefins based upon cis-carbostannylation (using tributyltin triflate). The mechanism of action of (242) as an irreversible inhibitor of arachidonate 5-lipoxygenase has been discussed.16o 162 It is proposed that inactivation of the enzyme which occurs in a time- and oxygen-dependent manner is due to the formation of a vinylic hydroperoxide of the type (243) (Scheme 107). This in theory rapidly decomposes by a radical mechanism causing lethal damage to the catalytic site. Chemists at Syntex have shownlG3 that the 4,5-allenic derivative (244) (Scheme 108) has approximately the same inhibitory activity as ETYA in preventing the formation of LTB, but was twice as potent in inhibiting the biosynthesis of 5-HETE.Because it is thought that a high-spin d' Fe"' ion plays a key role at the catalytic site of the arachidonate lipoxygenase enzymes a variety of potential chelating agents were prepared by Corey and co-w~rkers.'~~ Potent inhibitory activity towards arachidonate 5-lipoxygenase was obtained with N-hydroxy- NATURAL PRODUCT REPORTS 1988-T. W. HART ( C H11 1 CuLi I1 iii -v Bu,Sn Bu,Sn ‘SH1 1 \c5H1 iii -v (242) (2411 Reagents i HCGCH; ii Bu,SnOSO,CF,; iii BuLi; iv MgBr, LiCuC1 (catalyst); v (a-Bu,SnCH=CHCH,OAc; vi CuCN ; vii NaHSO, aqueous DME then LiOH Scheme 106 OOH h[CHz I3COzH P 5 -LO (2421 -3c02 ” (2431 (5 -LO = arachidonate 5 -lipoxygenase 1 Scheme 107 HC =C[CH,120SiMe2 But i -iv 4 v vi Cl[CH I2C ZZCt C H 1 0SiMe Bu t __I___) vii1 viii -CL [CH ,I2CH =C =CH[ CH l2 OSi Me But (2441 Reagents i LiNH,; ii ethylene oxide; iii MeS0,Cl; iv LEI; v H, Lindlar catalyst; vi CHBr, KOH phase-transfer catalyst; vii BuLi; viii standard methodology Scheme 108 NATURAL PRODUCT REPORTS 1988 R (245) R = H,Me or But (246) 0 CO H Br oHcXco2H... I I1 Me 0,C X\_/CIHll iii -vii _____) viii ,ix iiI - CO Me u ! C H ,l,CO 'SH1 1 H x -xii (&SHll Reagents i Ph,P=CHC,H1,; ii CH,N,; iii Bu',AIH at -78 "C; iv pyridinium chlorochromate; v Ph,P=CH[CH,],OSiMe,Bu'; vi Bu,N+ F-; vii CBr, PPh,; viii PPh, MeCN; ix sodium salt of (249) NaN(SiMe,),; x Bui,AIH at 0 "C; xi SO:, pyridine; xii Ph,P=CH[CH,],CO,H amides of the type (245).It is interesting to note that on a molar basis these derivatives are roughly 100000 times more potent as inhibitors of the synthesis of leukotrienes than is aspirin of the biosynthesis of prostaglandins. That the full icosanoid skeleton was not a prerequisite for activity was demonstrated by the potency of (246) (247) and (248) which displayed EC, values of 1.9 10 and 15 pmol dm- respectively at a concentration of 6 pmol dm-3 of arachidonate. A large number of leukotriene analogues containing varying degrees of unsaturation and different geometries about their double-bonds have been p~epared.l~~-~~~ It is notable that LTC and 11-trans-LTC as well as analogues of LTD that lack up to three double-bonds still possess considerable activity.Chemists at Hoffmann-La Roche17' have synthesized a series of 7-and 10-methylated analogues' of arachidonic acid which were all inhibitors of ionophore-induced biosynthesis of slow-reacting substance of anaphylaxis in rat peritoneal cells although their mode of action appeared to be on phospholipase A rather than on arachidonate 5-lipoxygenase. In an extremely interesting approach Nicolaou and co-worker~'~~~'~~ have prepared a number of monoethano- and polyethano-arachidonic acid derivatives in which the Z-olefin geometry is preserved but in which the important doubly allylic positions C-7 C-10 and C-13 have been substituted (Scheme 109).The synthesis of these analogues is characterized by the higher degree of geometrical control that is afforded by the Lindlar hydrogenations and the Wittig olefinations and perhaps even more so by the minimal use of protecting groups. Of particular interest was the bis-ethano-derivative (250) which was considered to be a potent inhibitor of arachidonate 12-lipoxygenase. In an extension of this rationale the C(7)-C(l3)-bridged derivative (251) (Scheme 110) was recently prepared17,via a divinylcyclopropane rearrangement. NATURAL PRODUCT REPORTS. 1988-T. W. HART v -vii _____) viii I ix x COzH A (251 1 Reagents i LiAlH,; ii ClC(O)C(O)Cl DMSO Et,N CH,Cl,; iii Ph,P=CHCrCSiMe,; iv AgNO, KCN EtOH H,O; v BuLi then C,H,,I; vi BuLi then (MeO),C[CH,],I; vii H,O’; viii 200 “C; ix H, Lindlar catalyst; x LiOH H,O THF Scheme 110 9 Bibliography ‘Advances in Prostaglandin Thromboxane and Leukotriene Re-search’ ed.B. Samuelsson R. Paoletti and P. W. Ramwell Raven Press New York 1983 Vol. 11. ‘Advances in Prostaglandin Thromboxane and Leukotriene Re-search’ ed. B. Samuelsson R. Paoletti and P. W. Ramwell Raven Press New York 1983 Vol. 12. N. H. Andersen ‘Structure-activity correlations for prostanoid ac-tion ’,‘in ‘Handbook of Prostaglandins’ ed. P. B. Curtis-Prior Churchill Livingstone Edinburgh. R. F. Newton S. M. Roberts and R. J. K. Taylor ‘Strategies em-ployed in the synthesis of prostacyclins and thromboxanes’ Synthesis 1984 449.Prostacyclins thromboxanes and leukotrienes ’ ed. S. Moncada Br. Med. Bull.. 1983 39 209. E. J. Corey D. E. Clark and A. Marfat ‘Structure elucidation and total synthesis of the leukotrienes’ in ‘The Chemistry and Biology of Leukotrienes and Related Substances’ ed. L. W. Charkin and D. M. Bailey Academic Press New York 1984 p. 14. E. J. Corey and A. Marfat ‘Chemical studies on slow reacting substances/leukotrienes ’ in ‘Second RSC-SCI Medicinal Chemistry Symposium’ ed J. C. Emmett The Royal Society of Chemistry London 1984 p. 207. R. H. Green and P. F. Lambeth ‘Leukotrienes’ Tetrahedron. 1983 39 1687. W. Kreutner and M. 1. Siege] ‘Biology of leukotrienes’ Annu. Rep. Med. Chem.1984 19 241. 10 References 1 S. M. F. Lai and P. W. Manley Nut. Aod. Rep. 1984 1 409. 2 B. Bergstrom Angew. Chem. Int. Ed. Engl. 1983 22 858. 3 B. Samuelsson Angew. Chem. Int. Ed. Engl. 1983 22 805. 4 J. R. Vane Angew. Chem. Int. Ed. Engl. 1983 22 741. 5 B. Riefling ‘Principles of prostaglandin synthesis Part 1 ’ Kuntakte (Darmstadt) 1983 2 26. 6 B. Riefling ‘Principles of prostaglandin synthesis Part 2’. 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Lombardo Tetrahedron Lett. 1984 25 227. 25 Y. Guindon R. Fortin C. Yoakim and J. W. Gillard Tetra-hedron Lett. 1984 25 4717. 26 Y. Ogawa and M. Shibasaki Tetrahedron Lett. 1984 25 663. 27 C. 0-Yang and J. Fried Tetrahedron Lett. 1983 24 2533. 28 M. M. Midland A. Tramontano A. Kazubski R. S. Graham D. J. S. Tsai and D. B. Cardin. Tetrahedron 1984 40 1371. 29 Y. Torisawa H. Okabe and S. Ikegami Chem. Lett. 1984 1555. 30 R. Noyori and M. Suzuki Angew. Chem. Int. Ed. Engl. 1984 23 847. 31 T. Tanaka A. Hazato K. Bannai N. Okamura S. Sugiura K. Manabe S. Kurozumi M. Suzuki and R. Noyori Tetrahedron L,ett. 1984 25 4947. 32 T. Tanaka T.Toru N. Okamura A. Hazato S. Sugiura K. Manabe and S. Kurozumi Tetrahedron Lett. 1983 24 4103. 33 M. Suzuki A. Yanagisawa and R. Noyori Tetrahedron Lett. 1984 25 1383. 34 S. Sugiura T. Toru T. Tanaka A. Hazato N. Okamura K. Bannai K. Manabe S. Kuruzomi and R. Noyori Chem. Pharm. Bull. 1984 32 4658. 35 R. E. Donaldson J. C. Saddler S. Byrn A. T. McKenzie and P. L. Fuchs J. Org. Chem. 1983 48 2167. 36 J. Nokami T. Ono Y. Kajitani and S. Wakabayashi Chem. Lett. 1984 707; see also J. Nokami T. Ono S. Nakagawa and S. Wakabayashi ibid. 1983 125 1. 37 L. L. Vasil’eva V. I. Mel’nikova E. T. Gainullina and K. K. Pivnitskii Zh. Org. Khim. 1983 19 941. 38 M. A. Dyadchenko Yu. A. Baslerova A. E. Grigor’ev V. I. Mel’nikova and K. K.Pivnitskii Zh. Ohshch. Khim. 1984 54 945. 39 L. L. Vasil’eva V. 1. Mel’nikova and K. K. Pivnitskii Zh. Org. Khim. 1984 20 690. 40 P. J. Brown D. N. Jones M. A. Khan N. A. Meanwell and P. J. Richards J. Chem. Soc. Perkin Trans. I 1984 2049. 41 H.-J. Gais T. Lied and K. L. Lukas Angew. Chem. 1984 96 495. 42 A. P. Kozikowski and P. D. Stein J. Org. Chem. 1984 49 2301. 43 D. P. Curran Tetrahedron Lett. 1983 24 3443. 44 S. Amemiya K. Kojima and K. Sakai Chem. Pharm. Bull. 1984 32 913. 45 J. P. Marino R. Fernandez de la Pradilla and E. Laborde J. Org. Chem. 1984 49 5279. 46 A. Misumi K. Furuta and H. Yamamoto Tetrahedron Lett. 1984 25 67 I. 47 H. J. Jaffer and P. L. Pauson J. Chem. Res. (8,1983 244. 48 S. Schwarz G. Weber M. Meyer H.Schick and H. P. Welzel J. Prakt. Chem. 1984 326 667. 49 H. Schick H. Schwarz F. Theil and S. Schwarz J. Prakt. Chem. 1984 326 426. 50 S. Schwarz C. Carl G. Weber and H. Schick J. Prakt. Chem. 1984 326 1016 51 P. A. Grieco and T. T. Vedananda J. Org. Chem. 1983 48 3497. 52 T. K. Schaaf M. R. Johnson M. R. Eggler J. F. Bindra J. W. Constantine and H. J. Hess in ‘Advances in Prostaglandin Thromboxane and Leukotriene Research ’ ed. B. Samuelsson R. Paoletti and P. Ramwell Raven Press New York 1983 Vol. 11 p. 313. 53 T. K. Schaaf M. R. Johnson J. W. Constantine J. S. Bindra H. J. Hess and W. Elger J. Med. Chem. 1983 26 328. 54 D. Favara U. Guzzi R. Ciabatti F. Battaglia and A. Depaoli Gazz. Chim. Ital. 1984 114 233. 55 E. J. Corey and K.Shimoji J. Am. Chem. Soc. 1983. 105 1662. 56 E. J. Corey S. Ohuchida and R. Hahl J. Am. Chem. Soc. 1984 106,3875;see also E. J. Corey C. Shih and J. R. Cashman Proc. Natl. Acad. Sci. USA 1983 80 3581. 57 J. Fried E. A. Hallinan and M. J. Szwedo Jr. J. Am. Chem. Soc. 1984 106 3871. 58 €-I. A. J. Carless and G. K. Fekarurhobo J. Chem. SOC., Chem. Commun. 1984 667. 59 M. F. Ansell J. S. Mason and M. P. L. Caton J. Chem. Soc. Perkin Trans. I 1984 1061. 60 P. W. Sprague J. E. Heikes D. N. Harris and R. Greenberg in ‘Advances in Prostaglandin Thromboxane and Leukotriene Research’ ed. B. Samuelsson R. Paoletti and P. Ramwell Raven Press New York 1983 Vol. 11 p. 337. 61 S. Ohuchida N. Hamanaka and M. Hayashi Tetrahedron. 1983 39 4257. 62 M.F. Ansell M. P. L. Caton. and K. A. J. Stuttle J. Chem. Soc. Perkin Trans. 1 1984. 1069. 63 M. F. Ansell M. P. L. Caton A. F. Drake and K. A. J. Stuttle Tetrahedron Lett. 1983 24 301 7. 64 Y. Bounameaux J. W. Coffey M. O’Donnell K. Kling R. J. Quinn P. Schonholzer A. Szente L. D. Tobias T. Tschopp A. F. Welton and A. Fischli Helv. Chim. Acta 1983 66 989. 65 D. Blondet and C. Morin J. Chem. Soc. Perkin Trans. I 1984 1085. 66 S. Ohuchida N. Hamanaka and M. Hayashi Tetrahedron 1983 39 4263. 67 S. Ohuchida N. Hamanaka and M. Hayashi Tetrahedron. 1983. 39 4269. 68 S. Ohuchida N. Hamanaka and M. Hayashi. Tetrahedron 1983 39 4273; see also S. Ohuchida N. Hamanaka and M. Hayashi in ‘Advances in Prostaglandin Thromboxane and Leukotriene Research’ ed.B. Samuelsson R. Paoletti and P. Ramwell Raven Press New York 1983 Vol. 11 p. 312. NATURAL PRODUCT REPORTS 1988 69 V. N. Kale and D. L. J. Clive J. Org. Chem. 1984 49 1554. 70 J. L. Adams and B. W. Metcalf Tetrahedron Lett. 1984 25 919. 71 E. J. Corey S. G. Pyne and A. I. Schafer Tetrahedron Lett. 1983 24 3291. 72 M. Katsura T. Mizamoto N. Hamanaka K. Konda T. Terada Y. Ohgahi A. Kawasaki and M. Tsuboshima in ‘Advances in Prostaglandin Thromboxane and Leukotriene’ Research ’ ed. B. Samuelsson R. Paoletti and P. Ramwell Raven Press New York 1983 Vol. 11 p. 351. 73 K. Shimizu J. D. 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Yamada Tetrahedron Lett. 1984 25 3621. 84 E. J. Corey B. De J. W. Ponder and J. M. Berg. Tetrahedron Lett. 1984 25 1015. 85 E. J. Corey and B. De J. Am. Chem. SOC. 1984 106 2735. 86 J. J. Stezowski L. Flohe and H. Bohlke J. Chem. Soc. Chem. Commun. 1983 1315. 87 T. Ichikawa M. Namikawa K. Yamada K. Sakai and K. Kondo Tetrahedron Lett 1983 24 3337. 88 R. G. Salomon D. B. Miller S. R. Raychaudhuri K. Avasthi K. Lal and B. S. Levison J. Am. Chem. Soc. 1984,106,8296; see also B. S. Levison D. B. Miller and R. G. Salomon Tetrahedron Lett. 1984 25 4633. 89 A. D. Baxter S. M. Roberts B. J. Wakefield G. T. Woolley and R. F. Newton J. Chem. Soc. Perkin Tram.I 1984 675. 90 M. Suzuki A. Yanagisawa and R. Noyori Tetrahedron Lett. 1983 24 1187. 91 S. Fischer and P. C. Weber Nature (London) 1984 307 165. 92 G. Galambos V. Simonidesz J. Ivanics K. Horvath and G. Kovacs Tetrahedron Lett. 1983 24 315 1281. 93 T. Ono I. Sibasaka J. Nokami and S. Wakabayashi Chem. Lett. 1983 1249. 94 L. Flohe H. 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Zamboni Tetruhedron Lett. 1984 25 1279. 104 N. Mongelli A. Andreon] L. Zuliani and C. A. Gandolfi Tetra-hedron Lett. 1983 24 3527. 105 H. Bestmann G. Schade and G. Schmid Ange,t*.Chem. Int. €d. Engl. 1980 19 822. NATURAL PRODUCT REPORTS 1988-T. W. HART 106 K. Ueno H. Suemune and K. Sakai Chem. Pharm. Bull. 1984 32 3768. 107 B. F. Riefling and H. E. Radunz Tetrahedron Lett. 1983 24 5487. 108 S. Amemiya K. Kojima and K. Sakai Chem. Phurm. Bull. 1984 32 1349. 109 S. Amemiya K. Kojima and K. Sakai Chem. Pharm. Bull. 1984 32 4746. 110 K. Kojima. S. Amemiya K. Koyama and K. Sakai Chem. Pharm. Bull. 1983 31 3775. 111 C.-L. J. Wang Tetrahedron Lett. 1983 24 477. 112 P. G. Baraldi A. Barco S. Benetti C. A. Gandolfi G. P. Pollini and D. Simoni Tetrahedron Lett. 1983 24 4871. 113 S. Amemiya K. Kojima and K. Sakai Chem. Pharm. Bull. 1984 32 805. 114 G. L. Bundy and J. M. Baldwin Tetrahedron Lett. 1978 1371.115 M. Shibasaki Y. Torisawa and S. Ikegami Tetrahedron Lett. 1983 24 3493. 116 Y. Torisawa H. Okabe M. Shibasaki and S. Ikegami Chem. Lett. 1984 1069. 117 M. Shibasaki H. Fukasawa and S. Ikegami Tetrahedron Lett. 1983 24 3497. 118 Y. Torisawa H. Okabe and S. Ikegami J. Chem. Soc. Chem. Commun. 1984 1602. 119 Y. Ogawa and M. Shibasaki Tetrahedron Lett. 1984 25 1067. 120 M. Shibasaki M. Sodeoka and Y. Ogawa J. Org. Chem. 1984 49 4096. 121 M. Sodeoka and M. Shibasaki Chem. Lett. 1984 579. 122 T. Mase M. Sodeoka and M. Shibasaki Tetrahedron Lett. 1984 25 5087. 123 K. Koyama and K. Kojima Chem. Pharm. Bull. 1984 32 2866. 124 R. H. Bradbury and K. A. M. Walker J. Org. Chem. 1983 48 1741. 125 S. R. Baker J. R. Boot S. E. Morgan D.J. Osborne W. J. Ross and P. R. Shrubsall Tetrahedron Lett. 1983 24 4469. 126 W. Bartmann G. Beck J. Knolle and R. H. Rupp in ‘Trends in Organic Synthesis ; Proceedings of the 4th International Con- ference’ ed. H. Nozaki Pergamon Press Oxford 1983 p. 15. 127 P. Heath. J. Mann E. B. Walsh and A. H. Wadsworth J. Chem. Soc. Perkin Trans. 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Webber J. Chem. Soc. Chem. Commun. 1984. 350.

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MASS SPECTROMETRY BULLETIN Mass Spectrometry Bulletin aims to cover all aspects of mass spectrometry including trends and developments in the theory instrumentation and application * Monthly issues produced by scanning over 400 primary journals * Also includes material from books technical reports abstracting publications and conference proceedings * 800 items per issue containing titles and bibliographic details * Five Issue Indexes Subject; Author; Elements; General and Compounds Classification; cumulated annually as a separate issue. PRICE Jan-Dec 1988 UK f230.00 USA $440.00 ROW f255.00 BENEFITS TO YOU THE MSB READER INCLUDE. . . ...A SIGNIFICANTADVANTAGE Because MSB covers all aspects of mass spectrometry its content is relevant to all applications within this broad field and you can be confident that it references every significant paper published in your area of interest.MSB contains three times as many references as any other secondary mass spectrometry source! . TAILORED INDEXES MSB contains indexes that other sources lack. Furthermore these five comprehensive indexes are designed to lead you to the mass spectrometric content of papers content not always apparent from document titles. As a mass spectroscopist you'll find MSB indexes tailored to suit your needs helping you to find the relevant information you require both quickly and easily! Many MSB entries are published within eight weeks of receipt of the primary journal making this a highly current secondary source.Use MSB; it will save you time and effort previously spent scanning the primary literature yourself freeing you to concentrate on other aspects of your work. To order by credit card -ROYAL PLEASE SEND ME A FREE SAMPLE OF MSB 0 Access Mastercard Eurocard SKIETY OF or Visa -phone (0602) CHEMISTRY Name f&/& 507411 quoting your credit card details or write to the Position address below. (We can of Address course accept payment by cheque or will issue pro-forma invoices if required.) ~ ~ Return this slip to Alison Cowley Sales &nPromotion Department ~~~b Royal Society of Chemistry The University Nottingham NG7 2RD England Looking for relevant information in the diverse field of biotech no Iog y ? Don’t let your time slip through the sandglass o manual literature search ng! Instead read CURRENT BIOTECHNOLOGY UK f248.00 USA $478.00 ROW f272.00 ABSTRACTS I CURRENT BIOTECHNOLOGY ABSTRACTS (CBA) is a monthly current awareness publication spanning all major growth areas of biotechnology.Each issue contains up to 500 items including abstracts and ( coverage includes UK European US and PCT (World) patents. For example 712 Substance useful as a thickening agent and/or emulsion stabilizer. Kawaguchi K. (Kureha Kagaku Kogyo Japan) European Patent Appl. EP 0247899. Pub. 2 Dec 1987. Appl. JP 125347/86,filed 30 May 1986.-The highly viscous substance BS-1 was obtained by cultivation of Klebsiellu pneumoniue KPS 5002 (FERM BP-625) in lactose at pH 4-8 and 2532°C for 3-7 days and was useful as a thickening agent or an emulsion stabilizer for foods medicines cosmetics or chemicals.CBA is also indexed by Subject Substance and Company to give you rapid and easy access to items of particular interest. Save time with CBA! ROYAL PLEASE SEND ME A FREE SAMPLE OF CBA 0 To order by credit card -SOCIETYOF Access Mastercard Eurocard CHEMISTRY Name or Visa -phone (0602) feNJ 507411 quoting your credit Position card details or write to the Address address below. LWe can of course accept payment by chequeor will issue pro-forma Information Return this slip to Alison Cowley Sales & Promotion Department invoices if required.) Services Royal Society of Chemistry The University Nottingham NG7 2RD England PRINTED IN GREAT BRITAIN BY THE UNIVERSITY PRESS CAMBRIDGE

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ISSN 0265-0568 NPRRDF 5 1-1-1-54 (1988) Natural Product Reports A journal of current developments in bio-organic chemistry Volume 5 Indexes CONTENTS ... 111 Preliminary pages for Volume 5 1-1 Index of Authors Cited 1-37 Subject Index ISSN 0265-0568 Coden NPRRDF Natural Product Reports A journal of current developments in bio- organic chemistry Volume 5 1988 The Royal Society of Chemistry London ~~ Natural Product Reports (ISSN 0265-0568) @ The Royal Society of Chemistry 1988 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers.Printed in Great Britain by the University Press Cambridge ISSN 0265-0568 NPRRDF 5 1-663 1-1-1-54 (1988) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 5 CONTENTS 1 Prostaglandins Thromboxanes Leukotrienes and Related Arachidonic Acid Metabolites T. W. Hart Reviewing the literature published during 1983 and 1984 47 Antibiotics with Antifungal and Antibacterial Activity Against Plant Diseases 67 Tropane Alkaloids G. Fodor and R. Dharanipragada Reviewing the literature published between July 1985 and December 1986 73 The Biosynthesis of Shikimate Metabolites P. M. Dewick Reviewing the literature published during 1986 99 Errata to The Biosynthesis of Triterpenoids and Steroids D.M. Harrison (Vol. 2 No. 6 p. 525) P. A. Worthington 101 The Use of N.M.R. Spectroscopy in the Structure Determination of Natural Products One-Dimensional Methods I. H. Sadler 129 The Biosynthesis of Penicillins and Cephalosporins J. E. Baldwin and Sir Edward Abraham 147 Steroids Reactions and Partial Syntheses J. Elks Reviewing the literature published during 1985 187 Non-Macrocyclic Trichothecenes J. F. Grove Reviewing the literature published between January 1971 and December 1986 21 1 Diterpenoids J. R. Hanson Reviewing the literature published during 1986 229 Naturally Occurring Isocyanides M. S. Edenborough and R. B. Herbert 247 The Biosynthesis of C5-C2, Terpenoid Compounds M. H. Beale and J. MacMillan Reviewing the literature published during 1986 265 P-Phenylethylamines and the Isoquinoline Alkaloids K.W. Bentley Reviewing the literature published between July 1986 and June 1987 293 Quinoline Quinazoline and Acridone Alkaloids M. F. Grundon Reviewing the literature published between July 1985 and June 1987 309 Book Review Secondary Metabolism (Second Edition) by J. Mann Reviewed by G. W. Kirby 309 Book Review Biologically Active Natural Products ed. K. Hostettmann and P. J. Lea Reviewed by A. Pelter NATURAL PRODUCT REPORTS 1988 CONTENTS 31 1 Steroids Reactions and Partial Syntheses Reviewing the literature published between December I985 and October I986 A. B. Turner 351 Imidazole Oxazole and Peptide Alkaloids and Other Miscellaneous Alkaloids J.R. Lewis Reviewing the literature published between July I985 and June I986 363 Brain Chemistry and Central Nervous System Drugs R. I. Brinkworth E. J. Lloyd and P. R. Andrews 387 The Biosynthesis of Triterpenoids Steroids and Carotenoids D. M. Harrison Reviewing the literature published during I984 and 1985 417 Book Review Dictionary of Antibiotics and Related Substances ed. B. W. Bycroft Reviewed by R. B. Herbert 419 Monoterpenoids D. H. Grayson Reviewing the literature published during I985 and I986 465 Trends in Protease Inhibition G. Fischer Reviewing the literature published between November I984 and January I987 497 Natural Sesquiterpenoids B. M. Fraga Reviewing the literature published during I986 523 The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites Reviewing the literature published between July I986 and June I987 541 Synthesis of Gibberellins and Antheridiogens L.N. Mander Reviewing the literature published to June I988 581 Natural Products from Plant Tissue Culture B. E. Ellis Reviewing the literature published between January I979 and December I986 613 Marine Natural Products D. J. Faulkner R. B. Herbert Reviewing the literature published between September I986 and December I987 I-1 Index of Authors Cited 1-37 Subject Index Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Professor M. F. Grundon University of Ulster at Coleraine Dr J.R. Hanson University of Sussex Dr R. B. Herbert U niversity of Leeds Professor M. I. Page The Polytechnic Huddersfield Professor T. J. Simpson University of Leicester Natural Product Reports is a journal of critical reviews published biomonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products. Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. This journal includes reviews of books relating to natural products. Volumes for review should be sent to the editorial office for which the address is The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF and marked for the attention of the Senior Editor Reviews. Contributors to Volume 5 Abraham Sir Edward 129 Faulkner D. J. 613 Kirby G. W. 309 Andrews P. R. 363 Baldwin J. R. 129 Beale M. H. 247 Bentley K. W. 265 Brinkworth R. I. 363 Dewick P. M. 73 Fischer G. 465 Fodor G. 67 Fraga B. M. 497 Grayson D.H. 419 Grove J. F. 187 Grundon M. F. 293 Lewis J. R. 351 Lloyd E. J. 363 MacMillan J. 247 Mander L. N. 541 Pelter A. 309 Sadler I. H. 101 Dharanipragada R. 67 Edenborough M. S. 229 Elks J. 147 Hanson J. R. 211 Harrison D. M. 99 387 Hart T. W. 1 Turner A. B. 311 Worthington P. A. 47 Ellis B. E. 581 Herbert R. B. 229 417 523 Nomenclature It is the policy of The Royal Society of Chemistry to en-courage the use of IUPAC and IUB Recommendations on nomenclature. Although many of the appropriate nomen-clature documents will be included in the new edition of the IUB publication ‘Biochemical Nomenclature and Related Documents ’ (to be published by The Biochemical Society London during 1989) a selection of recent Recommenda-tions that will be of particular interest to those who investigate the chemistry occurrence or biosynthesis of natural products includes Nomenclature of tetrapyrroles (Recommendations 1986) Pure Appl.Chem. 1987 59 779-832; Eur. J. Biochem. 1988 178 277-328. Nomenclature and symbols for folic acid and related compounds (Recommendations 1986) Pure Appl. Chem. 1987 59 833-836 ; Eur. J. Biochem. 1987 168 251-253. Nomenclature of prenols (Recommendations 1986) Pure Appl. Chem. 1987 59 683489; Eur. J. Biochem. 1987 167 181-184. Extension of Rules A-1.1 and A-2.5 concerning numerical terms used in organic nomenclature (Recommendations 1986) Pure Appl. Chem. 1986 58 1693-1696. [The original versions of these Rules are in ‘Nomenclature of Organic Chemistry Sections A B C D E F and H’ 1979 Edition] Nomenclature of glycoproteins glycopeptides and peptidoglycans (Recommendations 1985) Eur.J. Biochem. 1986 159 1-6. ‘Enzyme Nomenclature (Recommendations 1984) ’ Supplement 1 Corrections and additions Eur. J. Biochem. 1986 157 1-26. Recommendations for the presentation of thermodynamic and related data in biology (1985) Eur. J. Biochem. 1985 153 429434. Nomenclature for incompletely specified bases in nucleic acid sequences (Recommendations 1984) Eur. J. Biochem. 1985 150 1-5 (see also Eur. J. Biochem. 1986 157 1). ‘Enzyme Nomenclature 1984’ (Recommendations of the Nomenclature Committee of the International Union of Biochemistry on the nomenclature and classification of enzyme- catalysed reactions) Academic Press Orlando Florida 1984.Nomenclature and symbolism for amino acids and peptides (Recommendations 1983) Pure Appl. Chem. 1984 56 595-624; Eur. J. Biochem. 1984 138 9-37 (see also Eur. J. Biochem. 1985 152 1 and the Newsletter 1985 of NC-IUB and JCBN ibid. 1985 146 pp. 238 and 239 and the Newsletter 1986 ibid. 1986 154 pp. 485 and 486). Abbreviations and symbols for the description of conformations of polynucleotide chains (Recommendations 1982) Pure Appl. Chem. 1983 55 1273-1280; Eur. J. Biochem. 1983 131 9-15 (see also the Newsletter 1984 of NC-IUB and JCBN Eur. J. Biochem. 1984 138 p. 7). Symbols for specifying the conformation of polysaccharide chains (Recommendations 1981) Pure Appl. Chem. 1983 55 1269-1272; Eur. J. Biochem. 1983 131 5-7.Nomenclature of retinoids (Recommendations 198 I) Pure Appl. Chem. 1983 55 721-726; Eur. J. Biochem. 1982 129 1-5. Symbolism and terminology in enzyme kinetics (Recommendations 1981) Eur. J. Biochem. 1982 128 281-291. Polysaccharide nomenclature (Recommendations 1980) Pure Appl. Chem. 1982 54 1523-1526; Eur. J. Biochem. 1982 126 439441. Abbreviated terminology of oligosaccharide chains (Recommendations 1980) Pure Appl. Chem. 1982 54 1517-1522; Eur. J. Biochem. 1982 126 433437. Nomenclature of vitamin D (Recommendations 198 I) Pure Appl. Chem. 1982 54 1511-1516; Eur. J. Biochem. 1982 124 223-227. Nomenclature of tocopherols and related compounds (Recommendations 1981) Pure Appl. Chem. 1982 54 1507-1510; Eur. J. Biochem. 1982 123 473475. P The most recent of the lists of restriction endonucleases a their isoschizomers (compiled by R.J. Roberts) was in NudeT Acids Res. 1988 16 R271-R313 its predecessors being ibid. 1987 15 R189-R217 ibid. 1985 13 r165-r200 and ibid. 1983 11 r135-r167. Recent codes of nomenclature for organisms include ‘International Code of Nomenclature of Bacteria and Statutes of the International Committee on Systematic Bacteriology (1976 Revision)’ ed. S. P. Lapage P. H. A. Sneath E. F. Lessel V. B. D. Skerman H. P. R. Seeliger and W. A. Clark American Society for Microbiology Washington D.C. U.S.A. 1976. [Appendix 2 of this publication (Approved Lists of Bacterial Names) appeared in Znt. J. Syst. Bacteriol. 1980 30,225420.1 ‘International Code of Botanical Nomenclature (1987) ’ ed.W. Greuter H. M. Burdett W. G. Chaloner V. Demoulin R. Grolle D. L. Hawksworth D. H. Nicholson P. C. Silva F. A. Stafleu E. G. Voss and J. McNeill Koeltz Scientific Books Konigstein Federal Republic of Germany 1988. ‘International Code of Zoological Nomenclature ’ 3rd edn. ed. W. D. L. Ride C. W. Sabrosky G. Bernardi R. V. Melville J. 0. Corliss J. Forest K. H. L. Key and C. W. Wright International Trust for Zoological Nomenclature in association with the British Museum (Natural History) London U.K. and the California Press Berkeley and Los Angeles U.S.A. 1985.

ISSN:0265-0568    

DOI:10.1039/NP98805FP017

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Professor M. F. Grundon University of Ulster at Coleraine Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor M. I. Page The Polytechnic Huddersfield Professor T. J. Simpson University of Leicester Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products.Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products. Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568)is published bimonthly by The Royal Society of Chemistry Burlington House London W1V OBN England. 1988 Annual Subscription Price U.K. fl59.00,Rest of World €183.00,U.S.A. $342.00.Change of address and orders with payment in advance to The Rayal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 1 HN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003.Second-Class postage paid at Jamaica NY 11 431 -9998. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0The Royal Society of Chemistry 1988 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1988 U.K. f159.00 Overseas f183.00 U.S.A. US $342.00 Subscription rates for 1989 are U.K. €169.00 Overseas f 194.00 U.S.A. US $388.00 Subscription rates for back issues are (1984) (1985) (1986) (1987) U.K. f120.00 €1 25.00 f1 30.00 f142.00 Overseas f126.00 f131 .OO f143.00 f159.00 U.S.A. US $240.00 US $242.00 US $252.00 US $280.00 Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry 30 Russell Square LONDON WClB 5DT England

ISSN:0265-0568    

DOI:10.1039/NP98805FX021

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

BIOTRANSFORMATIONS A survey of the Biotransformations of Drugs and Chemicals in Animals Volume 1 Edited by David R. Hawkins Huntingdon Research Centre The series haspbeen devised to provide an up-to-date survey of the literature on the biotransformation of pharmaceuticals pesticides food additives and environmental and industrial chemicals in animals. The objective is to provide a comprehensive database which will allow an increased awareness of patterns in species differences and the influence of chemical structure on biotransformation pathways. The ability to predict biotransformation is the ultimate goal which could contribute to the discovery and development of new products. The material has been collated into chemical classes but an additional feature is the definition and allocation of key functional groups for each compound.The functional groups selected are those commonly associated with biotransformation. Indexing these functional groups provides ready access to reports on compounds containing common structural features. An additional index of biotransformation processes and compound names further increases the accessibility of relevant information. Contents Key Functional Groups; An Overview; Hydrocarbons Aliphatic Aromatic (Monocyclic/Bicyclic); Polycyclic Aromatic Hydrocarbons Unsubstituted Hydroxylated Derivatives Substituted; Alkenes Halogenoalkanes and Halogenoalkenes Alkenes (Epoxides) Halogenoalkanes Halogenoalkenes; Acyclic Functional Compounds; Substituted Monocyclic Aromatic Compounds Halogenoaryl Phenols Nitroaryl/NitrophenoIs Carboxylic Acids/Esters Ketones Aryl Amines Benzhydryls Arylalkylamines; Miscellaneous Aromatics; Heterocycles Monocyclic Five-membered Monocyclic Six-membered Monocyclic Seven-membered BicycWTricyclic; Functional Nitrogen Compounds; Nitrosamines; Amino Acids and Peptides; Steroids; Miscellaneous Inorganic and Organometallic Pyrethroids Organophosphorus Compounds Sulphur Compounds; Compound Index; Key Functional Group Index; Reaction Type Index ISBN 0 85186 157 1 February 1989 Hardcover 511 pages Price S75.00 ($150.00) CARBOHYDRATE CHEMISTRY Vol.20 Part I Senior Reporter Neil R. Williams Birkbeck College University of London Since Volume 14 Carbohydrate Chemistryhas been divided into two parts Part I -Mono- Di- and Tri-saccharides and their derivatives.Part 2 -Macromolecules. From Volume 19 Part I was renamed Monosaccharides Disaccharides and Specific Oligosaccharides. Carbohydrate Chemistry Volume 20 (Part I)provides a review of the literature published during 1986. Brief Contents Introduction and General Aspects; Free Sugars Glycosides and Disaccharides; Oligosaccharides; Ethers and Anhydro-sugars; Acetals; Esters; Halogeno-Sugars; Amino-sugars; Miscellaneous Nitrogen Derivatives; Thio-sugars; Deoxy-sugars; Unsaturated Derivatives; Branched-chain Sugars; Aldosuloses Dialdoses and Diuloses; Sugar Acids and Lactones; Inorganic Derivatives; Alditols and Cyclitols; Antibiotics; Nucleosides; NMR Spectroscopy and Conformational Features; Other Physical Methods; Separatory and Analytical Methods; Synthesis of Enantiomerically Pure Non-carbohydrate Compounds; Author Index.ROYAL ISBN 0 85186 242 X Published 1988 SOCIETYOF Hardcover 315pp Price E70.00 ($147.00) CHEMISTR’I For further information To Order please write to RSC Members are entitled to a please write to Royal Society of Chemistry Distribution discount on most RSC publications and Royal Society of Chemistry Centre Blackhorse Road Letchworth should write to lnformation Sales and Promotion department Herts SG6 1HN. U.K. The Membership Manager Services Thomas Graham House or telephone (0462) 672555 quoting Royal Society of Chemistry Science Park your credit card details. Thomas Graham House Milton Road We can now accept AccessNisal Science Park Milton Road Cambridge CB4 4WF.U.K. MasterCard/Eurocard. Cambridge CB4 4WF. U.K. NUCLEAR MAGNETIC RESONANCE Volume 17 Senior Reporter G. A. Webb University of Surrey Nuclear Magnetic Resonance Volume 7 7provides a review of the literature published between June 1986 and May 1987. Brief Contents N.M.R. Books and Reviews; Theoretical and Physical Aspects of Nuclear Shielding; Applications of Nuclear Shielding; Theoretical Aspects of Spin-Spin Couplings; Nuclear Spin Relaxation in Liquids; Solid State N.M.R.; Multiple Pulse N.M.R.; Natural Macromolecules; Synthetic Macromolecules; Conformational Analysis; Nuclear Magnetic Resonance of Living Systems; Oriented Molecules; Heterogeneous Systems. Nuclear Magnetic Resonance Volume 7 7 contains a foreword by the Senior Reporter and a detailed contents list.Each chapter includes extensive references. ISBN 0 85186 402 3 Specialist Periodical Report (1988) Hardcover 546 pages Price E1lO.OO ($220.00) PHOTOCHEMISTRY Volume 19 Senior Reporters D. Bryce-Smith and A. Gilbert University of Reading Photochemistry Volume 79 provides a review of the literature published between July 1986 and June 1987. Brief Contents Part l Physical Aspects of Photochemistry Photophysical Processes in Condensed Phases. Part /I Photochemistryof lnorganic and Organometallic Compounds The Photochemistry of Transition-metal Complexes; The Photochemistry of Transition-metal Organometallic Compounds; The Photochemistry of Compoundsof the Main Group Elements. Part 111Organic Aspects of Photochemistry:Photolysisof Carbonyl Compounds; Enone Cycloadditions and Rearrangements Photoreactions of Dienones and Quinones; Photochemistry of Alkenes Alkynes and Related Compounds; Photochemistry of Aromatic Compounds; Photo-reduction and -oxidation; Photoreactions of Compounds containing Heteroatoms other than Oxygen; Photoelimination.Part IV Polymer Photochemistry Part V Photochemical Aspects of Solar Energy Conversion Photochemistry Volume 79 has an author index and each chapter includes extensive references. “All photochemists remain in the debt of the hard-working crew of scientists who generate these reviews and the production editors who maintain very high standards of presentation.” lAPS Newsletter reviewing Volume 75. ISBN 0 85186 175 X Specialist Periodical Report (1988) Hardcover 598 pages Price E110.00 ($220.00) GENERAL AND SYNTHETIC METHODS Volume 10 Senior Reporter G.Pattenden University of Nottingham Generaland Synthetic Methods Volume 70provides a critical and comprehensive summary and assessment of the literature published from January to December 1985. Brief Contents Saturated and Unsaturated Hydrocarbons; Aldehydes and Ketones; Carboxylic Acids and Derivatives; Alcohols Halogeno-Compounds and Ethers; Amines Nitriles and other Nitrogen-containing Functional Groups; Organometallics in Synthesis; Saturated Carbocyclic Ring Synthesis; Saturated Heterocyclic Ring Synthesis; Highlights in Total Synthesis of Natural Products; Reviews on General Synthetic Methods.General and Synthetic Methuds Volume 70 contains an introduction by the Senior Reporter and is indexed by author. ROYAL SOCIETYOF CHEMISTRY ISBN 0 85186 914 9 Hardcover 648pages Specialist Periodical Report (1988) Price E125.00 ($250.00) Information Services For further information please write to Royal Society of Chemistry Sales and Promotion department Thomas Graham House Science Park Milton Road Cambridge CB4 4WF. U.K. To Order please write to Royal Society of Chemistry Distribution Centre Blackhorse Road Letchworth Herts SG6 1HN. U.K. or telephone (0462) 672555 quoting your credit card details. We can now accept AccessNisal MasterCard/Eurocard. RSC Members are entitled to a discount on most RSC publications and should write to The Membership Manager Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF. U.K. PRINTED IN GREAT BRITAIN BY THE UNIVERSITY PRESS CAMBRIDGE

ISSN:0265-0568    

DOI:10.1039/NP98805BX023

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Antibiotics with Antifungal and Antibacterial Activity Against Plant Diseases P. A. Worthington Department of Chemistry Imperial Chemical Industries PL C Plant Protection Division Jealott's Hill Research Station Bracknell Berkshire RG 12 6EY UK 1 Introduction 2 The Use of Medical Antibiotics for Control of Plant Diseases 3 Antibiotics Developed for Control of Plant Diseases 4 Other Promising Antibiotics 4.1 Polyenes 4.2 Macrolides 4.3 Nucleosides 4.4 Peptides 4.5 Polyethers 4.6 Aromatic Compounds 5 Antibiotics as Leads for Chemical Synthesis 6 Future Prospects for Natural Products 7 References I Introduction A great variety of chemical substances are currently used to control the spread of plant pathogens on the major economic crops of world agriculture.This has helped to improve the quality of the food we produce. Most of these chemical substances are synthetic compounds prepared by the organic chemist but a few are natural products of microbial origin. Natural products with antifungal and antibacterial activity also arise in plants either as pre-formed secondary metabolites or from pathogen-induced metabolism (phytoalexins). The phyto- alexins which have been tested on plant pathogens are not as active as the modern synthetic chemicals and are unlikely to be used as conventional fungicides. They will not be covered in this Report but have been dealt with in several review articles.'. This Report will deal with the antifungal and antibacterial antibiotics which are used in agriculture.It will also review selected new compounds from the literature which are being evaluated in crop protection or which have been leads for chemical synthesis. The testing of microbial cultures for antibiotics continues to reveal antifungal and antibacterial activity against plant pathogens with many chemicals (see for example the Index of Antibiotics and Other Microbial Products in issues of the Journal of Antibiotics). There is no intention of including all of these citations. This review will report on the isolation structure chemical synthesis biosynthesis and biological activity of the antibiotics outlined above. 2 The Use of Medical Antibiotics for Control of Plant Diseases Many of the early antibiotics that were developed for medical purposes were also investigated for activity against plant pathogens.The medical antibiotic streptomycin (I) produced by Streptomyces griseus was the first antibiotic to be applied against plant diseases. It is one of a group of compounds known as aminoglycoside antibiotics. These have carbohydrate molecules that contain one or more glycosidic linkages and several hydrophilic groups including amino- and/or guanidino- groups. Streptomycin (1) has been used to control fire blight of apple and pear by foliar application at a concentration of 200 p.p.m. in the United States of America since 1954.' In Japan it has been used for control of wild fire of tobacco (at 200 p.p.m.)5 and of bacterial leaf blight of the rice plant (at 200-500 p.p.m.).' A mixture of streptomycin (1) and oxytetracycline (2) (terramycin) which can be isolated from Streptomyces rimosus has also been applied against bacterial canker of peaches citrus canker soft rot of vegetables and other bacterial diseases.' Chloramphenicol (3) which can be isolated from cultures of the soil bacterium Streptomyces venezuelae has been used to control bacterial leaf blight of rice in Japan since 1964.' The antibiotic is produced industrially by chemical synthesis,' and the resulting mixture of D and L forms is used for the purposes of plant protection.NH NH II 11 NHCNHz 0 OH (1) R = NHMe 6 HOCH I HCNHC(0)CHC I2 I CH,OH 47 48 CH Me H2NC(0)0 OH 0 0 Me0 CI 4 (7 (8)R' R2 = H Me R3 H Me Et or Pr X = H CI or Br H2N4&Y--.-.-.NH2 HO,C H v N3 OH eOMe (1 3) (12) Novobiocin (4) also named cathomycin is produced by Streptomyces spheroides and Streptomyces niveus.A synthesis of (4) was reported in 1964' and a revised structure was proposed in 1976.9 It has been used since 1968 for reducing the occurrence of bacterial canker of tomato by dipping tomato seedlings in aqueous solutions of 100 p.p.m. of novobiocin.1° The medical antifungal antibiotic cycloheximide (9,also called actidione was discovered as a by-product of streptomycin in the culture medium of Streptomyces griseus. The cyclohex- imide molecule has four centres of asymmetry at C-2 C-4 C-6 and C-2'.11 A few of the possible stereoisomers and related compounds have been found to be produced by Streptomyces species namely isocycloheximide,12 naramycin B,13.14 and 'cycloheximide diastereoisomer '.15 Cycloheximide inhibits the growth of various plant-patho- genic micro-organisms at a very low dose level but its commercial application as a fungicide is limited because of its high phytotoxicity.Foliar sprays containing 2 p.p.m. of the antibiotic have been used for controlling downy mildew of onions in Japan since 1959.4 It is also used as a fungicide in forests where it is effective against shoot blight of Japanese larch.16 The stereoisomers and derivatives e.g. inactone (6)," of cycloheximide show less fungicidal activity than the original compound.l8 The antifungal antibiotic griseofulvin (7) was isolated from PeniciUium griseofuhum in 1939.19It has occupied a valuable place in the oral treatment of human and animal dermatophyte NATURAL PRODUCT REPORTS.1988 HN HN 0 -'OH 0 (5) (6) H (9) L Me (11) diseases,20 but it was initially of interest for the control of plant pathogens.21 The structure of griseofulvin was determined in 1951 ;22 several total syntheses have been rep~rted,~~,~~ most recently by Stork25 and by Danishefsky.26 Griseofulvin was introduced into plant protection for the control of early blight of tomato and of Botrytis cinerea on lettu~e.~' It is also used in Japan against blossom blight of apples28 and canker of melons.29 Over 300 analogues of griseofulvin e.g.(8) have been prepared and tested30 but none were sufficiently cost-effective to be developed. 3 Antibiotics Developed for Control of Plant Diseases Blasticidin S (9) isolated from culture filtrates of Streptomyces gri~eochromogenes,~~ was the first successful agricultural anti- biotic to be developed in Japan. Its unique structural feature consists of a new nucleoside cytosinine (lo) and a new amino acid blastidic acid (I 1).32-34 A synthesis of methyl 4-amino- 2,3,4-trideoxy-ol-~-erythro-hex-2-enopyranosiduronicacid (12) which is the carbohydrate fragment of cytosinine (lo) starting from methyl 6-O-trityl-4-azido-a-~-glucoside(13) has been together with the synthesis of the cytosinine moiety.36-38 The biogenesis of blasticidin S which has been ~ho~n~~.~~ to be derived from methionine arginine D-glucose and cytosine is depicted in Figure 1.Blasticidin S shows a potent curative effect against rice blast disease (caused by PyricuIaria ory~ae)~~ has been in and practical use for the control of rice blast since 1961. For spraying in the field to control rice blast the effective concentration of blasticidin S is usually 10-20 p.p.m. Three other members of the blasticidin family namely blasticidins A B and C have also been isolated from Streptomyces griseochrornogenes but are less active.42 The N-desmethyl-blasticidin S (14)43has equivalent activity to blasticidin S but NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON arginine I D -glucose cytosine Figure I The biogenesis of blasticidin S (14) (15) NH HO OH AH (16) has not been developed.Blasticidin H (15),44in which the 2-3 double-bond of the sugar moiety of blasticidin S is hydrated has much less biological activity. Kasugamycin (16) is a water-soluble antibiotic that is produced by Streptomyces kas~gaensis.'~ It rapidly superseded blasticidin S as an agricultural antibiotic for control of rice blast because of the wide margin between its curative and its phytotoxic dosage. The structure of kasugamycin was estab- lished in 1966 by and X-ray-crystallographic4' studies. It consists of three moieties 1D-chiro-inositol kasug- amine (2,4-diamino-2,3,4,6-tetradeoxyhexopyranose), and an iminoace tic acid side-c hain.Syntheses of kasugano biosamine (1 7) from D-glucose (1 8)48and from 6-methyl-3,4-dihydro-2H- pyran-2-one (19)49 have been reported. Kasuganobiosamine (17) is converted into kasugamycin (16)by treatment with the diethyl ester of oxalimidic acid and subsequent mild hydrolysis with hydrochloric acid as shown in Scheme l.48 Biosynthetic studies have shown that [U-14C]glucose and [U-''CC]mannose are incorporated into the kasugamine moiety,jO as shown in Figure 2. Also ''C-labelled myo-inositol is converted into the correspondingly labelled 1 D-chiro-inositol moiety5' of kasugamycin but 1D-chiro-inositol is Kasugamycin controls rice blast disease at concentrations as low as 20 ~.p.m."~ It has no phytotoxicity on crops and has very low toxicity to mammals.The polyoxins are a group of closely related pyrimidine several steps I HHO O h several steps OH HO Reagents i EtO,CC(NH)OEt ;ii HCI Scheme 1 H0,C-C II HN 2 $H,OH HO OH QH HO OH HO OH D -mannose myo-i nosit ol $H20H HO QH OH D -glucose Figure 2 The biosynthesis of kasugamycin NATURAL PRODUCT REPORTS 1988 0 R’ HOCH I CH20CNH2 II 0 R‘ R2 R3 Polyoxin A(20a) CH,OH Z OH Polyoxin B(20b) CH,OH HO OH Polyox in D(2Oc) CO,H HO OH Polyoxin E(20d) CO H HO Polyoxin F(20e) CO H z Polyoxin G(20f 1 C H,O H HO Polyox in H (209) Me z Polyoxin J (20h) Me HO OH Polyoxin K(20i 1 H z OH Pol yoxin L (2Oj) H HO OH Polyoxin M(20k) H HO H 0 H2Nw HO OH Polyoxin C(21a) R =OH Polyoxin I (2lb) R = +N NH R II I H,N-C NHC H,CHCH,-C-OH HOC H,C HC(0)NH I NHZ (24) R =OH (27) R = H nucleoside peptide antibiotics that have been isolated from Streptomyces cacaoi var.soe ens is.^^^^^ Polyoxins A-M [(20) and (21)] are a group of closely related ‘peptidic nucleosides’.56 All of the polyoxin structures have been rep~rted,~’ and a comprehensive review is also a~ailable.~~ Polyoxin C which is obtained by hydrolytic degradation of all of the other polyoxins was assigned the structure 1-(5-amino-5-deoxy-P-~-allofuran-uronosyl)-5-hydroxymethyluraci1on the basis of chemical5g and X-ray-crystallographic studies.6o The total synthesis of poly-oxin J6’ and that of deoxypolyoxin C62have been reported.Biosynthetic studies have shown the 5-substituted uracil base of the polyoxins to be derived from uracil and C-3 of ~erine.~~ It has also been reported that L-isoleucine is incorporated into the polyoximic acid fragment (22) of the polyo~ins.~~ All of the polyoxins except polyoxin C and polyoxin I show selective antifungal activity against various plant-pathogenic fungi.54 Polyoxin D is the most effective for the rice sheath- blight pathogen Pellicularia sasakii whereas polyoxins B and L are effective against pea black-spot fungus and apple cork-spot fungus at 5&100 p.p.m. They have been widely used in Japan for the control of these fungi since 1967.4 Validamycin A (23) is an antifungal antibiotic that was developed in Japan for the control of rice sheath blight.It was isolated from the culture filtrate of Streptomyces hygroscopicus subsp. limoneus,” which produces five additional components (designated validamycins B-F65,66) together with validoxyl- amines A and B. In the revised structure for validamycin A the hydroxyl group on C-1 of the validamine ring is substituted by a P-D-glucopyranosyl group67 and not the hydroxyl group at C-2 as had previously been suggested.68 CO-H Validamycin A can be seen to contain two kinds of CH-CHC0,H Streptomyces cacao/ var asoensIs H c hydroxymethyl branched cyclitols in its ~tructure.~~The validamycins A C D E and F contain validoxylamine A as a common fragment but they differ from one another by at least one of the following characteristics the configuration of the (22) anomeric centre of the glycoside the position of the glycosidic linkage and the number of molecules of ~-glucose.~~)In validoxylamine A [ I contrast validamycin B contains validoxylamine B in the molecule.70 The isolation of validamycin G and validoxylamine G has recently been reported.’l Validamycin A is the main component of the validamycin complex and is specially effective against certain plant diseases caused by Rhizoctonia species as w;p,” OH well as against sheath blight of rice plants.72 One spraying of a I I I III OH i I I I I valienamine i validamine IIi D-gl ucose (23) solution of 30 p.p.m.of validamycin A gives good control of sheath blight,73 and it has been used commercially for this purpose since 1973.Mildiomycin (24) isolated from Streptoverticillium rimoJiz- ciens B-9889 1,74.75 has good activity against powdery mildews on various plants and low toxicity to mammals. The structure was determined by ‘H and 13C n.m.r. studies as well as by partial degradati~n.?~. i7 On acid hydrolysis mildiomycin (24) gave 5-hydroxymethylcytosine (25) and L-serine which were NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON identified by comparison with authentic samples. However if (24) is oxidized with periodic acid it is degraded to 4-guanidino- 3-hydroxybutyric acid (26) as shown in Scheme 2. Mildiomycin closely resembles the structure of blasticidin S (9) which also contains the 2,5-dihydropyran sugar moiety.The 5-hydroxymethylcytosine fragment is formed by the hydrolysis of 5-hydroxymethylcytidine 5’-monophosphate which is itself derived from the hydroxymethylation of cytidine 5’-monophosphate. 78 Mildiomycin is highly effective against a wide range of powdery mildews on over fifteen kinds of plants,iY~Ho and was registered for such use in Japan in 1982.81 Mildiomycin D (27),82 which lacks the 8’-hydroxyl group of mildiomycin is less active than mildiomycin. (25) “1 OH HN NHCH,-c I H -CH,CO H H2N (26) Reagents i 2M-HCl; ii 6 % HIO, 2M-HCl Scheme 2 0 0 It II H N-C-CEC-C-NH (28) YHZ o=c Ezomycin A,(29a) R’ = O-cytosin-1-yl R2 = z Ezomycin Bl(29b) R’ = O-uracil-5-yl R2 = z Ezomycin Cl(29c) R’ = &-uracil -5-yl R2 = z Ezomycin A2(29d) R’ = O-cytosin-1-yl R2= OH Ezomycin B2(29e) R’ = O-uracil-5-yl R2 = OH Ezomycin C2(29f) R’ = 6-uracil-5-yl RZ= OH Two other antibiotics cellocidin and ezomycin have been used in plant protection but the consumption of these has been small.Cellocidin (28) is produced by Streptomyces chibaen~is.’~. It is acetylenedicarboxamide containing only four carbon atoms and is easy to synthesize from fumaric acid or from but-2-yne- 1,4-diol. Cellocidin has an excellent preventative effect against bacterial leaf blight of rice when sprayed on rice plants at 100-200 p.p.m.*’ and has been in practical use since 1964. Its consumption has decreased because of its phytotoxicity. The ezomycins are antifungal antibiotics that have been isolated from a strain of Streptomyces that is similar to S.kitazawaensis.86 The ezomycins A-D [(29) and (30)] are pyrimidine nucleosides many of them bearing the L-cysta- thionine ~ide-chain.~’.** It is the presence of L-cystathionine in the ezomycin molecule which is responsible for the specific fungicidal activity.*Y Ezomycin A was registered in 1970 as an agricultural antibiotic for the control of stem rot of kidney bean but is not important. 4 Other Promising Antibiotics There are many other promising antibiotics which are claimed to have plant antifungal activity from publications in the scientific and patent literature. These compounds which can be classified according to structural types will be presented in this section.4.1 Polyenes This family of polyhydroxylated macrolides in which the characteristic polyene chromophore occurs in a macrocyclic lactone ring has provided the majority of antifungal antibiotics of clinical importance.’ They also show high levels of activity in vitro against a wide range of fungal plant pathogens and are remarkably non-toxic to plants. In spite of these desirable properties only a few positive results have been obtained with these antibiotics against fungal diseases of plants. An important factor to explain this phenomenon is undoubtedly their instability to ultraviolet lights0 and to oxidation on plant surfaces. The overwhelming majority of polyenes are produced by 0=c OH H R2 OH Ezomycin D,(30a)R’ = uracil-5-yl R2 = z Ezomycin D2(30b) R1 = uracil-5-yl R2= OH 1 (N’-L-cystathionino) 1 NATURAL PRODUCT REPORTS.1988 OH pH ,,OH &y HO HO HO,C OH 0 OH OH OH 0 0 HO,C HO OH H0,C CH3 I 53 NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON -0Me r-(36)R = OMe (37)R = H (38) R = C(O)CH=CHCOzH (39) R = C(O)CH=CHC(O)NHz (40)R = H OR2 OH 0 I-,a, R10 Bafilomycin A (41) R' = R2 = H Bafilomycin A (42) R' = Me R2 =H Bafi lornycin B (43) R' = H R2 = C(O)CH=CHC(O)HN OH Bafilomycin B (44) R' = Me R2 = C(O)CH=CHC(O)HN 43 OH Bafilomycin C (45) R' = H R2 = C(O)CH=CHCO,H Bafilomycin C (46) R' = Me R2 = C(O)CH=CHCO,H Streptomyces species. Amphotericin B (3 1) which is widely used as a clinical antifungal shows little activity against plant diseases.Nystatin (32) shows activity against Botrytis tulipae on tulipss1 and against fungal spotting of Its structure was only recently revised.93 The structure of candicidin D (33) which is the major component of candicidin (which is claimed to control Cladosporium fulvum on tomatoess4) was reported in 1979.95Rimocidin (34) and pimaricin (35) have been shown to kill a deep-seated infection of Ascochyta pisi in pea ~eeds.";~~~ The structure of pimaricins8 has been known for over twenty years whereas that of rirno~idin~~~~~~ has only recently been elucidated. Several useful reviews devoted to polyene medical antibiotics are available.101~102 4.2 Macrolides Several new polyene antibiotics have been reported which differ in structure from the ones already described but which are still claimed to have antifungal activity.Rapamycin (36) which has been isolated from Streptomyces hygroscopicus NRRL 5491,lo3q104 is highly active against fungal pathogens of animalslo5 and might be expected to be active against plant pathogens The related compound demethoxyrapamycin (37) which also contains the triene fragment has been obtained from the same species.lo6 Members of a new family of antifungal antibiotics which includes the hygrolidins all share the common sixteen-membered unsaturated macrocyclic nucleus. Hygrolidin (38) (isolated from Streptomyces hygroscopicus D-1166) was the first to be characterizedlo7 and its stereochemical structure was proposed by Corey.lo8 This was based on the observation that the chiral appendage of these macrolides is closely related to that of the sixteen-membered dilactone azalomycin B whose chirality is known from X-ray-crystallographic analysi~.'~~~"~ The antibiotic is specifically active against Valsa ceratosperma (the pathogen which causes a canker disease of apple) at a concentration as low as 5 pg ml-l.lll Further screening to detect the minor components of the mixture of antibiotics that is produced by S.hygroscopicus resulted in the isolation of the two related metabolites hygrolidin amide (39)112and defumaryl-hygrolidin (4O).ll2 Both (39) and (40) exhibit selective antifungal activity against Valsa ceratosperma but their activities are much weaker than that of hygrolidin (38).1139114 The bafilomycins which have been isolated from Streptomyces griseus subsp. sulphurus (TU 1922),show similari- ties to the hygrolidins but differ in the substituents at C-2 and at C-23 as well as in the conformation of the tetrahydropyran ring. Bafilomycins A (41) B (43) and C (45) are natural products whereas the ketals bafilomycins A (42) B2 (44) and C (46) are formed during the isolation procedure. The natural bafilomycins (i.e. A, B, and C,) show equivalent activity against Botrytis cinerea in a disc diffusion assay. 114 Another sixteen-membered macrolide designated rhizoxin (47) has been isolated as a toxin that is produced by Rhizopus chinensis.This fungus is the causal agent of rice seedling blight. Rhizoxin exhibits potent activity against several phytopa- thogenic fungi including Pyricularia oryzae and Rhizoctonia solani.'I5 The isolation and structures of rustmicin (48)116 and of neorustmicin A (49),117 which are fourteen-mem bered A Me0 (48) R = OMe (47) (49) R =Me macrolide antibiotics that are produced by Micromonospora narashinoensis 980-MC and Micromonospora chalcea 1302-AV respectively have been reported. Both show strong activity against the stem rust fungus of wheat116p117 and neorustmicin A was found to be active against other phytopathogenic micro- organism~.~~~ Three congeners named neorustmicins B C and D have recently been described.lls Concanamycins which have been isolated from the mycelium of Streptomyces diastatochromogenes S-45 are novel eighteen- membered macrolide antibiotics that contain an ap,yd-unsatu- rated lactone ring.1199120 The structures of concanamycin A (50),121,122 concanamycin B (51),123 and concanamycin C (52)123 have been determined.They differ in structure by the nature of the alkyl substituent at C-8 and the substituent on oxygen at C-4'. All three antibiotics are equi-active against Pyricularia oryzae (the pathogen which is responsible for rice blast disease) at a minimal inhibitory concentration (MIC) of 25 pg ml-' in culture on agar and on glucose.12o The antibiotic virustomycin A (53) which is produced by Streptomyces AM-2604,lZ4 is structurally related to concana- mycin A (50).It contains the flavensomycinoyl moiety (54) attached to the aglycon of concanamycin A (50); this facilitated the determination of its The antibiotic is weakly active against Pyricularia oryzae (MIC 12.5 pg ml-1).124 The venturicidins are antifungal antibiotics that can be isolated from strains of Streptomyces aureofaciens. 126 Venturici-dins A (55) and B (56) are reported to be active against various important plant pathogens including Botrytis cinerea and Venturia inaeq~alis.~~~ The full structures have been determined by a combination of degradation n.m.r. studies and X-ray- crystallographic ana1ysis.lz8 A further metabolite of Streptomyces aureofaciens Duggar was found along with the venturicidins to be active against Botrytis cinerea.',' It was given the name botrycidin (57) but has been shown to be identical with rutamycin from Streptomyces griseus for which the structure has been determined by X-ray crystallography.Recently the isolation and structure of rutamycin B (58) (12-deoxyrutamycin) have been reported. 130 Rutamycin B (58) shows a similar spectrum of antifungal activity to that of rutamycin (57). The antibiotic irumamycin (59) which was obtained from a culture broth of Streptomyces subJlavus subsp. irumaensis AM-3603,131 is a twenty-membered macrolide in which a neutral sugar is attached to the epoxide aglycon. The gross ~tructure'~~,~~~ resembles that of the venturicidins [(55) and (56)] although the latter compounds possess no epoxide ring.The structure of irumamycin was determined by chemical degradation by 400 MHz lH n.m.r. spectroscopy and by experiments during which 13C-labelled precursors were fed to the bacteri~m.'~~ Irumamycin is active against the phytopathogenic fungi Pyricularia oryzae Sclerotinia cinerea and Botrytis cine re^.'^^ The two related compounds irumanolide I(60) and irumanolide I1 (61) have been produced from a mutant strain of Streptomyces during a study on the biosynthesis of irumamycin (59).13*These results indicate that irumamycin (59) is biosynthesized from irumanolide I1 (61) via irumanolide I (60) followed by attachment of the sugar moiety and epoxidation. The iru- manolides have weak activity against Sclerotinia cinerea and Pyricularia oryzae in an agar test.134 The neutral antibiotic cytovaricin (62) which has been isolated from cultures of Streptomyces H-230 and characterized is reported to be active against Pyricularia oryzae (its MIC is 500 ,ug ml-1).1'35 Capsimycin (63),136 from Streptomyces strain C 49-87 is a macrolide of a unique polyketide that contains the tetramic acid nucleus. 137 It exhibits marked inhibitory activity against Phytophthora capsici (leaf blight of cucumber) and Pythium debaryanum (damping-off disease of cucumber). The ansatrienins [produced by Streptomyces collinus subsp. collinus Lindenbein strain TU 19821 represent a new type of benzoquinonoid ansamycin antibiotic138 to which the myco- NATURAL PRODUCT REPORTS 1988 R20wo HO (50)R' = Et R2 = C(OINH2 (51) R' = Me R2 = C(O)NH (52)R' = Et R2 = H (54) ?H Ro+f (55) R = NH2C(0) (56)R = H (57) R =OH (58)R=H NATURAL PRODUCT REPORTS 1988-P.A. WORTHINGTON HO- Me R' R2 H (62) (60) H 0 Meo)H H H (611 H OH 0 H OH (63) 0 HO OMe "K0 0 +O ' (64) R =cyclohexyl (67) (65) R =Bus (66)R = Bu' 0 0 trienins13' 14' also belong. Ansatrienin B (67) which is the hydroquinone of ansatrienin A (64) seems to be identical with myc~trienin.''~Two further ansatrienins [A (65) and A (66)] have been isolated and the structures determined.14 These ansatrienins show antifungal activity against Botrytis cinerea in a paper disc Notonesomycin A (68)'" is a complex macrolide that has been isolated from the mycelium of Streptomyces aminophilus subsp.notonesogenes 647-AV1 and has been found to be effective in the treatment of sheath blight disease of rice in a glasshouse test.145 56 NATURAL PRODUCT REPORTS. 1988 0 R H 0 'C-N IH H,NCH I HCMe I HO OH I HO OH HOC H HOCH OH OH (69)R =CHO (71) (70) R =CO,H OH HOCH I MeCH 0 H02C C H,C CO H I H,CHI NH I c=oI H?N-CH R'w HO OH HO OH (72) X =N R'= OH R2 = uracil-1-yl (77) R = Q (73) X =N R' = OH R2 = u (78) R = uracil -1 -yl (74) X =CH R' = OH R2 = 0 (75) X = N R' = NHCH(CO,H)CH,CH,CO,H R2 = u 0 (76) X = N R' = NHCH(C02H)CH,CH2C02H R2 = uracil-1-yl 4.3 Nucleosides The production of neopolyoxins and nikkomycins which are structurally related to the polyoxins from other strains of Streptomyces has recently been demonstrated.Neopolyoxins A B and C [(69)+71)]146 were isolated from Streptomyces cacaoi subsp. asoensis and like the polyoxins were found to inhibit chitin synthase. The structures were shown by chemical and spectroscopic evidence14'- 148 to contain either the uracil base as in the case of neopolyoxins C (71) or the imidazoline moiety as in the case of neopolyoxins A and B. Neopolyoxins show inhibitory activity against phytopatho- genic fungi such as Pyriculuria oryzae Rhizoctonia soZuni and Botrytis cinerea at concentrations of 0.05-50 ,ug ml-1.146 The planar structures of nikkomycins X (73)149 and Z (72)150 (isolated from Streptomyces tendue) are reported to correspond to those of neopolyoxins A (69) and C (71).It is stated150 that the sugar moiety of the nikkomycins is not identical with that of the polyoxins. Further studies using X-ray and c.d. analysis,151 have established the absolute configuration of the amino-acid side-chain of these nikkomycins. Other nikko- mycins e.g. B (74)152 and I (75) J (76) M (77) and N (78),153 have been isolated and characterized but no biological test data are given. A further family of uridine nucleoside antibiotics initially isolated and ~haracterized'~~ from Streptomyces Zysosuper-cus is the tunicamycin (tsunikamycin) complex (79). High-perfor- mance liquid chromatography has now enabled ten tunica- mycins to be separated and identified.155 All contain the tunicaminyluracil residue (80) bearing N-acetylglucosamine (via a 1"-1"' saccharide bond) and a fatty acid (as an amide function).Tunicaminyluracil (80) is the common product of acid hydrolysis of tunicamycins. 156 The tunicamycins have been shown to inhibit the growth of the rice blast pathogen (Pyricularia oryzae). A new antibiotic dapiramicin A (81) has been isolated from the fermentation broth of Micromonospora SF-1917.15' 158 It belongs to the class of disaccharide nucleosides and its structure has been determined based on 'H and 13C n.m.r. spectral analysis.'59 On treatment with a mild acid dapiramicin A (81) epimerizes to epidapiramicin A (82). Dapiramicin B (83),'" which is related to epidapiramicin A (82) has also been identified from the Micromonospora species.Dapiramicin A (81) exhibits strong activity in vivo ,against sheath blight of rice plants (caused by Rhizoctoniu solani). The activity was equivalent to that of the standard i.e. validamycin (22) in a greenhouse test but dapiramicin A was less effective in field tests."O Epidapiramicin A (82) and dapiramicin B NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON 0 NHAC (79)a; R = CH=CH[CH2],CHMe2 b; R = CH=CH[CH,],CHMe c; R = CH=CH[CH,I,,Me d; R = CH=CHtCHZl, Me e; R= CH=CH[CH,I,CHMe f ; R = CH,CH,[CH2],CHMe2 g; R = CH=CH[CH,_],,CHMe2 h; R = CH=CH[CH,], Me i; R CH=CHrCHz],3Me j; R = CH=CH[CHJ, CHMe2 0 OH ?H HO OH (80) CH-OH H (81) MeoH~o/$./+ CH,OH J$j-JN N OH H HO H H (82) R = H (83)R =OH HO-U (84) R =OH (85)R = H 0 II RNHSOI II 0 L (86) R = H,N C HC(0) I Me (87) R = H NH, $p HO C II NHz HO OH (83) are less effective indicating that the a-configuration of the glucopyranosylamine bond is necessary for biological activity.Miharamycins A (84) and B (85) are antibiotics produced by Streptomyces miharaensis SF-489 and are active against rice blast disease.lG1 Although these compounds were isolated twenty years ago their structures remained unclear because suitable derivatives could not be prepared. They have been shown to be novel 1-substituted 2-aminopurine nucleoside antibiotics. 162 Ascamycin (86),lG3which has been isolated from a species of Streptomyces is structurally related to the nucleoside antibiotic AT-265 (87).164Ascamycin is the alanyl derivative of 2-chloro-5’-O-sulphamoyladenosine (87) and has been shown to be active against bacterial leaf blight of rice caused by Xantho-monas oryzae.Sinefungin (88),lG5 isolated from Streptomyces griseolus NRRL-3739 shows activity against some important foliar plant fungal diseases such as powdery mildew (Erysiphe polygoni) and bean rust (Uromyces phaseoli).lG6The aminogly-coside prumycin (89),16’ which was isolated from a culture broth of Streptomyces strain F-1028 is active against Botrytis cinerea and Sclerotinia cinerea.lG8 4.4 Peptides Antibiotics of peptidic nature are produced by bacteria actinomycetes and fungi and many have antifungal as well as antibacterial activity.None has yet been used for control of plant diseases in crop protection. NATURAL PRODUCT REPORTS 1988 (91) HyGln = threo -0-hydroxyglutamine P168 (90)16' is a peptide antibiotic that is produced by Paecilomyces lilacinus (Thorn) Samson. The sequence of the components in P168 (90) has been determined by its partial hydrolysis and by studying its mass-spectral fragmentation It shows fungicidal activity in vitro against Pyricularia oryzae and Botrytis cinerea at 100 p.p.m. in a paper disc bioassay.171 There are several examples of cyclic peptides which are reported to have fungicidal properties. Lipopeptin A (9 1),172 isolated from cultures of Streptomyces AC-69 is reported to be active against Pyricularia oryzae at a minimal inhibitory concentration of 150 pg m1-I.On acid hydrolysis it gave eight amino acids and a fatty acid. The sequence of these has been determined and a structure has been During a screening programme for inhibitors of biosynthesis of microbial walls,174 neopeptins A (92) and B (93) were isolated from a fermentation broth of Streptomyces K710.175 Acid hydrolysis of the neopeptins gave seven amino acids and a fatty acid which has enabled their structures to be deter- mined.176 The structures show a close resemblance to that of lipopeptin A (91) described above. A minor component neopeptin C (94) has also been isolated from the neopeptin complex and ~haracterized.~~~ Bacillus subtilis produces several series of antifungal cyclic peptidolipids these include bacillomycin F (99 which has been patented17' for the control of various phytopathogenic fungi.Numerous cyclic dipeptides that contain the diketopiperazine ring and a disulphide bridge have interesting antifungal properties. Hyalodendrin (96) which is a simple relative of phenylalanylserine that has been obtained from a species of Hyalodendron is reported to prevent the germination of sporangia of Phytophthora infestans. la0The antibiotic aspiro- chlorine (97) which was first isolated from Aspergillus tamarii'" and for which the structure has more recently been revised,Ia2 inhibits the growth of mycelia of Phytophthora species.1a1 Another more complex structure is gliovirin (98),la3 which is produced by Gliocladium virens and which is selectively active against some Oomycetes such as Pythium ~ltimum.'~~ 4.5 Polyethers The polyethers are ionophorous antibiotics produced by Streptomyces species.Typically they are linear long-chain I Me( threo) C 04\L L .CO,H jHx H HO ;-c-c-II I 0 NH 'R (92) R = C(0)[CH21,0CHMe2 (93) R = C(O)[CHz1,&HMeEt (94) R = C(0)[CH,19CHMez Me,CH[CH I CHCH,C(O)+ L-Asn-D-Tyr-+ D-Asn 'O1 HNt L -Thr C-D -Asn+L -Pro+ L-GI n (95) monocarboxylic acids consisting of tetrahydro-pyran or -furan rings that bear alkyl and oxygen functional groups. They have potent activity against Gram-positive bacteria and are antipro- tozoal. Some particularly monensin and lasalocid are used in the area of animal health as growth promoters and anticoc- cidials.Ferensimycins A (99a) and B (99b),lB5 which have been isolated from Streptomyces strain 5057 and leuseramycin (10O)la6 (isolated from Streptomyces hygroscopicus TM-53 1) are reported to be active against phytopathogenic fungi. NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON Me Me0 0 (96) (971 (98) HO,C R (99)a; R =H b; R =Me .-OMe H02C HO % 0 R 0 Nanaomycin D (101) Nanaomycin A (102) R = C02H Nanaomycin C (105) R = C(OINH2 NanaomycincfA(106)R = COzMe Nanaomycin0 A (107) R = CH20H 0 k 0 R Nanaomycin E (103) R = CO,H Nanaomycin B(104) R = C02H Nanaomycin a E (108) R = C02Me Nanaomycin cf B(110) R = C02Me Nanao mycin 0 E (109)R = CH,OH strain OM-173 which was isolated from soil was found to 4.6 Aromatic Compounds produce five other nanaomycin-type antibiotics.These compo- Several antifungal antibiotics that contain aromatic rings nents have been named nanaomycins aA (106) PA (107) aB have been reported. Some of the quinone antibiotics particu- (1 lo) ccE (108) and PE (109).lg2 The biosynthetic sequence for larly nanaomycins A (102) B (104) C (105) D (101) and E the nanaomycins has been proposedlg3 to be D-+A+E-+B (103) (isolated from the culture broth of Streptomyces rosa var. and the sequence for the antibiotic compounds from strain notoensis) have been known for more than ten In OM- 173 is speculatedlg2 to be aA(/3A)-+ccE(PE)-uB. Nanao-subsequent screening for new antimycoplasmic antibiotics mycin A shows a high level of activitylg2 against Pyricularia oryzae (MIC = 0.4 pg ml-l) and the other nanaomycins are less active.Carbazomycins A (111) and B (1l2)lg4 have been isolated from Streptoverticillium ehimense. The structure of carbazo- mycin B (1 12) was determined to be 4-hydroxy-3-methoxy-1,2-dimethylcarbazole by 'H and 13C n.m.r. spectralg5 and by X-ray-crystallographic analysis. lg6 Carbazomycin A (1 1 1) was postulated to be 3,4-dimethoxy-I ,2-dimethylcarbazole by analogy with carbazomycin B (1 12).195,196 Both compounds show weak activity against phytopathogenic fungi including Pyricularia oryzae. lg4 OR (111) R =Me (112) R =H RZ Me0,C "'-.Me (113) R' = RZ =H (114) R' = MeO R2 = CL (115) R' = R H 7= NATURAL PRODUCT REPORTS 1988 Several fungal metabolites with an aryltriene structure have been described.Strobilurin A (1 13) also known as mucidin,lg7 is a fungicidal natural product that has been found in the basidiomycete fungi Oudemansiella mucidaIg8 and Strobilurus tenacellu~.'~~ The re-assignment to the (E,Z,E)-configuration (1 13)200 is based on spectroscopic and chemical evidence which has allowed the original (all-E) configuration to be corrected.lgg This has been confirmed by a recent stereocontrolled synthesis of strobilurin A (1 13) (see Scheme 3);201its activity in vitro against a range of plant-pathogenic fungi has also been reported. 201 Strobilurins B (1 14) and C (1 15) have been isolated202 from mycelial surface cultures of Xerula longipes and their structures have been assigned the (E,Z,E)configuration by analogy with strobilurin A (1 13).201 They both inhibit a broad spectrum of phytopathogenic fungi at very low concentrations and are potent inhibitors of eukaryotic respiration.Oudemansin A (1 16) which has been isolated from Oudeman-siella mucida is structurally related to the strobilurins and its relative configuration was established by X-ray studies.202 A further example oudemansin B (1 17) was obtained from Meo C02Me R2 "-0Me (116) R' = Rz =H (117) R' = MeO R2 = CL Reagents i LiAlH, Et,O; ii MnO, CH,Cl,; iii LiC(SMe), THF at -70 "C; iv HgCl, HgO MeOH-H,O (12 I) v MnO, CH,Cl,; vi Ph,P=CHOMe Et,O Scheme 3 HO ,CHO Ho,NH ...I iCO H CO,H (118) Reagents i NH,OH pH < 3; ii NaBH,CN MeOH pH -= 3; iii (MeCO),O HC0,H Scheme 4 NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON (Z) -ox i me iil CHO OH WL 87353 (119) L H L Reagents i BrCHMeCO,H NaOEt ; ii 2M-HCl; iii Ac,O HC0,H; iv NH,OH Et,N Scheme 5 N/OH HN ,OH H0dCH3 Reagents i NaBH,CN MeOH pH 4; ii H, Pd/C; iii NaNO, HCl; iv BuONO MeCN Scheme 6 surface cultures of Xerula longipes and Xerula melanotricha. ,03 Both antibiotics inhibit the growth of a wide variety of phytopathogenic fungi. 5 Antibiotics as Leads for Chemical Synthesis The majority of antibiotics that have been mentioned so far in this review are complex molecules which would not be prepared by chemical synthesis but by fermentation technology.However there are several fungicidal antibiotics for which the structure is very simple in chemical terms. These compounds are now being used by chemists as leads in order to optimize the fungicidal N-Formyl-N-hydroxyglycine (1 18) also known by the trivial name of hadacidin because of its inhibitory action against human adenocarcinoma was isolated from the fermentation broth of Penicillium frequent an^.^^^ The chemical synthesis of hadacidin (1 18) starting from glyoxylic acid (see Scheme 4),06 is an improvement on the previous procedures.207. ,08 It was known that hadacidin and its derivatives are active as inhibitors of certain enzymatic Unexpectedly it CI H (121) CI-CHO CI ACHO I CI CI [40-60 "10 3 t 30-40°~01 Reagents i Na,CO,; ii ArN,+ CuCI,; iii NH, H,O diglyme at 100 "C Scheme 7 has been shown that certain compounds of this chemical type show valuable fungicidal activity.210 In particular N-formyl-N- hydroxy-L-alanine (WL87353) (1 19) which can be chemically prepared by two routes (see Scheme 5) gave good control of vine downy mildew (Plasmopara viticola)when applied at 2 kg ha-' as a post-harvest treatment.211*212 The antibiotic nitrosofungin (propanosine) (120) which can be isolated from a mixed culture of Streptomyces plicatus UC 8272,13 and a bacterium of the genus Alcaligenes (UC 91 52) as well as from a culture filtrate of Micromonospora chalcea 671-AV2,214 has structural similarities to (1 19).It has been chemically ~ynthesized~~~.~'~ (see Scheme 6) and is highly active against Valsa ceratosperma which is the pathogen of apple canker disease.,'* Pyrrolnitrin (121) is an antibiotic with a very simple structure that has been isolated from Pseudomonas pyrrocinia215 and which is used in Japan and in some European countries as 'Pyro-ace ' for the topical treatment of dermatophyte infec- tions.,16 The chemical struct~re'l'*~~~ of the antibiotic has been investigated by X-ray analysis.Various procedures have been described for preparing pyrrolnitrin (12 1)219-221 but they involve a large number of manufacturing steps which is commercially undesirable. A three-step synthesis of 3-phenylpyrrole deriva- tives which looks very attractive (see Scheme 7) has been reportedz2 in a recent patent.However these known phenyl- pyrroles cannot be used in agricultural application because the compounds are unstable in sunlight and their residual effects are low. It would appear from the patent literature that 1-acetyl-4-(2-chlorophenyl)-3-cyanopyrrole(1X!)223 is highlyeffec- tive as a plant fungicide for controlling Botrytis ciizerea. The ii fiC' H Reagents i p-MeC,H,SO,CH,NC NaH ;ii AcCl Et,N Scheme 8 R40=g R3 H R' R' R2 R3 R4 (121) H NO CI H (123) Cl NO H H (124) H NO CI OH (125) Cl NO CI H (126) H NO H H (127) H NH Cl H ::y$p 0 (1 28) substituted pyrrole ring is prepared in an efficient manner by using tosylmethyl isocyanide (Tosmic) (see Scheme 8).224 Many congeners of pyrrolnitrin (1 21) e.g.isopyrrolnitrin (1 23),225 oxypyrrolnitrin (124),2262-chloropyrrolnitrin (1 25),,, deschloropyrrolnitrin (1 26),228 and aminopyrrolnitrin (1 27),228 have been isolated from cultures of Pseudomonas pyrrolnitrica and Ps. pyrrocinia and brominated pyrrolnitrin~~~~* 230 have been produced by directed biosynthesis. These compounds are not reported to have the high fungicidal activity of pyrrolnitrin. Pyoluteorin (1 28) a 2-aroyl-pyrrole (isolated from Pseudo-monas aeruginosa T359,231 and related structurally to pyrrolni- trin) is reported to be active against Phytophthora infestans on tomatoes at 10 ~.p.m.,~ Other pyrrole compounds e.g. pyrrolomycins,233-236 are active against fungal pathogens of animals.The antibiotics holomycin (129),237 thiolutin (1 30),238 aureo-thricin (1 3 1),228 and isobutyropyrrothine (1 32)239 are produced by certain species of Streptomyces. Their structures have been shown by degradation studies to have the pyrrolinonodithiole Two other antibiotics (133) and (1 34) bearing a formamide group as the side-chain have also been iso- lated.2409 241 NATURAL PRODUCT REPORTS 1988 R\N,cHo s-0 S IS 0 R' H (129) R' = H R2 =Me (133) R = H (130)R' = R2 = Me (134) R = Me (131) R' = Me R2 =Et (132) R' = Me R2 =Pr' 0 N\ CH,Ph iii IV / HN jio.. BU'S V-VII <'I I C H P h CH,Ph (135) Reagents i ButSNa; ii PhCH,NH, TiCl,; iii ClC(O)C(O)Cl, Et,N; iv NH,OAc at 140 'C- MeOCH,C(O)Cl; vi Hg(OAc),, CF,CO,H ; vii I, CHCI Scheme 9 The total syntheses of holomy~in,~~~-~~~ 246 thiol~tin,~~~,~~~ 243.246 and aure~thricin~~~.have been described and their fungicidal activity has been highlighted. The synthesis of thiolutin analogues (135) (see Scheme 9) and their activity against Puccinia recondita Venturia inaequalis Pyricularia oryzae Cercospora arachidicola and Plasmopara viticola are described in a recent patent.24s Several other simple antibiotics are reported to show activity against phytopathogenic fungi and could be used as leads for further chemical synthesis. Oxetin (136),249 a new amino acid antimetabolite was isolated from the fermentation broth of Streptomyces OM-2317 which had itself been isolated from soil.It is the first natural product that possesses an oxetane ring and is active against Pyricularia oryzae (MIC = 12.5 pg ml-') as well as exhibiting herbicidal activity. Substance SF-1836 (1 37) was isolated as colourless crystals from the fermentation broth of Streptomyces zaomyceticus SF- 1836.250 Its structure was determined to be (3S)-2-azabicyclo[2.1 .O]pentane-3-car- boxylic on catalytic hydrogenation it gave a quantitative yield of L-proline. The crystals showed an antimicrobial activity in a nutritionally restricted medium against Xanthomonas species251 and were effective in control- ling bacterial leaf blight of rice plants under glasshouse conditions. The antibiotic SF-2185 (138),252 which is a substituted azetidine that has been isolated from the actinomycete Dactylosporangium aurantiacum subsp.gifuense is active against plant pathogens particularly the causal organisms of cucumber downy mildew and rice blast. Acetomycin (139)'53 NATURAL PRODUCT REPORTS 1988-P. A. WORTHINGTON (produced by Streptomyces ramulosus Tii 34 and containing the highly substituted y-lactone ring254) has been known for nearly thirty years. The absolute configuration of (139) has recently been indirectly together with some details of its fungicidal activity against Pyricularia oryzae and Botrytis cinerea. 6 Future Prospects for Natural Products The research and development of agricultural antibiotics for use as plant fungicides is more advanced in Japan than in other countries of the world.Most of these compounds have been targeted against diseases that are important to the Japanese market e.g. rice blast and rice sheath blight and would not be useful in countries where rice growing is not so important. It will be interesting to see whether mildiomycin (23) which demonstrates an outstanding effect against powdery mildew of fruit trees and vegetables will become an important compound outside Japan. Certainly the rapid progress in biotechnology and gene manipulation will facilitate the mass production of antibiotics and their use may increase as the price is lowered. It is expected that more use will be made of natural products as leads for chemical synthesis in the hope of improving upon the biological activity of the natural compounds and of overcoming some of their disadvantages (e.g.instability and complexity of structure). This will certainly be the case when the mode of action of the antibiotic is known and is critical for the inhibition of fungi. For instance the antibiotic A25822B (140),256 which was isolated from the fungus Geotrichum JlavobrunneumNRRL 3862 is active against species of Candida and Trichophyton and phytopathogenic fungi such as Botrytis Fusarium and Verticillium specie^.^^',^^* It is also known to inhibit the biosynthesis of which is an essential component of the membranes of many fungi.260 Also natural products with antifungal properties that have been isolated from other sources such as plants and marine organisms might become important products.7 References 1 J. F. Ryley R. G. Wilson M. B. Gravestock and J. P. 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Higashikawa S. Kuyama and S. Tamura Agric. Biol. Chem. 1981 45 1023. 172 K. Tsuda T. Kihara M. Nishii G. Nakamura K. Isono and S. Suzuki J. Antibiot. 1980 33 247. 173 M. Nishii T. Kihara K. Isono T. Higashijima and T. Miyazawa Tetrahedron LRtt. 1980 21 4627. 174 K. Isono M. Uramoto and M. Ubukata in ‘Pesticide Chemistry Human Welfare and the Environment’ (Proceedings of the 5th International Congress of Pesticide Chemistry Kyoto 1984) ed. J. Miyamoto and P. C.Kearney Pergamon Press Oxford 1983 Vol. 2 p. 63. 175 T. Satomi H. Kusakabe G. Nakamura T. Nishio M. Uramoto and K. Isono Agric. Biol. Chem. 1982 46 2621. 176 M. Ubukata M. Uramoto and K. Isono Tetrahedron Lett. 1984 25 423. 177 M. Ubukata M. Uramoto J. Uzawa and K. Isono Agric. Biol. Chem. 1986 50 357. 178 J. Shoji Adv. Appl. Microbiol. 1978 24 187. 179 G. Michel F. Peypoux F. Besson and D. Yavordios Fr. De- mande 2 508 766 1980. 180 M. A. Stillwell L. P. Magasi and G. M. Strunz Can. J. Micro-biol. 1974 20 759. 181 D. H. Berg R. P. Massing M. M. Hoehn L. D. Boeck and R. L. Hamill J. Antibiot. 1976 29 394. 182 K. Sakata H. Masago A. Sakurai and N. Takahashi Tetra-hedron Lett. 1982 23 2095. 183 R. D. Stipanovic and C. R. Howell J.Antibiot. 1982 35 1326. 184 C. R. Howell and R. D. Stipanovic Can. J. Microbiol. 1983,’29 321. 185 Y. Kusakabe,-T. Mizuno S. Kawabata S. Tanji A. Seino H. Seto and N. Otake J. Antibiot. 1982 35 1119. 186 T. Eizutani M. Yamagishi H. Hara A Kawashima S. Omura M. Ozeki K. Mizoue H. Seto and N. Otake J. Antibiot. 1980 33 137. 187 H. Tanaka Y. Koyama JIAwaya H. Marumo R. biwa M. Katagiri T. Nagai and S. Omura J. Antibiot. 1975 28 860. 188 H. Tanaka Y. Koyama T. Nagai H. Marumo and S. bmura J. Antibiot. 1975 28 868. 189 H. Tanaka H. Marumo T. Nagai M. Okada K. Taniguchi and S. Omura J. Antibiot. 1975 28 925. 190 S. bmura H. Tanaka Y. Okada and H. Marumo J. Chem. SOC. Chem. Commun. 1976 320. 191 M. Kasai K. Shjrahata S. Ishii K. Mineura H.Marumo H. Tanaka and S. Omura J. Antibiot. 1979 32 442. 192 Y. Iwai K. Kimura Y. Takahashi K. Hinotozawa H. Shimizu H. Tanaka and S. Omura J. Antibiot. 1983 36 1268. 193 C. Kitao H. Tanaka S. Minami and S. Omura J. Antibiot. 1980 33 711. 194 K. Sakano K. Ishimaru and S. Nakamura J.Antibiot. 1980,33 683. 195 K. Sakano and S. Nakamura J. Antibiot. 1980 33 961. 196 M. Kaneda K. Sakano S. Nakamura Y. Kushi and Y. Iitaka Heterocycles I98 1 15 993. 197 P. Sedmera V. Musilek F. Nerud and M. VondraEek J. Anti-biot. 1981 34 1069. 198 V. Musilek J. Cerna V. Sasek M. Semerdzieva and M. Vondra- Eek Folia Microbiol. (Prague) 1969 14 377. 199 T. Anke F. Oberwinkler W. Steglich and G. Schramm J. Anti-biot. 1977 30 806; Chem. Ber. 1978 111 2779.200 T. Anke G. Schramm B. Schwalge B. Steffan and W. Steglich Liebigs Ann. Chem. 1984 1616. 201 K. Beautement and J. M. Clough Tetrahedron Lett. 1987,28,475. 202 T. Anke H. J. Hecht G. Schramm and W. Steglich J. Antibiot. 1979 32 11 12. 203 T. Anke H. Bes U. Mocek and W. Steglich J. Antibiot. 1983 36 661. 204 B. C. Baldwin in ‘Mode of Action of Antifungal Agents’ ed. A. P. J. Trinci and J. F. Ryley (British Mycological Society Sympo- sium Vol. 9) 1984 p. 43. 205 H. T. Shigeura and C. N. Gordon J. Biol. Chem. 1962 237 1932. 206 E. G. E. Jahngen Jr. and E. F. Rossomando Synth. Commun. 1982 12 601. 207 E. Buehler and G. B. Brown J. Org. Chem. 1967 32 265. 208 E. F. Schoenewaldt R. B. Kinnel and P. Davis J. Org.Chem. 1968,33,4270. 209 H. T. Shigeura J. Biol. Chem. 1963 238 3999. 210 Shell International Research Eur. P. 57 027 1981. 21 1 C. L. Dunn and S. P. Klein in ‘Fungicides for Crop Protection Vol. 2’ (British Crop Protection Council Monograph 31) 1985 p. 407. 212 M. Wade D. P. Highwood C. L. Dunn J. M. Moncorge and G. Perugia in ‘Fungicides for Crop Protection Vol. 2’ (British Crop Protection Council Monograph 31) 1985 p. 455. 213 L. A. Dolak and T. M. Castle J. Antibiot. 1983 36,916. 214 Y. Abe J. Kadokura A. Shimazu H. Seto and N. Otake Agric. Biol. Chem. 1983 47 2703. 215 K. Arima H. Imanaka M. Kousaka A. Fukuta and G. Tamura Agric. Biol. Chem. 1964 28 575. 216 M. Nishida T. Matsubara and N. Watanabe J. Antibiot. 1965 18 211.217 H. Imanaka M. Kousaka G. Tamura and K. Arima J. Antibiot. 1965 18 207. 218 Y. Morimoto H. Hashimoto and K. Hattori Tetrahedron Lett. 1968 209. 219 H. Nakano S. Umio K. Kariyone K. Tanaka T. Kishimoto H. Noguchi I. Ueda H. Nakamura and Y. Morimoto Tetra-hedron Lett. 1966 737. 220 J. Gosteli Helv. Chim. Acta 1972 55 451. 221 Nippon Soda Br. P. 2013 187 1978. 222 Nippon Soda Eur. P. 92 890 1982. 223 Nippon Soda Br. P. 2 024 824 1978. 224 A. M. van Leusen H. Siderius B. E. Hoogenboom and D. van Leusen Tetrahedron Lett. 1972 5337. 225 M. Hashimoto and K. Hattori Bull. Chem. SOC. Jpn. 1966 39 410. 226 M. Hashimoto and K. Hattori Chem. Pharm. Bull. 1966 14 1314. 227 R. Hamill R. Elander J. Mabe and M. Gorman Antimicrob.Agents Chemother. 1968 388. 228 M. Hashimoto and K. Hattori Chem. Pharm. Bull. 1968 16 1144. 229 M. Ajisaka K. Kariyone K. Jomon H. Yazawa and K. Arima Agric. Biol. Chem. 1969 33 294. 230 R. L. Hamill R. P. Elander J. A. Mabe and M. Gorman Appl. Microbiol. 1970 19 721. 231 R. Takeda J. Am. Chem. Soc. 1958,80,4749. 232 Monsanto Chem. Co. US. P. 3 298 910 1967. 233 N. Ezaki T. Shomura M. Koyama T. Niwa M. Kojima S. Inouye T. Itd and T. Nida J. Antibiot. 1981 34 1363. NATURAL PRODUCT REPORTS 1988 234 M. Kaneda S. Nakamura N. Ezaki and Y. Iitaka J. Antibiot. 1981 34 1366. 235 N. Ezaki M. Koyama T. Shomura T. Tsuruoka and S. Inouye J. Antibiot. 1983 36 1263. 236 N. Ezaki M. Koyama Y. Kodama T. Shomura K. Tashiro T. Tsuruoka and S.Inouye J. Antibiot. 1983 36 1431. 237 L. Ettlinger E. Glumann R. Hutter W. Keller-Schierlein F. Kradolfer L. Neip V. Prelog and H. Zahner Helv. Chim. Acta 1959 42 563. 238 W. D. Celmer and I. A. Solomons J. Am. Chem. SOC. 1955 77 2861. 239 D. S. Bhate R. K. Hulyalkar and S. K. Menon Experientia 1960 16 504. 240 W. Daehne W. 0.Godtfredson L. Tybring and K. Schaumburg J. Antibiot. 1969 22 233. 241 B. Jensen J. Antibiot. 1969 22 231. 242 U. Schmidt and F. Geiger Angew. Chem. 1962 74 328. 243 U. Schmidt and F. Geiger Liebigs Ann. Chem. 1963 664 168. 244 G. Buchi and G. Lukas J. Am. Chem. SOC. 1963 85 647. 245 G. Buchi and G. Lukas J. Am. Chem. Soc. 1964 86 5654. 246 K. Hagio and N. Yoneda Bull. Chem. SOC. Jpn. 1974 47 1484.247 J. E. Ellis J. H. Fried I. T. Harrison E. Rapp andC. H. Ross J. Org. Chem. 1977 42 2891. 248 Imperial Chemical Industries PLC Br. P. 8 504 869 1985. 249 S. omura M. Murata N. Imamura Y. Iwai H. Tanaka A. Furusaki and T. Matsumoto J. Antibiot. 1984 37 1324. 250 M. Iwata Y. Suzuki Y. Kondo T. Inohara T. Watanabe and Y. Sekizawa Ann. Phytopathol. Soc. Jpn. 1979 45 192. 251 M. Shimura M. Iwata S. Omoto and Y. Sekizawa Agric. Biol. Chem. 1979 43 2279. 252 K. Matsumoto T. Shpmura M. Shimura J. Yoshida M. Ito T. Watanabe and T. Ito J. Antibiot. 1985 38 1487. 253 L. Ettlinger E. Gaumann R. Hutter W. Keller-Schierlein F. Kradolfer L. Neip V. Prelog and H. Zahner Helv. Chim. Acta 1958 41 216. 254 W. Keller-Schierlein M. Lj. Mihailovic and V.Prelog Helv. Chim. Ada 1958 41 220. 255 H. Uhr A. Zeeck W. Clegg E. Egert H. Fuhrer and H. H. Peter J. Antibiot. 1985 38 1684. 256 J. W. Chamberlain M. 0.Chaney S. Chen P. V. Demarco N. D. Jones and J. L. Occolowitz J. Antibiot. 1974 27 992. 257 K. H. Michel R. L. Hamill S. H. Larsen and R. H. Williams J. Antibiot. 1975 28 102. 258 R. S. Gordee and T. F. Butler J. Antibiot. 1975 28 112. 259 R. J. Rodriguez and L. W. Parks Antimicrob. Agents Chemother. 1981 20 184. 260 B. C. Baldwin Biochem. SOC.Trans. 1983 11 659.

ISSN:0265-0568    

DOI:10.1039/NP9880500047

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Tropane Alkaloids G. Fodor and R. Dharanipragada" Department of Chemistry West Virginia University Morganto wn WV 26506-6045 USA Reviewing the literature published between July 1985 and December 1986 (Continuing the coverage of literature in Natural Product Reports 1986 Vol. 3 p. 181 ) 1 Occurrence and Structure of New Alkaloids 2 The Chemistry of Tropanes 3 The Synthesis of Homotropanes including Anatoxin-a 4 Pharmacology 4.1 Atropine and its Derivatives 4.2 Cocaine 4.3 Scopolamine 4.4 Miscellaneous 5 Analysis 6 References 1 Occurrence and Structure of New Alkaloids A limited number of new tropane alkaloids have recently been isolated by Evans er al. from members of the Erythroxylaceae.'V2 The root-bark of Eryrhroxylum hypericifolium which is indigenous to Mauritius and to Reunion contains relatively the highest amounts (1.63 %) of the major alkaloid.The chemical analysis was based on mass spectroscopy;3 the prominent ions were of m/z 124 and in the nor-derivatives of m/z 110 similar to other tropanol esters. In all natural alkaloids in which there are substituents at C-6 or at C-7 these groups appear to be exo. Detailed n.m.r. analysis provided the characteristics of a tropan-3a-yl ester in the major product. Mass spectroscopy indicated that the esterifying acid is either 3- or 4-hydroxy- phenylacetic acid; hydrolysis confirmed the presence of the former. Therefore the base is tropan-3myl 3-(3-hydroxy- phenylacetate) (la). Such a combination had not been found in previously isolated natural tropane bases.The second major base was characterized as the 3-phenylacetate of (+)-tropane-3,6-diol (2a) ; the absolute con- figuration of the (-)-diol had earlier been determined by ~orrelation.~ The (+)-and the (-)-bisphenylacetate (2b) were prepared from the diols and the (-)-form proved to be identical with the product that was obtained from the natural product. Tropan-3ol-yl 3-phenylacetate (1 b) was the third alkaloid of E. hypericifolium. It was already known as an alkaloid from Erythroxylum dekir~dtii.~ A fourth crystalline alkaloid C,,H,,- NO, gave a crystalline picrate and was identified as tropane- 3a 6p-diyl 3-phenylacetate 6-acetate (2c). Evidence was pro- vided for its biogenesis from (+)-(3R,6R)-tropane-3a76p-diol.a hybrid of two species of Duboisia shows a twelve-times greater change for hyoscyamine than for hyoscine.' There is a correlation between alkaloid composition and atropine esterase activity in callus and in differentiated tissues of D. myoporoides.' It was found that the scopolamine and hyoscyamine contents of the five top leaves of Duboisia myoporoides are representative. 2 The Chemistry of Tropanes During a search for neuroleptic agents 3-cyanotropane was treated with 4-fluorophenylmagnesium bromide9 to give 4- fluorophenyl tropan-3P-yl ketone (4) which proved instead to have depressant activity on the central nervous system. Catalytic reduction of 6-phenyltrop-6-ene gave 6a-phenyltropane where- as lithium aluminium hydride attacked on the bridgehead to give 5-methy lamino-3-phenylcyclohept-1-ene.lo 6-Aryltropanols in which alkoxyaryl groups are probably P-oriented have been prepared.After N-demethylation (the method by which this was achieved is not specified) 6- phenylnortropanol was alkylated with P-benzoylethyl p-cyanoethyl groups etc. to produce compounds (5). The new compounds proved to be weak opiate antagonists." A great variety of new N-alkyl-norscopolamines have been synthesized by demethylation of scopolamine followed by re-alkylatiorl with 26 different groups. The new derivatives were anti-cholinergically active. Among the quaternary salts N-ethyl- norscopolaminium methobromide is particularly active as a bronchospasmolytic. l2 In the search for new membrane-active compounds that resemble histrionicotoxin several 1 -substituted alkyl- alkenyl- ""??IC(O)CH Ph RO-MeNFiR ( 1 1 o ; R= C(0)CH2C6HLOH -3 (2)a; R=H b ; R=C(0)CH2Ph b ; R=C(O)CH,Ph c; R=C(O)Me A phenylacetic ester of tropane-3,6,7-triol was discovered as a minor component.Finally the structure of nortropan-3a-yl 3-phenylacetate (3) was ascribed to another minor alkaloid based on mass-spectral data since the fragment of m/z 119 suggested that phenylacetic acid is present rather than toluic acid. In summary the new alkaloids that were obtained by Evans and co-workers1*2 were already known as far as the alkamine component is concerned but the esterifying acids are new and represent distinctive features of certain species.Furthermore the combination of acetic phenylacetic and 3-hydroxyphenylacetic acids is unique. The seasonal variation6 of the content of tropane alkaloids in * Present address Department of Chemistry University of California Los Angeles CA 90024. 67 (3) R"P Ar +OR2 ( 5 ) Ar H Ph ,L -MeOC6HLefC. R' = Me ,[CH2],C(0)Ph ,[CH2I2CN [CH2I2Ph efc. R 2:H or Me NATURAL PRODUCT REPORTS 1988 .CH,OMe CHO b; R C(0)Me +-Ph3P-CHCH2C SCH R RN fi -Po-MeNpocJoH (12) II Ph 0" (13) and alkenynyl-tropanols have been synthesized.l3 The key intermediates were 1-methoxymethyltropan-3~-ol (7a) and 1-fonnyltropan-3P-yl acetate (8) which were obtained by the Robinson reaction from 2,5-dimethoxy-2-methoxymethyltetra-hydrofuran (6) followed by demethylation reduction and VNpf R selective oxidation of the primary alcohol group.The structural variation was achieved by using the Wittig reaction to produce (9) and (1 1) and by hydrogenating (9) to yield (10). A new method of entry into the tropane field,14 starting with pyrroles and the oxyallyl cation in the presence of di-iron nonacarbonyl (as a catalyst) has now been described in detail and in a more general context by N0~0ri.l~ Trop-6-en-3-one (12) was converted into trop-6-en-3a-01,~~ esterified with (9-0-acetyltropoyl chloride and the double-bond was then reduced (by catalytic hydrogenation) to give hyoscyamine (1 3) after Me,+ ,H partial hydrolysis. l5 Trop-6-en-3a-yl tropate was epoxidized Me N earlier17 to hyoscine.2,4-Diamino-5-(N-arylnortropan-3-yl)pyrimidines(14)have &cO; been synthesized as novel inhibitors of dihydrofolate re-0- ductase.l8 A computer-assisted analysis of the three-C02H dimensional structures of the binary complexes of the dihydro- folate reductase of Escherichiu coli with methotrexate and with other compounds led to the design of compounds (14) which are potent inhibitors of E. coli. The nortropanones have been prepared by the Robinson synthesis ; methoxyanilines were used as the amine components. Knoevenagel condensation of the N-arylnortropanones with ethyl cyanoacetate afforded Me\ Me the olefins and their subsequent hydrogenation gave the N N tropan-3a-yl cyanoacetates. Reduction with lithium in liquid ammonia led to the exo 3P-stereoisomers.Ultimately con- densation with guanidine resulted in the formation of the 3-(5-pyrimidyl)tropanes. The amide group in the diamino- dihydropyrimidinones was eliminated in the usual way by phosphoryl chloride followed by reductive dehalogenation. NATURAL PRODUCT REPORTS 1988-G. FODOR AND R. DHARANIPRAGADA OH (18) (19) (20)a; R=H (17) b; R-Me BUt0,C I tBu 0,C I C H Ph 0P Bu'0,C U CH,Ph (22) (23)a; R=H ( 21 1 b; R = CH2Ph f-- -Me + H02C* Me I 0 0 CH2Ph CH Ph (26) a; R = CH2Ph (25) (2Ll b;R=H c; R = C02But 0 Me (27) Scheme 1 The synthesis of an intermediate in the synthesis of cocaine N-methylpyrrolidine-2,5-diaceticacid (1 6) has been accomplished in four steps.19 N-Methylpyrrole and acetylene- dicarboxylic acid gave a Diels-Alder adduct N-methyl-7- azabicyclo[2.2.1 ]hep ta- 2,5-diene-2,3-dicarboxylicacid which upon catalytic hydrogenation under pressure gave a di-carboxylic acid (15).The cleavage of the C-C bond in the dimethyl ester of (1 5)between the carboxyl groups was achieved at -78 "C with sodium in liquid ammonia; the product was (16). 3 The Synthesis of Homotropanes including Anatoxin-a Pseudopelletierine oxime by analogy with tropinone oxime,20 is chiral and was recently resolved by Razdan and Sharma.21 The phenomenon was predicted by Shriner in 1943 and named 'geometrical enantiomerism' by Lyle and Lyle22 in 1959 when they resolved cis- 1-methyl-2,6-diphenylpiperidin-4-one oxime.We reported in these Reports (Nat. Prod. Rep. 1985 2 pp. 222-225) the total synthesis of (+)-and of (-)-anatoxin-a. A recent short and efficient route23 to anatoxin-a starts with cis-cyclo-octane- 1,5-diol which upon oxidation and con-densation gives the bicyclic hemiketal aminal (1 7). Pyridine hydrobromide and bromine at 115 "Cresulted in reorganization of the aminal to the homotropan-2-one (18) presumably via bromination and cyclization of 5-methylaminocyclo-octanone. The homotropanone gave the intermediate24 @-unsaturated nitrile (19). Finally deprotonation (with LiNPrL) and trapping (with oxygen) of the delocalized anion followed by hydrolysis afforded N-methylanatoxin-a (20b) which had previously been converted into anatoxin-a (20a).Synthetic and conformational studies have been performed on anatoxin-a by Rapoport and co-w~rkers.~~ The thiolactam (2 l) which is readily available from D-pyroglutamic acid was alkylated with the trifiate of a protected ketohexanoate followed by sulphur contraction to yield the vinylogous carbamate (22) as shown in Scheme 1. Ammonium formate then gives the secondary amine (23a) from (22) in one step. The cis-N-benzyl isomer (24) was cyclized to (26a) via the iminium ion (25). The N-deprotected and re-protected bicyclic homo- tropanyl methyl ketone (26c) was then converted into the homotropenyl methyl ketone (27) by trimethylsilylation (to form the enol ether) and oxidation with lead(@ acetate; (27) was then deacylated to (20a). Extensive conformational analysis of anatoxin-a proved that the seven-membered ring adopts a twist-chair conformation.NOE experiments revealed that the acetyl side-chain is almost freely rotating while crystal-packing forces in the solid state force the enone into a single conformation. NATURAL PRODUCT REPORTS 1988 -ii,iii 0 ____) -QH Q+ I I OH I 0 (28) (29) OH h Reagents i PhH reflux; ii MnO, CH,Cl,; iii m-ClC H CO,H CH,Cl,; iv HO[CH,],OH TsOH PhH reflux; v MsCl Et,N CH,Cl,; vi NiCl, LiAlH, THF at -78 "C; vii AcC1 then H,6; & TsOH Me,CO Scheme 2 8u*O2C 4 Br 8 I P HQH -Br Br Br Br Br (35) (361 (37) (38) v vi 1 Reagents i PhHgCBr,; ii NaBH,CN NH,OAc MeCH(OH)Me 3A molecular sieves; iii TsOH then AgOTs MeCN; iv HBr hv then Et,N MeCN at 70"C then di-t-butyl dicarbonate CH,Cl,; v MeC(O)N(Me)OMe ButLi THF ; vi F,CCO,H CH,Cl Scheme 3 An independent synthesis of anatoxin-a is based on Tufa- riello's nitrone approach (Scheme 2).26 1-Pyrroline 1-oxide (28) gave upon cycloaddition with hexa-3,5-dien-2-01(29) a bicyclic adduct (30).This was oxidized to a second monocyclic nitrone (3 1). A second ring-closure afforded a cyclo-adduct (32) which then through a series of operations [via (33) and (34)] gave racemic anatoxin-a (20a). Another new strategy has been developedz7 for the synthesis of racemic anatoxin-a (Scheme 3). An aminobicyclo-octane intermediate (36) (as a mixture of stereoisomers) was prepared by reductive amination of a dibromobicyclo-octanone (35) and was converted (by a disrotatory electrocyclic cleavage -transannular cyclization) into the bromocyclo-octenylamine (37).This was converted into (38) which was allowed to react with N-methoxy-N-methyl- acetamide in the presence of t-butyl-lithium and then hydrolysed to give anatoxin-a (20a). A conformational study of homotropan-3-one and of homotropane itself has been carried out; both lH and 13C n.m.r. spectroscopy and measurements of dipole moments were used.28 The results pointed to a chair conformation of the homopiperidine ring (39) as expected. The 'H n.m.r. data and the dipole moments were similar to those that were reported for tropanes twenty years ago? 4 Pharmacology 4.1 Atropine and its Derivatives Tropine 3,5-dichlorobenzoate was synthesized and its effects on the flare response to intradermal injection of 5-hydroxy- tryptamine were examined.30 The effects of a series of atropine derivatives (analogues) some being substituted by an oxygen function and some having acetic or benzoic acid as the esterifying component instead of tropic acid and of nortropines and N-oxides were studied in the specific binding of 3H-labelled quinuclidinyl benzilate to muscarinic receptors in rat brain.31 The use of tropan-3-yl3,4,5-trichloro-and alkoxy-benzoates for the successful treatment of migraine has been patented.32 The formation of solid compounds (1 :1 ratio) between atropine scopolamine and other tropane derivatives with Bromocresol Green at pH 2.9 has been observed.33 The binding occurred NATURAL PRODUCT REPORTS 1988-G.FODOR AND R. DHARANIPRAGADA Me help understanding of the mode of action of anaesthetics. The +/ Br -microvascular effects of anisodamine were studied in the spinotrapezius muscle of a rat that was under alfathesin anesthesia ;anisodamine increased the arteriolar diameter and the velocity of cell AOW? (39) (LO)R= (S1-tropoyl 5 Analysis Atropine sulphate has been potentiometrically titrated with sodium tetraphenylborate ;ion-selective electrodes were used to detect the end-p~int.~' Anisodamine-selective electrodes were upon the tetraphenylborate or dipicrylamine salt in c1-analogy with the previous reference on atropine.47 Accordingly other alkaloids interfered with the determination.Atropine and scopolamine were determined in Belladonna tincture by using separation by t.1.c. on Siluf0'01.~~ Atropine sulphate has been MeNfloR HO OC(0)CPh,OH determined in lumitropine tablets by colorimetry with Bromo- cresol Green.50 Contamination of automatic injectors by A (Ll) R = (S)-tropoyl ( 12 1 material within the cartridge has been in~estigated.~~ formulation that contained atropine sulphate was found to be lethal to mice. The toxic material originated from zinc henolic hydroxyl group Of the dye and the lone comnounds that were nresegk,7iq,,&gm .m.Qng$>.m$la 1c__--ectrdns of The rropane-nitrogen giving :ocqpairs IGs quan-irties of atropine ic cornmerciai -preparations havc been difficult to understand how quaternary tropanium salts can determined by high-performance liquid chromatography in form such complexes.The visible ultraviolet and infrared injections in eye drops and in emulsions,52 or by h.p.1.c. with spectra of the complexes were Tropan-3a-yl 1H-fluorescence detection.53 Biological evaluation of injections of indole-3-carboxylate was studied for its antiarrhythmic and atropine sulphate was used -in comparison to analytical-electrophysiological effects as an antagonist of 5-hydroxy- chemical determination^^^ (cf. ref. 47). The stability of atropine tryptamine.34 and hyoscyamine in syrups as a function of pH has been The tropic acid residue in atropine was replaced by 4- studied;55 40% of the samples lost their activity above pH 7. morpholyl- and 4-piperazinyl-alkanoic acids and the central Studies on PVC atropine-selective electrodes have been ac-cholinolytic effect of these esters was investigated concerning ~omplished.~~ A photometric method has been elaborated for neuronal electric activity in rabbits.35 the determination of atropine and scopolamine in Belludonna extract^,^' based on t.1.c.of the extracts on silica gel. A novel t.1.c. technique was applied to differentiate cocaine from 4.2 Cocaine amphetamines and other stimulants of the central nervous A review (with 126 references) has appeared on the neuro- Ultramicrotitrimetric determination of alkaloids in chemical and physiological effects of cocaine related to the Datura flowers has been carried out by titration with 0.05N behavioural and learning mechanism^.^^ Cocaine was known to perchloric acid of the chloroform-methanol extracts.59 A induce teratogenesis and the mechanism has now been shown method for single-reagent polarization fluoroimmunoassay of to involve inhibition of the uptake of norepinephrine and benzoylecgonine which is the major metabolite of cocaine in placental vasoconstriction.37 urine has been worked out.60 Anisodamine has been studied by The effect of three different routes of administration of Raman spectroscopy in its interaction with phospholipid cocaine to rhesus monkeys was studied in order to learn about membranes.61 Trospium chloride is N-spirobutano-3a-benzil-the discriminative stimulus properties of cocaine and d-oyloxynortropanium chloride (42) which is metabolized to amphetamine.38 the spirotropanol in human plasma and urine.Its determination has been achieved62 by fluorometry after derivatization of the alcoholic hydroxyl group with benzoxaprofen chloride and 4.3 Scopolamine separation by h.p.1.c. The bioavailability of the quaternary Migraine headaches are being treated with transdermal compound trospium chloride has been determined as 2.9% in scop01amine.~~ A theoretical description of transdermal drug men from urinary extraction data.63 delivery has been developed. The levels of scopolamine in plasma have been predicted by using this theoretical Cimetropium bromide [N-cyclopropylmethylscopolaminium 6 References bromide (40)] has been studied as to its antimuscarinic properties ;41 in vitro cimetropium ion displaces [N-methyl-1 M.S. Al-Said W. C. Evans and R. J. Grout Phytochemistry 3H]scopolamine that is bound to muscarinic receptors in 1986 25 851. peripheral organs. Cimetropium bromide is as potent as 2 M. S. Al-Said W. C. Evans and R. J. Grout J.Chem. Soc. Perkin Trans. I 1986 957. atropine in inhibiting acetylcholine-induced intestinal spasms 3 E. Blossey H. Budzikiewicz M. Ohashi G. Fodor and C. in cats.42 Djerassi Tetrahedron 1964 20 585. The influence of ipratropium bromide (N-isopropylscopol- 4 G. Fodor and F. Soti J. Chem. SOC. 1965 6830. aminium bromide) on the frequency of beating of ciliary hairs 5 M. A. I. A1 Yahya W. C. Evans and R. J. Grout J. Chem. Soc. in human nasal mucosa has been in~estigated.~~ Perkin Trans. 1 1979 2130. 6 T. Ikenaga K. Hama S.Takemoto and H. Ohashi Nettai Nogyo 1985 29 229 (Chem. Abstr. 1986 104 106317). 4.4 Miscellaneous 7 Y. Kitamura H. Miura and M. Sugii Chem. Pharm. Bull. 1985 has been 33 5445. Anisodamine (41) i.e. 6P-hydroxyhyo~cyamine,~~ studied by e.s.r. It increases the fluidity of 8 T. Ikenaga S. Takemoto and H. Ohashi Nettai Nogyo 1985,29 231. dipalmitoyl phosphatidic acid liposomes. In a different 9 J. A. Fontenla A. Eirin and J. M. Calleja Arch. Farmacol. freeze-fracture electron microscopy was used to study the Toxicol. 1984 10 151. effect of anisodamine on the formation of lipidic particles in egg 10 G. H. Dewar R. T. Parfitt and L. Sheh J. Chem. Res. (9,1985 phosphatidylethanolamine liposomes. All of this is supposed to 1. NPR 5 11 G. H. Dewar R.T. Parfitt and L. Sheh Eur. J. Med. Chem.- Chim. Ther. 1985 20 228. 12 R.Banholzer and K. H. Pook Arzneim.-Forsch. 1985 35 217. 13 R.Dharanipragada and G. Fodor J. Chem. SOC. Perkin Trans. I 1986 545. 14 Reviewed by G. Fodor in ‘The Alkaloids’ ed. M. F.LGrundon (Specialist Periodical Reports) The Chemical Society London 1976 Vol. 6 p. 65. 15 R. Noyori and Y. Hayakawa Tetrahedron 1985 41 5879. 16 G. Fodor J. Toth 1. Koczor P. Dob6 and I. Vincze Chem. Ind. (London) 1956 764; J. Chem. SOC. 1959 3461. 17 G. Fodor Magy. Tud. Akad. Kem. Tud. Oszt. Kozl. 1963 20 338 (Chem. Abstr. 1964 60,573b). 18 H. Maag R. Locher J. J. Daly and I. Kompis Helv. Chim. Acta 1986 69 887. 19 A. P. Krapcho and J. A. Vivelo J. Chem. SOC. Chem. Commun.1985 233. 20 H. Singh and B. Razdan Indian J. Chem. 1968 569. 21 B. Razdan and A. K. Sharma Curr. Sci. 1984 53 1183. 22 R. E. Lyle and G. G. Lyle J. Org. Chem. 1959 24 1679. 23 J. R. Wiseman and S. Y. Lee J. Org. Chem. 1986 51 2485. 24 P. S. Watt and R. R. Wroble J. Org. Chem. 1976 41 2939. 25 A. Koskinen and H. Rapoport J. Med. Chem. 1985 28 1301. 26 J. F. Tufariello H. Merckler K. Pushpananda and A. Senaratne Tetrahedron 1985 41 3447. 27 R. L. Danheiser J. M. Morin Jr. and E. J. Salaski J.Am. Chem. SOC.,1985 107 8066. 28 P. Scheiber and K. Nador Liebigs Ann. Chem. 1985 913. 29 R. J. Bishop G. Fodor A. R. Katritzky L. E. Sutton and F. J. Swinbourne J. Chem. SOC. C 1966 74. Ref. 28 erroneously gave 1976 as the year of this publication.30 J. M. Orwin and J. R. Fozard Eur. J. Clin. Pharmacol. 1986,30 209. 31 X.-Y. Niu and Z.-H. Ren Yaoxue Xuebao 1984 19 326 (Chem. Abstr. 1985 103 47831). 32 J. R. Fozard and M. W. Gittos. U.S. Patent 4563455 (1981) (Chem. Abstr. 1986 105 54608). 33 A. Hernandez and J. Thomas Cienc. Ind. Farm. 1985 4 284 (Chem. Abstr. 1986 104 193019). 34 F. M. Williams A. L. Rothaul K. A. Kane and J. R. Parratt J. Cardiovasc. Pharmacol. 1985 7 550. 35 S. N. Kozhechkin and L. M. Kostochka Byull Eksp. Biol. Med. 1985 100 468 (Chem. Abstr. 1986 104 28389). 36 S. Castellani and E. H. Ellinwood Psychopharmacology (Amster- dam) 1985 2 442. 37 M. P. Mahalik R. F. Gautieri and D. E. Marin Jr. Res. Com- mun. Subst. Abuse 1984 5 279. 38 R. de la Garza and C.E. Johanson Pharmacol. Biochem. Behav. 1986 24 765. NATURAL PRODUCT REPORTS. 1988 39 M. N. Innes U.S. Patent 4532244 (Chem. Abstr. 1985 103 129 097). 40 R. H. Guy and J. Hadgraft J. Controlled Release 1985 1 177. 41 A. Schiavone G. B. Schiavi L. de Conti R. Micheletti A. Sagrada R. Hammer and A. Giachetti Arzneim.-Forsch. 1985 35 796. 42 A. Sagrada A. Schiavone L. Cervo and A. Giachetti Boll. Chim. Farm. 1986 125 75. 43 G. Akkoclu and N. Konietzko Atemwegs-Lungenkrankh. 1985 11 527. 44 A. Romeike Naturwissenschaften 1962 49 281 ; G. Fodor I. Koczor and G. Janzso Arch. Pharm. (Weinheim Ger.) 1962 295 91. 45 F. Hwang J.-W. Chen B.-C. Chao and Z.-F. Wang Bopuxue Zazhi 1984 1 481 (Chem. Abstr. 1986 104 200023).46 R. J. Xiu F. A. DeLano and B. W. Zweifach Adv. Chin. Med. Muter. Res. Int. Symp. 1984 1985 545 (Chem. Abstr. 1986 104 161 942). 47 M. E. Carrera A. Momberg and E. Cifuentes Bol. SOC. Chil. Quim. 1984 29 333. 48 L. Shen Y. Zhang and R.-Q. Yu Yaoxue Xuebao 1985 20 151 (Chem. Abstr. 1985 103 27363). 49 M. S. Grishina V. V. Dyukova L. L. Kovalenko and D. M. Popov Farmatsiya (Moscow) 1986 35 24 (Chem. Abstr. 1986 104 230558). 50 X. Wang Yaoxue Tongbao 1984 19 261 (Chem. Abstr. 1985 103 59394). 51 R. 1. Ellin A. Kaminskis P. Zvirblis W. E. Sultan M. B. Shutz and R. Matthews J. Pharm. Sci. 1985 74 788. 52 A. Better0 and P. Bolletin Ann. Chim. (Rome) 1985 75 351. 53 U. R. Cieri J. Assoc. Ofl.Anal. Chem. 1985 68 1042. 54 I. Shukrallah and A.Kandil J. Drug. Res. 1984 15 37. 55 H.-X. Lin H. Liu and G.-L. Shen Yaowu Fenxi Zazhi 1985 5 150 (Chem. Abstr. 1986 104 39816). 56 C. Kahn-Borenstein J. Pharm. Belg. 1986 41 5. 57 I. A Petrishek A. V. Gaevskii M. Ya. Lovkova A. B. Golovkin and N. 1. Grinkevich Khim.-Farm. Zh. 1986 20 710 (Chem. Abstr. 1986 105 102688). 58 J. M. Bonicamp and L. Pryor J. Tenn. Acad. Sci. 1986 61 9. 59 L.-S. Xu and A.-K. Liu Yaowu Fenxi Zazhi 1985 5 240 (Chem. Abstr. 1986 104 10685). 60 D. L. Colbert D. S. Smith J. Landon and A. M. Sidki Ann. Clin. Biochem. 1986 23 37. 61 Y. Sun and S. Wang Kexue Tongbao (Foreign Lung. Ed.) 1986 31 413 (Chem. Abstr. 1986 105 25333). 62 G. Schladitz-Keil H. Spahn and E. Mutschler J. Chromatogr. 1985 345 99. 63 G. Schladitz-Keil H. Spahn and E. Mutschler Arzneim.-Forsch. 1986 36,984.

ISSN:0265-0568    

DOI:10.1039/NP9880500067

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

The Biosynthesis of Shikimate Metabolites P. M. Dewick Department of Pharmacy University of Nottingham Nottingham NG7 2RD Reviewing the literature published during 1986 (Continuing the coverage of literature in Natural Product Reports 1986 Vol. 3 p. 565) 1 The Shikimate Pathway 1.1 DAHP Synthase 1.2 3-Dehydroquinate Synthase 1.3 3-Dehydroquinase 1.4 Shikimate Dehydrogenase 1.5 Quinate Dehydrogenase 1.6 Shikimate Kinase 1.7 EPSP Synthase 1.8 Chorismate Synthase 1.9 Chorismate Mutase 1.10 Phenylalanine and Tyrosine 1.1 1 Anthranilic Acid p-Aminobenzoic Acid and Related Compounds 2 Tryptophan and Related Compounds 2.1 Tryptophan Synthase 2.2 Indole-3-acetic Acid and Related Metabolites of Tryptophan 3 Phenols and Phenolic Acids 4 Phenylpropanoids 4.1 Phenylalanine Ammonia-lyase 4.2 Cinnamic Acids and Esters 4.3 Phenylpropane and Phenylethane Derivatives 4.4 Coumarins 4.5 Lignins 4.6 Lignans 5 Flavonoids 5.1 General Aspects 5.2 Chalcone Synthase 5.3 Flavanones Dihydroflavonols Flavonols and F1avo n e s 5.4 Catechins and Proanthocyanidins 5.5 Anthocyanidins 5.6 Methylation and Glycosylation of Flavonoids 5.7 Sulphation of Flavonoids 5.8 Isoflavonoids 6 Quinones 7 Miscellaneous Shikimate Metabolites 7.1 Cyclohexyl Fatty Acids 7.2 Sporopollenin 8 References This report reviews the literature that was published during 1986 on the biosynthesis of non-nitrogenous compounds that are derived wholly or partly from shikimate and continues the coverage in Volume 3 of Natural Product Rep0rts.l A book entitled ‘The Shikimic Acid Pathway’ has been published,2 containing the invited papers that were presented at The Phytochemical Society of North America Symposium held in June 1985.This book does not aim to provide a totally comprehensive coverage but it contains excellent reviews describing recent advances in many areas relating to shikimate- derived materials. Most of these articles will be cited in the following sections under the appropriate subject material. An early chapter presents a valuable overview of many aspect^.^ 1 The Shikimate Pathway 1.1 DAHP Synthase The first reaction in the shikimate pathway (Scheme 1) involves the condensation of phosphoenolpyruvate (PEP) (1) with erythrose 4-phosphate (2) and is catalysed by the enzyme 3- deoxy-~-arabino-heptulosonate-7-phosphate synthase (DAHP synthase) [phospho-2-dehydro- 3-deoxyheptonate aldolase ; E.C.4.1.2.151. In any particular organism one or more forms of this enzyme may exist and these forms are characterized by different sensitivities towards feedback inhibition especially by the aromatic amino acids. Members of the group of prokaryotes which includes Escherichia coli may possess one or more of the co; I PEP (1) + 4 NAD+ 00 ““tLOH H 0“ OH DAHP (3) OH Erythrose 4-phosphate (2) co; I iii 0OOH 0 I I OH OH 3 -De>ydroshiki mate (5) 3-Dehydroquinate (4) co, I 6 HO’ OH H OR*OOH I I OH OH Shi kimate (6) Quinate (7) Enzymes i DAHP synthase; ii 3-dehydroquinate synthase iii 3-dehydroquinase ; iv shikimate dehydrogenase ; v quinate deh ydrogenase Scheme 1 73 four distinct isozymes DAHP synthase-0 (insensitive to feedback inhibition) DAHP synthase-Phe DAHP synthase- Tyr or DAHP synthase-Trp the latter isozymes being sensitive to feedback inhibition by the appropriate aromatic amino acid.4 It is thought that DAHP synthase-0 and DAHP synthase- Tyr were present in a common ancestor of these organisms and that the newly evolved DAHP synthase-Trp once possessed sensitivity to feedback inhibition by chorismate as well.Sensitivity to chorismate is retained in several pseudomonads. DAHP synthase-Phe probably evolved recently and is presently found only in E. coli and in its close relatives within this group of prokaryotes. The enzyme activity from Bacillus polymyxa has been found to be subject to feedback inhibition by all three aromatic amino acids,5 and that from a Pseudomonas species is subject to inhibition by tyrosine tryptophan anthranilate and phenylpyruvate.6 Similarly isozymes of DAHP synthase have been shown to exist in plants. In cultured cells of Nicotiana silvestris the two isozymes DAHP synthase-Mn and DAHP synthase-Co have been identified,' the abbreviations indicating the requirement of the isozyme for a divalent cation (either Mn2+ or Co2+ respectively).The different properties of the two isozymes allowed assays to be developed for the detection of either isozyme in plant extracts and a variety of monocots and dicots were analysed. In general the pair of isozymes seems to be present in higher plants with higher activity being observed for DAHP synthase-Co in all cases that have yet been studied. Surprisingly only DAHP synthase-Mn had been recognized in many earlier studies. The DAHP synthase from tubers of potato (Solanum tuberosum) closely resembles that which had previously been isolated from carrot (Daucus carota); it shows a hysteretic lag is stimulated by Mn2+ and L-tryptophan and can be resolved into two forms8 1.2 3-Dehydroquinate Synthase The complete sequence of amino-acid residues of the enzyme 3-dehydroquinate synthase [E.C.4.6.1.31 which catalyses the conversion of DAHP (3) into 3-dehydroquinate (4) has been el~cidated.~ The enzyme catalyses a complex sequence of reactions requiring an oxidation a p-elimination a reduction and an intramolecular aldol condensation and the study of its NATURAL PRODUCT REPORTS 1988 properties has been hampered by the low natural levels of this enzyme. The sequencing of the enzyme was made possible because larger amounts were accessible through gene cloning and the construction of overproducing strains of Escherichia coli. Synthetic analogues of DAHP containing fluorine at position 3 were transformed by the 3-dehydroquinate synthase from E.coli and their further conversion into 6-fluoro-derivatives of 3-dehydroshikimate and shikimate was also investigated.lo 1.3 3-Dehydroquinase 3-Dehydroquinase [3-dehydroquinate dehydratase; E.C. 4.2.1.101 catalyses the dehydration of 3-dehydroquinate (4) to 3-dehydroshikimate (9,and has now been isolated in relatively large amounts by gene cloning and by constructing a strain of E. coli that overproduces this enzyme." This has allowed the complete amino-acid sequence to be determined. The enzyme appears to be dimeric and has properties similar to those of the 3-dehydroquinase component of the pentafunctional arom enzyme complex of Neurospora crassa. l2 The monofunctional 3-dehydroquinase has not previously been purified.1.4 Shikimate Dehydrogenase Shikimate dehydrogenase [E.C. 1.1.1.251 is an NADP+-linked dehydrogenase that catalyses the reversible reduction of 3- dehydroshikimate (5) to shikimate (6). The enzyme from the conifer Pinus sylvestris has been isolated and partially purified ; it has been shown to be separable into three isozyme~.'~ In conifers in contrast to other plants all three isozymes are active not only with NADP' but also with NAD'. It has been suggested that the NAD+-dependent shikimate dehydrogenase catalyses the initial reaction of an alternative pathway in which shikimate is converted into hydroxybenzoic acids. 1.5 Quinate Dehydrogenase Quinate (7) is frequently encountered in Nature especially in plants usually in combination with other materials (e.g.with caffeic acid in chlorogenic acid; see Section 4.2). The reversible reduction of 3-dehydroquinate (4) to quinate (7) is catalysed by co co2-co; I I I OH OH OH Shikimate (6) Shikimate 3-phosphate (8) EPSP (9) I OH 6H Prephenate (11) Chorismate (10) Enzymes i shikimate kinase ; ii EPSP synthase; iii chorismate synthase; iv chorismate mutase Scheme 2 NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK quinate dehydrogenase [E.C. 1.l. 1.241. The enzyme activity has been observed in needles of larch (Larix sibirica) and of pine (Pinus sylvestris) and both NAD+-dependent and NADP+- dependent activities could be demonstrated. l4 The action of larch quinate dehydrogenase which had been separated from shikimate dehydrogenase on quinic acid led to the accumulation of protocatechuic and gallic acids though the intermediates 3-dehydroquinate and 3-dehydroshikimate were detectable in labelling studies.The cofactor requirement varied according to conditions; it has been suggested that in conifers quinate can be metabolized either via shikimate or by alternative pathways and the functional role of quinate dehydrogenase depends on the nature of the cofactor. 1.6 Shikimate Kinase Phosphorylation of shikimate (6) to shikimate 3-phosphate (8) is brought about by shikimate kinase [E.C. 2.7.1.711 in the presence of ATP (Scheme 2). Gene cloning has allowed an overproducing strain of Escherichia coli to be constructed. This has for the first time yielded a purified monofunctional enzyme shikimate kinase II.15 The enzyme is monomeric and examination of its amino-acid sequence has shown a region that is homologous with other kinases and ATP-requiring enzymes.Shikimate kinase I1 has very different Michaelis constants from the isozyme shikimate kinase I suggesting that shikimate kinase I1 is the isozyme that normally functions in the biosynthesis of aromatic compounds. Metal ions preferably Mg2+ are necessary for its activity.16 1.7 EPSP Synthase The condensation of shikimate 3-phosphate (8) with phospho- enolpyruvate to produce 5-enolpyruvylshikimate 3-phosphate (EPSP) (9) is catalysed by EPSP synthase [3-phosphoshiki- mate 1-carboxyvinyltransferase; E.C. 2.5.1.191. This enzyme is inhibited strongly by the herbicide glyphosate.Adapta- tion of plants to this herbicide is accompanied by an over- production of EPSP synthase to ensure that the shikimate pathway functions normally. Further plants that are capable of achieving this have been identified. Cultures of a glyphosate- tolerant cell line of Petunia hybrida had 15-20-fold increased levels of the enzyme but the enzyme itself was still herbicide- sensitive." Similar results were found in cultured cells of a tomato hybrid Lycopersicon esculentum x L.peruvianum." The hybrid could tolerate 100 times the concentration of glyphosate that was needed to affect wild-type cells and when it was treated with the herbicide it produced 8-13 times as much EPSP synthase activity. Again the enzyme was glyphosate- sensitive.Although increased levels of EPSP synthase may be obtained by using plants that are adapted to the presence of glyphosate its isolation and subsequent purification is still rather tedious. Since the enzyme is predominantly found in the chloroplasts preliminary manipulation of the plant tissue to give a chloroplast fraction facilitates the purification of the enzyme.19 The inhibition of biosynthesis of aromatic amino acids by glyphosate is covered in detail in a recent review.2o 1.8 Chorismate Synthase The elimination of phosphoric acid from EPSP by the enzyme chorismate synthase [E.C. 4.6.1.43 yields chorismate (10). This enzyme has been characterized from microbial sources but had not previously been identified in a plant.An anaerobic chorismate synthase from pea (Pisum sativum) has now been detected in tissue extracts and in chloroplast preparations.21 The reaction that is catalysed is formally a trans-1,4-elimination but a 1,6elimination might be expected to proceed more favourably if the substituents were cis. An alternative mechanism that has been proposed is via an initial suprafacial 3,3-rearrangement [to form the allylic isomer iso-EPSP (12)] c 0; * co, I 1 OH bH EPSP (9) Chorisrnate (10) OH is0 -EPSP (12) Enzyme i chorismate synthase Scheme 3 followed by a trans-1,2-elimination (Scheme 3). Synthetic iso- EPSP (12) has been evaluated as a substrate for the chorismate synthase of Neurospora crassa. It proved to be an inhibitor of the enzyme and not an alternative substrate.22 1.9 Chorismate Mutase Chorismate mutase [E.C.5.4.99.51 catalyses the Claisen-like rearrangement of chorismate (10) to prephenate (1 l) trans- ferring the phosphoenolpyruvate-derivedside-chain so that this becomes directly bonded to the carbocycle and generates the basic skeleton of the phenylpropanoids. A monofunctional enzyme (CM-F) and a further isozyme (CM-P) the latter being a component of the bifunctional P-protein [chorismate mutase- prephenate dehydratase ; E.C. 5.4.99.5 and E.C. 4.2.1.51 are known to exist in prokaryotes. In plants two mono-functional isozymes (CM- 1 and CM-2) have been identified. Antibodies to these two isozymes from Sorghum bicolorx S. sudanensis have been raised,23 and the lack of any cross- reaction between the isozymes and their antisera indicates that there is no immunological similarity between the two isozymes from this source.CM- 1 is activated by tryptophan but inhibited by tyrosine and by phenylalanine whereas CM-2 is not regulated by any of these amino acids. During further studies on a wider range of plants24 it was demonstrated that the regulated form CM-1 was always present and that most plants also contain the unregulated form CM-2. Nevertheless the regulatory properties of CM- 1 were found to differ significantly between plants. The antisera that were raised for the Sorghum isozymes showed good cross-reactivity with the isozymes from maize (Zea mays) and some reactivity with those from barley (Hordeum vulgare) but all other species that were examined were antigenically distinct from Sorghum bicolor.1.10 Phenylalanine and Tyrosine The biosynthesis of the aromatic amino acids L-phenylalanine (14) and L-tyrosine (17) from chorismate may occur by several NATURAL PRODUCT REPORTS 1988 PL P + dNH2 Prephenate (11) Phenylpyruvate (13) L -Phenylalanine (14) (enz yme-bound1 - t. c0; I I iV PLP I OH OH Chorismate (10) Prephenate (111 L -Arogenate (15) (PLP = pyridoxal 5'-phosphate) viii kNH2 PLP OH OH 4 -Hydroxyphenylpyruvate (16) L -Tyrosine (17) Enzymes i chorismate mutase (monofunctional); ii chorismate mutase-prephenate dehydratase (bifunctional); iii phenylpyruvate aminotransferase ;iv prephenate aminotransferase ;v arogenatedehydratase ;vi arogenate dehydrogenase ;vii prephenate dehydrogenase ;viii 4-hydroxyphenylpyruvate aminotransferase Scheme 4 pathways (Scheme 4).The pathway that is used is dependent proceeds via arogenate.27 High arogenate dehydrogenase on the organism and sometimes several routes operate in activity could be detected but there was no evidence of a particular species. A study of several alkaloid-producing prephenate dehydrogenase activity thus indicating that trans-strains of the ergot-producing fungi Claviceps purpurea and amination of prephenate precedes aromatization. The aro-C. fusiformis indicated that all of the strains that were genate dehydrogenase was strongly inhibited by tyrosine but investigated utilize both arogenate (15) and phenylpyruvate unaffected by phenylalanine prephenate or tryptophan.The (13) as intermediates in the biosynthesis of phen~lalanine.~~properties suggest that this enzyme plays an important role in Thus the enzymes prephenate dehydratase [E.C. 4.2.1Sl] prephenate aminotransferase and arogenate dehydratase were detected. Tyrosine was preferentially or exclusively synthesized via the arogenate pathway as demonstrated by the presence of arogenate dehydrogenase in all strains and of prephenate dehydrogenase [E.C. 1.3.1.121 or prephenate dehydrogenase (NADP') [E.C. 1.3.1.131 in some. The enzymes of the arogenate pathway were insensitive to any feedback inhibition by the two aromatic amino acids. Cultured cells of Nicotiana silvestris contain arogenate dehydratase but not prephenate dehydratase thus establishing that phenylalanine in this species is derived from arogenate but not from phenylpyruvate.26 Arogenate dehydratase was also found in chloroplasts of spinach (Spinacia oleracea) and the enzymes from both plants were shown to be specific for L-arogenate as substrate being inhibited by L-phenylalanine but activated by L-tyrosine.The biosynthesis of tyrosine in sorghum (Sorghum bicolor x S. sudanensis) also the regulation of biosynthesis of tyrosine in sorghum and that arogenate could also function as a precursor of phenylalanine in this plant. The production of arogenate from prephenate by prephenate aminotransferase was also demonstrated in Sor-ghum bicolor x S. sudanensis.28The enzyme utilized glutamate as the amino donor though aspartate could serve as a less efficient substrate.The reaction was freely reversible and in the forward direction was unaffected by tyrosine phenylalanine or tryptophan. The sensitivity of prephenate dehydratase to feedback inhibi-tion by phenylalanine that had been demonstrated in a wild-type strain of Bacillus polymyxa was found to have disappeared in the enzyme from a mutant that is resistant to analogues of ~henylalanine.~ The deregulation and increased activity of the enzyme led to overproduction of phenylalanine in the culture. The presence or absence of enzymes that are involved in the conversion of chorismate into phenylalanine and tyrosine in NATURAL PRODUCT REPORTS 1988 -P.M.DEWICK Shiki mate NIH shift C horismate X OH Prep hen ate co2-H?f I t)H bH L -Arogenate (15) Spiro-arogenate (181 Scheme 5 several pseudomonads has been used to indicate how the various species may have In this respect changes in regulatory properties also become important markers. The biosynthesis of the aromatic amino acids and the role of arogenate are discussed in recent reviews.3o* 31 A spiro-lactam variant of arogenate called spiro-arogenate (18) had been identified in cultures of a mutant Neurospora crassa though the significance of this metabolite remains to be established. The origins of this compound have been studied further in experiments in which labelled shikimate was supplied to the mutant.32 Label quickly appeared in various related metabolites in the sequence chorismate prephenate and finally arogenate and then labelled spiro-arogenate appeared but only after a delay of several hours.This establishes a likely biosynthetic sequence (Scheme 5) but suggests that the postulated ‘arogenate spirase ’ enzyme may have a relatively low affinity for arogenate. A further route to tyrosine is by direct aromatic hydroxylation of phenylalanine. The sequence is employed particularly by mammalian systems. Phenylalanine hydroxylase [phenylalanine 4-mono-oxygenase;E.C. 1.14.16.13 requires molecular oxygen as the oxygen source and a tetrahydropterin as cofactor. The relative activities of this enzyme in the presence of tetra-hydrobiopterin (as the natural cofactor) or of 6-methyltetra- hydropterin were markedly different depending on whether rat liver or rat kidney was the source of the The enzymes of kidney and liver appear to be in different states of activation (probably a dimer for the highly active kidney hydroxylase) and may be regulated in different ways.Phenyl- alanine hydroxylase from Chromobacterium violaceum con-tains a stoicheiometric amount of The hydroxylation step is accompanied by an NIH shift of the 4-hydrogen to position 3 or 5 and this phenomenon has now been detected in Man.35 Oral doses of ~-[ring-~H,]phenylalanine were admin- istered and the concentrations of labelled L-phenylalanine and L-tyrosine in the plasma were detected via mass spectro- metry. The distribution of 2H label in tyrosine was calculated to be consistent only with the NIH shift mechanism followed by random loss of one of the substituents from position 3 or 5 (Scheme 6).The formation of tyrosine and the related o-tyrosine and m-tyrosine from L-phenylalanine in rats has been shown 6 @H X OH OH Scheme 6 co; NANPI + PH H’z 0 (19) [20) Enzyme 4-aminobenzoate hydroxylase Scheme 7 OH NH* (21) to depend on hydroxylases but phenylalanine hydroxylase catalyses only the 4-hydroxylation and not the 2-or the 3-hydro~ylation.~~ The isolation purification and properties of phenylalanine hydroxylase3’ and the mechanism of action of the enzyme38 have been reviewed. 1.11 Anthranilic Acid p-Aminobenzoic Acid and Related Compounds Anthranilate (o-aminobenzoate) is an intermediate in the biosynthetic pathway to L-tryptophan and is derived from chorismate in a reaction that is catalysed by anthranilate synthase [E.C.4.1.3.271. Cell lines of tobacco (Nicotiana tab- acum) contain two forms of the enzyme one being resistant to feedback inhibition by tryptophan and the other being almost completely inhibited by low levels of the amino acid.39 p-Aminobenzoate (19) derives from chorismate by a similar sequence to that which yields anthranilate (see ref. 1). Further metabolism gives the 4-hydroxyaniline moiety of N-(L-glutam- 5-yl)-4-hydroxyaniline (2 l) which occurs in high concentration in the fruiting body of the edible mushroom (Agaricus bisporus). A mono-oxygenase 4-aminobenzoate hydroxylase which catalyses the conversion of (19) into 4-hydroxyaniline (20) has been identified.40 The decarboxylative hydroxylation (Scheme 7) requires either NADH or NADPH and molecular oxygen is needed as the source of the oxygen; the enzyme is FAD-dependent.Other substituted benzoates with free amino-groups and carboxyl groups in an ortho or para relationship (e.g. anthranilate or 4-aminosalicylate) would serve as sub- strates but in these cases the hydroxylation was accompanied by the formation of hydrogen peroxide. The reaction is analogous to that catalysed by salicylate hydroxylase [salicyl- ate 1-mono-oxygenase ;E.C. 1.14.13. I] but 4-aminobenzoate hydroxylase does not act on salicylate. CH20@ Ho-%hO H “2 02 QE) -Ql3 H H (22) L -Tryptophan (23) QoH (241 (cc and 0 refer to subunits of tryptophan synthase) Scheme 8 E H Internal aldimine L -Serine form of enzyme -bound PLP E + 0 @A-N +/ H NHZ H NATURAL PRODUCT REPORTS 1988 2 Tryptophan and Related Compounds 2.1 Tryptophan Synthase Tryptophan synthase [E.C.4.2.1.201 is a multi-enzyme complex (the a2p complex) comprising two a subunits and a p2dimeric subunit. This enzyme catalyses the final reaction in the biosynthesis of tryptophan [i.e. the synthesis of L-tryptophan (23) from L-serine and indole-3-glycerol phosphate (22)] and both the aldolytic cleavage of indole-3-glycerol phosphate to indole (24) and the formation of tryptophan from L-serine and indole (Scheme 8).The second and third reactions are also catalysed by the a and p2 subunits respectively of tryptophan synthase. The replacement of the P-hydroxyl group of L-serine with indole which is catalysed by the p subunit requires pyridoxal 5’-phosphate and the distinctive ultraviolet-visible spectral properties of this compound provide a sensitive probe for the detection and identification of intermediates during the reaction. In continuation of earlier work (see ref. l) but using more refined techniques the reaction of L-serine with indole that is catalysed by the a,P2 complex from Escherichia coli has been studied via rapid-scanning stopped-flow ultraviolet-visible ~pectroscopy.~~ These studies have confirmed the reaction sequence that was proposed previously (Scheme 9) and have indicated both that the a-aminoacrylate Schiff s-base intermediate (25) is highly reactive towards indole and that the steps in the sequence before this one limit the rate of the reaction.Binding of indole alters the spectrum of the a-aminoacrylate prior to the formation of a covalent bond. Monoclonal antibodies have been used during investigations of the conformational effects of the binding of ligands on the p2 Extended conformational rearrangements of the protein are brought about by fixation of the coenzyme pyridoxal 5’-phosphate and the substrate L-serine. The associ- ation of the a and p subunits is also accompanied by 0- H enzyme-bound oc-aminoacrylate Schiff’s base with PLP (25) lndole I L -Tryptophan H Scheme 9 NATURAL PRODUCT REPORTS 1988 -P.M. DEWICK H ti L-Tryptophan (23) Indole (24) Scheme 10 H H H H H Schiff's base of (35)-5-f I uoro-2,3 -dihydro-L-Trp (26) Scheme 11 H CH CO HQrzJH C HZCH CO HI (2 8) IAA (29) important conformational changes on the p2 subunit. This brings about an increase in tryptophan synthase activity and abolishes the serine deaminase activity of the p2 subunit. Although tryptophan synthase catalyses a number of pyridoxal-5'-phosphate-dependent/?-elimination reactions and /?-replacement reactions that are also catalysed by trypto- phanase [E.C. 4.1.99.11 a principal and puzzling difference between the two enzymes has been the apparent inability of tryptophan synthase to catalyse the p-elimination of indole from L-tryptophan.It has now been shown for the first time that the /?, subunit and the a2P2complex of tryptophan synthase from E. coli and from Salmonella typhimurium do catalyse a slow /?-elimination reaction (Scheme 10) which produces indole pyruvate and ammonia.43 The rate of reaction was significantly higher in the presence of the a subunit and could be increased by enzymically removing the products of the reaction (by supplying substrates and thus exploiting the other catalytic activities of tryptophan synthase). That the reaction was not due to contaminating tryptophanase was demonstrated by using specific inhibitors of the enzymes. (3R)- 2,3-Dihydro-~-tryptophan, which is a specific inhibitor of tryptophanase had no effect but (3S)-2,3-dihydro-~-trypto-phan which is a specific inhibitor of tryptophan synthase completely inhibited the reaction.The cleavage reaction was also inhibited by D-tryptophan which is the product of a slow racemization reaction. It was concluded that tryptophan synthase is similar to tryptophanase in its reaction mechanisms and specificity but several of the reactions are catalysed at very different rates. To explore aspects of the reactions that are catalysed by the a2,8 complex of tryptophan synthase from Escherichia coli several 5-fluorinated substrates and reaction-intermediate ana- logues were adaed to the enzyme and their fates were followed by 19Fn.m.r.meas~rements.~~ Tryptophan synthase was shown to bind the (3S)-diastereoisomers of both 5-fluoro-2,3-dihydro- D-tryptophan and 5-fluoro-2,3-dihydro-~-tryptophan both specifically and tightly but it bound 5-fluoro-~-tryptophan more tightly than 5-fluoro-~-tryptophan. Unexpectedly a slow isomerization of 5-fluorotryptophan of tryptophan and of (3$)-5-fluoro-2,3-dihydrotryptophanwas detected. The reac- tion was extremely slow being lo3 to lo5times slower than the /?-replacement and /?-elimination reactions that are catalysed by tryptophan synthase and probably has no biochemical sig- nificance in vivo. Whether tryptophan synthase itself serves a catalytic role in the isomerization or the enzyme simply binds the substrate and pyridoxal 5'-phosphate so that chemical isomerization of the Schiff s base (26) may occur is not known (Scheme 11).A novel tryptophan analogue 3-(indazol- 1 -yl)-L-alanine (27) was produced when the tryptophan synthase a2/?, complex from E. coli was supplied with the indole analogue indazole (28).45This is the first example of a /?-replacement reaction that is catalysed by tryptophan synthase but which occurs at a position other than position 3 of indole analogues. Several reviews relating to the biosynthesis of tryptophan have been published including descriptions of genetic aspects,46 ~egulation,~' and conformational studies on tryptophan synthase.48 2.2 Indole-3-acetic Acid and Related Metabolites of Tryptophan Indole-3-acetic acid (IAA) (29) is an essential plant growth hormone (auxin).It is derived in Nature by oxidative NATURAL PRODUCT REPORTS 1988 (30) R = GIC (31) R= NHCHC0,H I CH,CO H H (34) R = H (35) R =OH Indole-3 -acet aldox ime / Indole-3- acet amide -H (32) R = AC (331 R =H bNH";"'02~ C H CO H H (36) R =H (37) R = GIC Tryptophan I I ndole -3 -pyr u v ic acid Tryptamine I Indole-3- acetaldehyde Indole -3 -e t ha n o I (Tryptophol) Indole -3-acetic acid Indole-3-methanol Indole -3-car balde h yde Indole-3- car box y lic acid Scheme 12 metabolism from tryptophan. Several pathways may operate via the intermediates indole-3-pyruvic acid tryptamine indole- 3-acetamide or indole-3-acetaldoxime (Scheme 12).Indole-3- acetic acid may be subjected to further metabolism and can yield a wide variety of indole and oxindole derivatives. Labelling studies using chloroplast fractions from pea (Pisum sativum) have shown that indole-3-methanol is a major catabolite in this In leaf segments of wheat (Triticum aestivum) 14C-labelled IAA gave glucosides of indole-3-methanol and indole- 3-carboxylic acid as did labelled indole-3-methanol when it was admini~tered.~~ Conjugates of IAA such as indole-3-acetyl-P-D-glucose (30) and indole-3-acetylaspartic acid (3 l) may also be formed.51 In addition a non-decarboxylative pathway that leads to a number of oxindole derivatives exists in T. aestivum. The concentration of IAA increases after wheat has been infected with the rust fungus Puccinia graminis and this may be due to a contribution from the fungus itself.Studies of non-transformed and Agrobacterium-tumefaciens-transformed cells of tobacco (Nicotiana tabacum) have shown that labelled tryptophan is converted into indole-3-acet-aldoxime and indole-3-ethanol in both cell types but indole-3- acetamide occurs exclusively in the transformed cells.52 81 NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK dOH HO" I I AH OH OH Quinate (7) 3 -Dehydroquinat e (4 1 3-Dehydroshi kimate (5) Shikimate (6) 6 HO \ OH OH OH Protocat echuate (38) Gallate (39) Enzymes i quinate dehydrogenase ;ii 3-dehydroquinate dehydratase ;iii shikimate dehydrogenase ;iv 3-dehydroshikimate hydro-lyase Scheme 13 OH HO OH 11 0 0 -Glucogallin (401 Indole-3-acetaldoxime yielded IAA and indole-3-ethanol in both tissues with indole-3-acetamide again occurring only in transformed cells.Labelled IAA was rapidly conjugated with aspartic acid to give indole-3-acetylaspartic acid though with increased efficiency in the transformed cells. The overall results suggested that in the transformed cells auxin genes from the Agrobacterium are integrated into the host altering the host's capacity for both biosynthesis and conjugation of IAA and thus producing the characteristic tissue of a crown gall tumour. In Pseudomonas syringae pv. savastanoi which is the causative agent of olive knot disease and oleander knot disease IAA is derived from tryptophan via indole-3-acetamide.Water- soluble lysine conjugates e.g. (32) and the previously reported compound (33) have been detected in cultures of strains of the pathovar from oleander though not from those that affect olive.53 A main catabolite of IAA in seedlings of maize (Zea mays) is the oxindole derivative oxindole-3-acetic acid (34).54 In roots of broad bean (Viciafaba) the formation of conjugates of 3- hydroxyoxindole-3-aceticacid (dioxindole-3-acetic acid) (35) appears to be a major route of metabolism of IAA.55 Over 70 % of the activity from labelled IAA was recovered in the two aspartic acid conjugates (36) and (37) after a period of 24 hours. The metabolic sequence to these compounds was investigated by feeding experiments in which labelled precursors were Indole-3-acetylaspartic acid (3 l) but not di-oxindole-3-acetic acid (35) was found to be a precursor of dioxindole-3-acetylasparticacid (36) and double-labelling experiments proved that the conjugate was incorporated intact.The hydroxy-compound (36) was glucosylated to (37) in cotyledons of V.faba though the transformation was very slow in its roots. The glucoside appears to be formed in the cotyledons and is then transported to the roots. The biosynthesis and regulation of the formation of IAA has been re~iewed.~' 3 Phenols and Phenolic Acids Some simple phenolic acids are derived directly from 3-dehydroshikimate (which is an intermediate on the shikimate pathway) and retain the full carbon skeleton of this acid. Studies of biosynthesis in young seedlings of Pinus sylvestris have shown that protocatechuic acid (3,4-dihydroxybenzoic acid) vanillic acid (4-hydroxy-3-methoxybenzoicacid) and gallic acid (3,4,5-trihydroxybenzoicacid) are all formed from either [14C]quinate or [14C]shikimate precursor^.^^ The presence of key enzymes of the shikimate pathway e.g.quinate dehydrogenase shikimate dehydrogenase 3-dehydroquinate dehydratase and 3-dehydroshikimate hydro-lyase was also demonstrated. Protocatechuic acid (38) and gallic acid (39) were produced when quinic acid was treated with a quinate dehydrogenase preparation from larch (Larix sibirica). l4 The shikimate dehydrogenase activity had been removed from this preparation so these acids result from the action of other enzymes on 3-dehydroquinate and 3-dehydroshikimate.Trace amounts of these intermediates could be demonstrated to be formed by labelling studies (Scheme 13). An enzyme that has been isolated from leaves of oak (Quercus robur) catalyses an exchange reaction between P-glucogallin (1 -0-galloyl-P-D-glucose) (40) and free glucose. 59 This acyltransferase achieves no overall chemical change but if ['4C]glucose was supplied to the preparation it was incorporated into the P-glucogallin. Gallic acid itself was not exchanged and other potential sugar donors (such as @-glucose 1-phosphate a-D-glucose 1-phosphate D-glucose &phosphate gentiobiose or sucrose) were not accepted. However the enzyme would react with benzoylglucose p-coumaroylglucose and sinapoyl- glucose.The role if any of this acyltransferase in the biosynthesis and metabolism of gallotannins is unknown but 82 its use provides a very convenient method to prepare labelled /3-glucogallin and related 1-0-acyl esters. The biosynthesis of hydroxybenzoic acids and the role of gallic acid in secondary metabolism form the subject of a detailed review.6o 4 Phenylpropanoids 4.1 Phenylalanine Ammonia-lyase The enzyme phenylalanine ammonia-lyase (PAL) [E.C. 4.3.1.51 catalyses the elimination of ammonia from L-phenylalanine producing trans-cinnamic acid and effectively controls the flow of material from the shikimate pathway into many important phenylpropanoid-based secondary metabolites. Recent work has shown that purified enzyme preparations from cell suspension cultures of French bean (Phuseolus vulgaris) that had been exposed to a polysaccharide elicitor from the cell walls of the phytopathogenic fungus Col-letotrichum lindemuthianum are inherently unstable.61 The native subunit (M 77000) breaks down to yield partial degradation products (M 70000 and 53000) both in vitro and in vivo.This degradation was noted with four different forms of the enzyme that could be isolated from P.vulgaris. The four forms are resolvable and are characterized by different pl values. The elicitor-induced PAL activity in P. vulgaris cells OH I PhC H,CH CO,H PhCH,CH-P=O I It ONH NH2 OH L -AOPP (41) APEP (42) HO Ho*o&oH \ OH + OH 0 NATURAL PRODUCT REPORTS 1988 declines rapidly if the cells are subsequently treated with the reaction product trans-cinnamic acid.62 Other demonstrated inhibitors of PAL from germinating seeds of lettuce (Lactuca sativa) include D-phenylalanine 4-fluorophenylalanine p-phenyl-lactic acid and ~-tryptophan.~~ The synthetic L-phenylalanine analogue ~-a-amino-oxy-,8-phenylpropionic acid (L-AOPP) (41) also causes significant inhibition of PAL activity at very low concentrations.Other evidence from experiments in which cell cultures of Cryptomeriu juponica and Perilla frutescens var. crispa were used suggests that this compound may inhibit the formation of PAL although it is usually considered to be a competitive inhibitor of the enzyme.64 Phenylalanine ammonia-lyase from buckwheat (Fagopyvum esculenturn) has been used to test other synthetic analogues for potential inhibitory action.65 The phosphonic analogue (1 -amino-2-phenylethyl)phosphonic acid (APEP) (42) was found to competitively inhibit buckwheat PAL the (R)enantiomer being more effective than the (5') form.The corresponding phosphonous analogues were less inhibitory. If APEP was applied to hypocotyls of buckwheat seedlings it inhibited the synthesis of anthocyanins and caused an increase in the concentration of phenylalanine. Seedlings of kohlrabi developed normally in the presence of APEP though their anthocyanin content was greatly reduced. The isolation and subsequent purification of the enzyme from developing fruit of oranges (Citrus sinensis) has been described.66 Specific inhibitors of PAL are described in a recent review.2o 4.2 Cinnamic Acids and Esters Hydroxycinnamic acids are in most cases obtained by aromatic hydroxylation of the cinnamic acid that is formed by the action of PAL gradually building up the oxygenation pattern and 0qnC02H -dOH OH AH (431 Quinic acid (44) OH Chlorogenic acid (45) Scheme 14 H H o s o d OOMe HO OH 0 (47) O h O\ MOH e OMe IL6) OMe Me,:-oH 0 Sinapine (48) Choline (49) NATURAL PRODUCT REPORTS 1988 -P.M. DEWICK giving the commonly encountered 4- 3,4- and 3,4,5-oxy- genated products. There is ample evidence to demonstrate that 3-hydroxylation of 4-hydroxy-substituted phenylpropanoids occurs but surprisingly the process has not been well studied at the enzymic level.In a recent preparations from tubers of potato (Solanum tuberosum) have been shown to catalyse the 3-hydroxylation of 4-hydroxyphenylpropanoid carboxylic acids including p-coumaric acid and tyrosine ; NADH (or NADPH) and FAD (or FMN) were necessary cofactors. Among a range of 4-hydroxylated C,C and C,C compounds that were tested only 4-hydroxyphenylacetic acid and p-cresol were hydroxylated. The hydroxylase showed some features of phenolase hydroxylation and is probably concerned in the biosynthesis of chlorogenic acid in potato. Further modification of cinnamic acids often requires an activated form of the acid to be produced initially and glucose esters are frequently encountered in this role as well as esters of coenzyme A.The biosynthesis of chlorogenic acid (5-0-caffeoylquinic acid) (45) involves a transesterification reaction between 1-0-caffeoyl-@-glucose (43) and quinic acid (44) (Scheme 14). The enzyme that catalyses this reaction in roots of sweet potato (Ipomoea batatas) has been purified and its substrate specificity investigated.,’ Although the enzyme demonstrated strict specificity towards compounds that are related to quinic acid as acceptors (shikimic acid was also transformed but less effectively than quinic acid) it had broad substrate specificity towards hydroxycinnamoyl-D-glucoses as donors. 1-0-Cinnamoyl-D-glucose I -0-p-coumaroyl-~-glucose and I -0-caffeoyl-D-glucose were all readily trans-formed into the corresponding products.The hydroxycinnamoylglucose substrate may however function as both the acyl donor and the acyl acceptor and such a process is observed in the biosynthesis of 1,2-di-O-sinapoyl-P-D-glucose (46) in seedlings of radish (Raphanus sativus var. sativu~).~~ The enzyme which is a hydroxycinnamoyl-transferase catalyses the formation of (46) from two molecules of 1-0-sinapoyl-P-D-glucose (47) showing strict specificity of transfer to the 2-hydroxyl of the acceptor. However it has broad substrate specificity towards glucose esters of phenyl- propane acids transforming esters of sinapic ferulic and p- coumaric acids yet shows no activity towards glucose esters of C,C acids e.g. 1 -0-benzoylglucose and 1-0-galloylglucose.Sinapine synthase enzymes have been isolated from seeds of radish (Raphanus sativus var. sativus) and of mustard (Sinapis aIba).’O Sinapine (48) is the choline ester of sinapic acid and the hydroxycinnamoyltransferase sinapine synthase [sinapoyl- CO H + HO-CH / C(0)SCoA ‘CO H (50)R =H Tartronic acid (53) (51) R =OH (52)R =OMe + HSCoA (54)R =H (55)R =OH (56)R =OMe Scheme 15 glucose-choline sinapoyltransferase ; E.C. 2.3.1.911 uses 1-0-sinapoyl-6-D-glucose (47) as the acyl donor and choline (49) as the acceptor. The purified enzymes from these two sources had similar properties and though sinapoylglucose was the favoured substrate ferulic and p-coumaric esters of glucose were also transformed. Acyl donors that were not acceptable included the 6- and 3-0-sinapoylglucoses 1-0-benzoylglucose and 1-0-galloylglucose.Conjugates of p-coumaric acid caffeic acid and ferulic acid with tartronic acid (53) are present in young plants of mung bean (Phaseoh radiatus L. [syn. P. aureus Roxb. and Vigna radiata (L.) R. Wilczek]). In contrast to the above examples glucose esters are not involved in the formation of the tartronates (54F(56) but instead the coenzyme A esters (50)-(52) feature as the activated cinnamic acids (Scheme 15).71 Thus no products were formed when an enzyme preparation was incubated with 1-0-(p-coumaroy1)glucose but p-coumaroyl and caffeoyl coenzyme A esters were utilized. Assessment of the substrate specificity for the reaction was facilitated by exploiting its freely reversible nature.No reaction was observed with esters of tartaric malic or quinic acid. Seedlings of Stachys albens and other Stachys species synthesize a number of caffeic acid esters including chlorogenic acid (49 verbascoside (57) and stachyoside (58). Feeding experiments using leaves of S. albens have demonstrated that phenylalanine and cinnamic acid are incorporated into the caffeoyl moiety of all three compounds with the 3,4-dihydroxyphenylethyl moiety of (57) and (58) arising from tyrosine or better from t~ramine.~’ Incorporation data indicate that stachyoside probably arises by further glucosylation of verbascoside and the results are consistent with earlier studies on the biosynthesis of verbascoside in lilac (Syringa vulgaris) (Scheme 16).How tyramine is transformed into the dihydroxyphenylethyl portion of (57) and (58) has yet to be established. However the tyrosine decarboxylase [E.C. 4.1.1.251 in cell cultures of Syringa vuIgaris appears to be strongly inhibited by the phenylalanine analogue L-AOPP as is PAL (see Section 4.1).73 It is suggested that there may be some metabolic co-ordination between the two convergent pathways that lead to verbascoside and related compounds. 4.3 Phenylpropane and Phenylethane Derivatives Genetic analysis of hybrids of Perilla frutescens has been undertaken to outline the biosynthetic sequences leading to a number of allylbenzenes that are produced by this plant.74 A Phenylalan ine Ty rosine Cinnamic acid Tyramine 0 OH R OH Verbascoside (57) R = Rha Stachyoside (58) R = Rha-Glc Enzymes i phenylalanine ammonia-lyase ; ii tyrosine decarboxylase Scheme 16 NATURAL PRODUCT REPORTS I988 u Me0 / Dillapiole (611 Methyleugenol (59) OMe MeoooMe Elemicin (62) Scheme 17 pathway that was proposed many years ago (Scheme 17) appears to be operative since biosyntheses of dillapiole (61) and elemicin (62) are controlled by two independent genes expressing for reactions a and b respectively.Only myristicin (60) is produced in the absence of both of these dominant genes. The role of methyleugenol (59) is unfortunately still hypothetical because it has not yet been detected in Perilla OH OH frutescens. Homogentisic acid (63) is a tyrosine-derived phenylethane (16) Homogentisic acid (63) metabolite that is formed by the action of 4-hydroxy-phenylpyruvate dioxygenase [E.C.1.13.1 1.271 on 4-hydroxy- Enzyme i 4-hydroxyphenylpyruvate dioxygenase phenylpyruvate (16) (Scheme 18). Whilst many features of this Scheme 18 complex conversion are being resolved (see ref. l) a new piece of information has recently been presented. 75 A spectroscopic investigation of the non-haem iron-containing dioxygenase from a species of Pseudornonas has shown the presence of tyrosine that is co-ordinated to iron in the active site. The PhycoZH enzyme thus belongs to the class of iron-tyrosinate proteins NH2 but the precise function of the tyrosine has yet to be established. During biosynthesis of the antibiotic virginiamycin S by Streptornyces virginiae L-phenylalanine is incorporated by way of L-phenylglycine (64).In theory the transformation of phenylalanine into (64) could occur via an intermolecular P h w CO H transfer of nitrogen e.g. as shown in Scheme 19 or via some Ph-Co2H intramolecular pro~ess.'~ That an intermolecular pathway is 0 involved has been confirmed by a feeding experiment with DL-[3-13C l5N]pheny1alanine. Carbon- 13 n.m.r. analysis of the phenylglycine portion showed no labelled nitrogen remaining [ -COzI and it has been suggested that the rearrangement (Scheme 19 path b) resembles that which occurs during the formation of p-tyrosine from tyrosine. 0 The chromenes demethoxyencecalin (65) O-demethyl-PhE C 02 H encecalin (66) and encecalin (67) appear to be related by a logical biosynthetic sequence that involves hydroxylation and then methylation based on observations of the levels of these compounds in Ageratina adenophora during the plant's t ransami not\ion development and also from feeding experiments with unlabelled material^.^^ That the compounds may be derived from shikimate is suggested because of the massive reduction in the total concentration of chromenes if the plant is treated with glyphosate (an inhibitor of EPSP synthase; see Section 1.7).(641 However based on earlier studies with related compounds the acetophenone moiety appears to be more likely to be acetate- Scheme 19 derived than shikimate-derived. NATURAL PRODUCT REPORTS 1988 -P.M.DEWICK 4.4 Coumarins A series of feeding experiments in which shoots of Daphne mezereum were used have been conducted to investigate the biosynthesis of daphnetin (7,8-dihydroxycoumarin) (69).78 Umbelliferone (68) was incorporated more efficiently than p-coumaric acid and caffeic acid was poorly utilized. The findings support the idea of umbelliferone being a rather general precursor of other plant coumarins that bear further oxygen R (65) R = H Umbelliferone(68) R = H (66) R = OH Daphnetin (69) R = OH (67) R = OMe Meorno HO \ Scopolet in (70) Ayapin (71 1 GlcO \ Meorno Scopolin (72) Scheme 20 substituents on the aromatic ring rather than that the additional substitution occurs at the cinnamic acid stage.Daphne mezereum also contains skimmin which is the 7-0-glucoside of daphnetin and it has been suggested that glucosylation occurs at the coumarin stage. Coumarins accumulate in stem sections of sunflower (Helianthus annuus) after they have been infected with fungi and although scopoletin (70) and scopolin (72) may be detected in uninoculated tissue their concentrations increase markedly in infected stems. Ayapin (71) is found only in infected plant^.'^ If labelled scopoletin was supplied to stem sections of Helminthosporium-carbonum-infected sunflower it was incorporated into the glucoside scopolin (72) and par- ticularly efficiently into the methylenedioxy-derivative ayapin (Scheme 20). Both ayapin and scopoletin were rapidly degraded by the sunflower pathogen Alternaria helianthi.(E)-2-Hydroxy-4-methoxycinnamic acid (73) has been isolated from Artemisia dracunculus and has been proposed as the precursor of herniarin (74) in this plant.*O Indeed this cinnamic acid is unstable in ultraviolet light and rapidly cyclizes to herniarin. Compound (73) could not be detected in Lavandula oficinafis when studies on the biosynthesis of herniarin were first conducted some years ago. Many natural phenolic derivatives contain a furano sub- stituent that is known to be derived by loss of a three-carbon unit from an isopropyldihydrofurano-system which itself arises by cyclization of a prenyl substituent with an ortho-hydroxyl group (see also Section 5.8). Thus (+)-marmesin (75) has been shown (from incorporation studies) to be a precursor of the furanocoumarin psoralen (76) (Scheme 21).Microsomal fractions from cell suspension cultures of parsley (Petroselinum crispum) which had been challenged with an elicitor from either Alternaria carthami or Phytophthora megasperma fsp. gfycinea have now been shown to catalyse the conversion of (+)-marmesin into psoralen.81 The system requires NADPH and molecular oxygen as cofactors the reaction being catalysed by an elicitor-induced cytochrome-P-450-dependent enzyme psoralen synthase. Although 14C-labelled (& )-marmesin was used in the incubation experiments dilution experiments with either (+)-or (-) -marmesin demonstrated that (+)-marmesin was in fact the substrate; (-)-marmesin was not converted.The observations support the hypothesis that a 3’-hydroxylation step may be involved perhaps via the mechanism in Scheme 21 if this hydroxyl group is cis to the hydroxyisopropyl group. The cis configuration is found in most naturally occurring examples of such compounds. A 3’-hydroxylated intermediate may not accumulate if hydroxylation is the rate-limiting step ;indeed no r Me0m0 MeO\ COHO Z H \ intermediates between marmesin and psoralen were detectable. However an unidentified product that was neither a precursor (731 Herniarin (74) nor a product of psoralen was isolated from incubations with Psoralen (76) Scheme 21 86 Alternaria-induced microsomes but not from Phytophthora- induced preparations. Methylation of furanocoumarins is a further transformation that has been encountered in elicitor-stimulated parsley cells.Cultured cells that had been treated with elicitor from Phytophthora megasperma f.sp. glycinea contained two 0-methyltransferases which catalyse the S-adenosylmethionine- dependent methylation of xanthotoxol(77) to xanthotoxin (78) and of bergaptol (79) to bergapten (80) respectively.82 The 5 R Xanthotoxol (77)R =OH Ber gapto‘ (79) = OH Xanthotoxin (78)R =OMe Bergapten(80) R =OMe R U3Xo OMe 5-Hydroxyxanthotoxin (811R =OH Isopimpinellin (82) R =OMe NATURAL PRODUCT REPORTS 1988 latter enzyme was also shown to catalyse the methylation of 5-hydroxyxanthotoxin (8 1) to isopimpinellin (82). Simple coumarins were either not converted or very poor substrates and the utilization of 5,8-dihydroxypsoralen and 8-hydroxy- bergapten by either enzyme was only minimal.The activities of both enzymes showed transient increases when the elicitor was applied and these occurred a few hours later than the increases in PAL and 4-coumarate-CoA ligase activities. A review on the biosynthesis of plant coumarins has been published.83 4.5 Lignins Infection of leaves of wheat (Triticum aestivum) with a biotic elicitor that can be isolated from the rust fungus Puccinia graminis f.sp. tritici results in lignification preceded by an increase in PAL This increase in enzyme activity is then accompanied by increases in the activity of other enzymes of the general phenylpropanoid pathway and of the specific pathway of lignin biosynthesis including 4-coumarate-CoA ligase cinnamyl-alcohol dehydrogenase and peroxidase.Lignification is assumed to occur exclusively by oxidative polymerization of the (E) monomers p-coumaryl alcohol (83) coniferyl alcohol (84) and sinapyl alcohol (85) (monolignols). The isolation of the (2)-monolignols cis-coniferyl alcohol (86) and cis-sinapyl alcohol (87) from bark of beech (Fagus grandif~lia)~~ suggests that lignification might also involve the (Z) monomers. Polymeric lignins that were derived by incubating H202 and peroxidase with either (9-or (2)-coniferyl alcohol appeared to be identical. Thus both (E)-and (2)-monolignols may be used for lignification or alternatively the lignifying enzymes are indeed highly specific and (9-monolignols accumulate in beech bark because they are not suitable substrates.4.6 Lignans It has been shown that a range of tumour-inhibitory aryltetralin lignans in Podophyllum hexandrum can be subdivided bio- synthetically into two groups. One group contains a 3,4,5-trimethoxy-substituted pendent aromatic ring and its members are derived from desoxypodophyllotoxin (88). Members of the other group contain a 4-hydroxy-3,5-dimethoxy-substituted pendent ring and are derived from 4’-O-demethyldesoxy- KHzoH R \ OMe podophyllotoxin (89). The major lignans podophyllotoxin (90) OH OH and 4’-O-demethylpodophyllotoxin(91) are produced by hydroxylation of (88) or (89) at C-4 (Scheme 22). Further (83) R’ = R2 = H (86) R =H feeding experiments in which intact plants of P.peltaturn were (84) R’ = OMe R2 = H (87) R = OMe used,86 have confirmed earlier suggestions that the peltatins (85) R’ = R2 = OMe P-peltatin (92) and a-peltatin (93) are derived from (88) and ?H ____) OR OR OR O-Peltatin (92) R =Me Desoxypodophyllotoxin (88)R = Me Podophyllotoxin(90) R = Me a-Peltatin (93) R = H (89) R = H L’-O-Demethylpodophyllotoxin(91) R = H Scheme 22 NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK OH OH Matarresinol (94) (95) t;’ Me0Met&o \ OMe +OMe 0 Yatein (96) (97) A nh ydr opodor hi zol (98) t;‘ H OMe OMe (88) Podorhizol (99) Podop hyllot oxin Scheme 23 (89) respectively by aromatic hydroxylation at C-5. The incorporation of desoxypodophyllotoxin (88) into podophyllo- toxin (90) and P-peltatin (92) was also demonstrated to occur in P.hexandrum. Intermediates in the biosynthesis of podophyllotoxin prior to desoxypodophyllotoxin have been investigated by feeding ex- periments using P.hexandrum plants that involved a range of dibenzylbutyrolactone lignans that are structurally related to the Podophyllum lignans and known to co-occur with aryl- tetralin lactone lignans in various planks7 Yatein (96) proved to be a satisfactory precursor; the corresponding cis-isomer (100) was also incorporated to a lower extent probably via yatein. Podorhizol (99) epipodorhizol (10I) and anhydro- podorhizol (98) were not incorporated into podophyllotoxin despite the demonstrated presence of both podorhizol and anhydropodorhizol in P.hexandrum plants. A biosynthetic sequence (Scheme 23) from yatein to podophyllotoxin via a key quinone methide intermediate (97) which can cyclize to NATURAL PRODUCT REPORTS 1988 H OMe OMe (100) OH 0 (2s)-Nor ingenin (102) R = H Dihydrokaempferol (104)R = H (1061 (2Sl-EriodictyoL (103)R =OH Dihydroquercetin (105) R = OH KaempferoI (107) R = H Quercetin (108) R = OH desoxypodophyllotoxin (88) has been proposed. This inter- mediate is probably also the percursor of both podorhizol (99) and anhydropodorhizol (98) by addition of water or by loss of a proton respectively. It is known that the 4-0-methyl series and the 4’-0-demethyl series of Podophyllurn lignans are formed separately from some common precursor.This is logically suggested to be matairesinol (94) which could be modified to either yatein (96) or 4’-0-demethylyatein (95) prior to cyclization giving the two groups of aryltetralin lactones. That the pattern of trimethoxy-substitution of podophyllotoxin is derived by a sequence that does not involve the hydroxy- dimethoxy pattern (as in 4’-0-demethylpodophyllotoxin) is demonstrated by an analysis of the labelling in these methyl substituents for samples of (90) and of (91) that had been obtained from feeding [S-rnethyl-14C]methionine. Quite differ- ent labelling patterns were observed and it was concluded from these that the branch-point compound will be either 4’- hydroxy- 3'-methox y-or 4’ 5’-dihydroxy-3'-methox y-substituted in the aromatic ring that ultimately becomes the pendent aryl group.The biosynthesis of lignans is briefly covered in a review of the chemistry of lignans.88 5 Flavonoids 5.1 General Aspects An overview of flavonoid biosynthesis has been published.8g 0 Apigeni n (109) R = H Lut eolin (110)R = OH 5.2 Chalcone Synthase Chalcone synthase [naringenin-chalcone synthase; E.C. 2.3.1.741 appears to be the rate-limiting enzyme for biosynthesis of flavonoids in the primary leaves of oat (Avena ~ativa).~~ However the purified enzyme is not inhibited by C-glucosyl- flavones which are the end-products of the biosynthesis of flavonoids in oat and to date there is no indication that chalcone synthase is regulated by feedback or by similar enzyme-modulation mechanisms in this plant.Nevertheless there is a clear correlation between chalcone synthase activity and the rate of accumulation of flavonoids during the development of a leaf. The binding of one of the substrates of the chalcone synthase reaction i.e. 4-coumaroyl-CoA was competitively and strongly inhibited by the flavone apigenin though this compound has not been implicated as an intermediate in the biosynthetic pathway to the major oat flavonoids. The chalcone synthase from buckwheat (Fagopyrurn esculenturn) has also been isolated and purified.g1 The enzyme utilizes malonyl-CoA and 4-coumaroyl-CoA as substrates though caffeoyl-CoA or feruloyl-CoA could substitute for the latter material albeit less effectively.Antibodies to the enzyme have been developed and characterized for specificity. In mixing experiments using extracts from two cell lines of carrot (Daucus carota) tissue cultures that either contained or were devoid of chalcone synthase activity a strong inhibition of chalcone synthase could be dem~nstrated.~~ The inhibition was NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK (+I-Dihydroquercetin (105) (111) (+)-Catechin (11 2) Scheme 24 OMe 0 (-)-Epicatechin (113) (114) Malvidin (115) traced to the presence of a heat-labile 3’-nucleotidase [E.C. 3.1.3.61 in the cells that lacked chalcone synthase activity. The the flavone apigenin (109) giving eriodictyol (103) quercetin (108) and luteolin (1 10) respe~tively.~~ Its cofactor requirements enzyme hydrolyses the phosphate group at C-3’ of adenosine for 0 and NADPH together with other properties suggest in the CoA thioester substrates.Although 4-coumaroyl-3’- that the enzyme is a cytochrome-P-450-type mono-oxygenase. dephospho-CoA was still able to act as a starter group for the reaction of chalcone synthase the dephosphorylated malonyl- CoA could not be used as a chain extender and indeed acted 5.4 Catechins and Proanthocyanidins as an efficient inhibitor of chalcone synthase. Coenzyme A itself Flavan-3,4-diols (leucoanthocyanidins) and flavan-3-01s (cat- lost its inhibitory action after it had been 3’-dephosphorylated. echins) arise by successive reduction steps from dihydro- Such processes may play an important role in regulation of the flavonols.The double reduction step has now been demon- biosynthesis of flavonoids. strated with an enzyme preparation from maturing grains of barley (Hordeurn v~lgare).~~ A soluble NADPH-dependent 5.3 Flavanones Dihydroflavonols Flavonols and Flavones Dihydroflavonols are important intermediates in the bio-synthetic sequences to other flavonoid derivatives and are formed by 3-hydroxylation of flavanone precursors. A (2s)- reductase converted (+)-2,3-dihydroquercetin (105) into the (2R,3&4S)-flavan-3,4-diol (+)-2,3-trans-3,4-cis-leucocyanidin (1 11) but was strongly inhibited by the product of the reaction. A second less-active NADPH-dependent reductase catalysed the reduction of (111) to (+)-catechin (112) (Scheme 24). flavanone 3-hydroxylase [3-dioxygenase] from flowers of Proanthocyanidins (or condensed tannins) contain catechin Petunia hybrida has been purified and shown to have similar elements that possess 2,3-trans [e.g.(+)-catechin (1 12)] and properties to enzymes from other The enzyme 2,3-cis stereochemistry [e.g.(-)-epicatechin (1 13)]. There is is a typical 2-oxoglutarate-dependentdioxygenase requiring much speculation but little agreement on how the 2,3-cis- 2-oxoglutarate7 oxygen Fe2+ and ascorbate as cofactors. (2s)- compounds are derived in Nature. The recent isolation of the Naringenin (102) is converted by the enzyme into (2R,3R)-2,3- first natural 2,3-cis-dihydroflavonol (I 14) from Acacia melano- dihydrokaempferol (104) but (2R)-naringenin is not an xylong7 reinforces the suggestion that this stereochemical acceptable substrate.Similarly (2S)-eriodictyol (1 03) was transformed into (2R,3R)-2,3-dihydroquercetin(lOS) though the (2S)-3’,4’,5’-trioxygenated flavanone 2,3-dihydromyricetin (106) was not metabolized. In addition if 5,7-dihydroxy-flavanone (pinocembrin) or if either of the related flavanones naringin or prunin (which are naringenin 7-0-glycosides) was added to the standard enzyme incubation it had no effect on the conversion of naringenin into 2,3-dihydrokaempferol. Thus the enzyme appears to have high stereospecificity and a rather narrow substrate specificity. Independent studies with the same plant have demonstrated the same cofactor requirements and substrate specifi~ity.~~ In addition there was substantial correlation between the activity of this enzyme in a series of genetic lines of P.hybrida and the flavonol content in their buds feature may be introduced at the dihydroflavonol stage.Perhaps 3-hydroxylation of flavanones may occur giving either configuration at this centre. However since all flavanone 3-hydroxylase enzymes that have so far been investigated yield 2,3-trans stereochemistry in the products an alternative sequence (with the involvement of a C-3 epimerase and conversion of 2,3-trans-compounds into 2,3-cis-compounds) must also be considered. Although leaves of Ginkgo biloba and Ribes sanguineum contain major amounts of catechins and dimers in which there is 2,3-cis stereochemistry cell cultures that had been derived from the leaves tended to synthesize 2,3- trans-isomers instead.98 Several other variations in patterns of proanthocyanidins catechins and their flavonoid precursors between leaf and cultures were noted.. and flowers. Hydroxylation at C-3’ of the aromatic ring occurs at the flavonoid level but is not restricted to any particular oxidation 5.5 Anthocyanidins state of the flavonoid skeleton. Thus a microsomal broad- spectrum flavonoid 3’-mono-oxygenase from seedlings of maize (Zea mays) has been observed to 3’-hydroxylate the Anthocyanidins represent a further group of flavonoids that are derived from dihydroflavonols via flavan-3,4-diols. The violet colour of flowers of Hedysarum carnosum is attributable flavanone naringenin (1 02) the flavonol kaempferol (1 07) and to the presence of the anthocyanidin malvidin (1 1S) whereas NATURAL PRODUCT REPORTS 1988 OMe 0 0 (116) (1171 Gossypetin(ll8) R = H Corniculatusin(ll9) R = Me 0 = H Hesperetin (122) Isovitexin (123) 8-Hydroxykaernpfer'ol (120) R Sexangularetin (121) R = Me R2 HO Pelargonidin (124) R' = R2 = H Cyanidin (125) R'=OH R2=H Delphinidin (126) R' = R2= OH white or violet-spotted mutants are deficient in this com-pound containing colourless flavonols instead.These derive by dehydrogenation of the dihydroflavonol intermediates. The accumulation of flavonoid derivatives in mutants of H. carnosum has been shown to be controlled by genes relating to one or other of the two processes that are involved in the biosynthesis of anthocyanidins i.e. the conversion of dihydroflavonols into flavan-3,4-diols and then of flavan- 3,4-diols into an tho cyan id in^.^^ 5.6 Methylation and Glycosylation of Flavonoids A flavonol 0-methyltransferase from flowers of Chrysosplenium americanum has been demonstrated to methylate the 2'-or the 5'-hydroxyl group of the flavonol glucosides (1 16) and (1 17) respectively.loO Compounds (I 16) and (1 17) and their sub- sequently formed methyl ethers represent four of the major partially methylated flavonol glucosides that have been found in this plant.The development of a yellow colour in flowers of Lotus corniculatus can be correlated with the formation of 8-substituted flavonols particularly gossypetin (8-hydroxy- quercetin) (118) and corniculatusin (8-methoxyquercetin) (1 19) together with smaller amounts of sexangularetin (8-meth- oxykaempferol) (121).lol The accumulation of these pigments involves an 0-methyltransferase activity that uses 8-hydroxy- Isorhamnetin (127) quercetin and 8-hydroxykaempferol (1 20) respectively as its substrates. The albedo of grapefruit (Citrus paradisi) is characterized by the presence of the very bitter-tasting flavanone glycoside naringin (naringenin 7-0-neohesperidoside). Grapefruit cells in suspension culture do not accumulate flavanone glycosides but are able to specifically 0-glucosylate naringenin (1 02) and hesperetin (122) giving the 7-0-glucosides prunin and hes- peretin 7-0-glucoside respectively."' These products have not previously been reported in grapefruit but may well serve as precursors for the biosynthesis of flavanone rhamnoglucosides in the intact tissue.Further glycosylation of the flavone C-glucoside isovitexin (6-C-glucosylapigenin) (123) in the various parts of white campion (Silene pratensis) has been studied in relation to the enzymes controlling the processes and to the genetic factors that control the production of enzyrnes.lo3 Genes controlling glucosylation of the 7-hydroxyl group were expressed in all parts of the plant but those controlling 7-0-xylosylation were expressed only in the petals. In vegetative parts 7-0-xylosylation appeared to be replaced by 7-O-galactosylation but the two reactions do not originate from the same gene. Two different enzymes that catalyse the biosynthesis of isovitexin 7- 0-galactoside were identified.Enzymes catalysing 7-0-glu- cosylation also show variation in substrate specificity and NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK (25)-Naringenin (102) R OH (2s)-Liquiritigenin (128) R H Genistein (131) R =OH (130) (129) Oaidzein (132) R =H Scheme 25 genetic aspects have been investigated.lo4 One 7-O-glu-cosyltransferase transfers glucose to isovitexin but not to isovitexin 2”-O-rhamnoside ;the other glucosylates isovitexin 2”-O-rhamnoside but not isovitexin. Glucosylation of anthocyanidin derivatives at position 3 or 5 has been demonstrated by using enzyme extracts from flowers of stock (Matthiola incana). The enzyme that catalyses the transfer of glucose from uridinediphosphoglucose to the 3- hydroxyl group of pelargonidin (124) was also able to catalyse a similar reaction with the flavonol quercetin (108).’05 Acyanic or pale mutants that lack anthocyanin pigments were blocked in the pathway after dihydroflavonol intermediates but also had drastically reduced glucosyltransferase activity.Cell cul- tures of carrot (Daucus carota) contain an enzyme with similar properties.1o6 Although the cultures contain cyanidin (125) as the only flavonoid aglycon the enzyme glucosylated the anthocyanidins perlargonidin (1 24) cyanidin (1 25) and del- phinidin (1 26) and the flavonols kaempferol(lO7) and quercetin (108) at position 3. The flavanones naringenin and eriodictyol and the dihydroflavonol dihydrokampferol were not glu-cosylated. For this enzyme evidence was presented for the requirement for the presence of some heat-stable organic cofactor that is separable by ultrafiltration.A Matthiola- incana-derived UDPglucose :anthocyanin 05-glucosyltransfer- ase was able to glucosylate perlargonidin and cyanidin 3-O- glycosides and their acylated derivatives. lo’ The best substrates were 3-xylosylglucosides that were acylated with p-coumarate followed by 3-xylosylglucosides and then the 3-glucosides that were acylated with p-coumarate. The 3-glucosides themselves were very poor substrates. Levels of enzyme activity correlated exactly with the formation of 5-glucosylated anthocyanins during the development of a bud. Similarly a xylosyltransferase that catalyses the transfer of xylose from UDPxylose to the glucose of cyanidin 3-glucoside has been isolated from flowers of M.incana.’08 The 3-glucosides of pelargonidin and del- phinidin together with cyanidin 3-(p-coumaroyl)-glucoside and cyanidin 3-(caffeoy1)-glucoside also acted as substrates for the enzyme. Again the accumulation of 3-glucoside derivatives that occurred during the development of a flower could be correlated with this enzyme activity. 5.7 Sulphation of Flavonoids The composite Flaveria bidentis contains a range of flavonol 3-O-glucosides together with a number of flavonol sulphate esters based on quercetin (108) and isorhamnetin (127).lo9 The sulphate esters include 3-sulphates 3,7-disulphates 3,3’,7- trisulphates and 3,3’,4’,7-tetrasulphates.Labelled cinnamic acid was predominantly incorporated into the flavonol glu- cosides suggesting that the sulphation step is likely to be a late stage in the biosynthesis of the sulphate esters.Sulphate that was labelled with 35Swas well incorporated into these esters. 5.8 Isoflavonoids During the biosynthesis of isoflavonoids from flavonoid C,C,C precursors the shikimate-derived aromatic ring migrates to the adjacent carbon of the C unit. An isoflavone synthase activity that is capable of effecting this crucial step was recently detected in a microsomal preparation from cell suspension cultures of soybean (Glycine max) that had been challenged with an elicitor from Phytophthora megasperma f.sp. glycinea. It was shown to convert the flavanone substrates (2q-naringenin (102) or (2S)-liquiritigenin (1 28) into the isoflavones genistein (13 1) or daidzein (132) respectively.The enzyme is a mono-oxygenase requiring NADPH and molecular oxygen as cofactors and a hypothetical pathway via epoxi-dation of the enol form of the flavanone was proposed (Scheme 25). This mechanism has been criticizedl10 and a more favourable one in which the migrating aryl ring is epoxidized rather than the heterocyclic ring has been suggested. A spiro-dienone intermediate analogous to (129) is included however NATURAL PRODUCT REPORTS 1988 (2Sl-Nari ngenin or (2s)-Liquir it igeni n 0 0 0 Genist ein HO or f-Doid zei n Scheme 26 (Scheme 26). Further study of the isoflavone synthase pre- paration has resulted in the isolation of an intermediate believed to be 2,4’,5,7-tetrahydroxyisoflavanone(133) in the transformation of (2q-naringenin (102) into genistein (131).ll1 HO The conversion of (102) into (133) requires NADPH oxygen OH and cytochrome P-450 but the formation of genistein from this intermediate which is formally a dehydration requires none of (133) (134) these cofactors.The 2-hydroxyisoflavanone (1 33) has been suggested to be derived from the carbo-cation (130). A 2’- hydroxylating system could also be demonstrated to be present in the microsomal preparation via the isolation of small amounts of 2’-hydroxygenistein (134). The incorporation of [13C,]acetate into the rotenoid amor- CH,-CO,H phigenin (135) by seedlings of Amorpha fruticosa has been ++ OwAr demonstrated to be analogous to its incorporation into other isoflavonoids which have resorcinol oxygenation patterns in 00 the acetate-derived ring.110 Although only low levels of enrichment were attained the labelling pattern (Scheme 27) was established by using the INADEQUATE pulse sequence to obtain a 13C n.m.r.spectrum. This labelling pattern confirms that the ‘missing’ oxygen function is removed before the polyketide portion cyclizes. The rotenoid skeleton is derived from 2’-methoxyisoflavones ; J the majority of natural examples contain an additional prenyl substituent that is added after this basic skeleton has been formed. Typically the prenyl substituent cyclizes to form an isopropyldihydrofuran ring (as in amorphigenin) or a di-methylchromene system [as in deguelin (1 38)] though these structures are by no means restricted to rotenoids but occur in many classes of natural phenolic compounds.A widely held view is that these rings arise via epoxidation and ring-closure OMe followed by dehydration (Scheme 28 path a) but an alternative sequence (via an ortho-quinone methide and cyclization) is also OMe chemically feasible for the formation of chromenes (Scheme 28 path b).Labelled (6aS 12aS)-rot-2-enonic acid (136) has been Amor p higenin (1351 demonstrated to be well incorporated into deguelin (138) in seedlings of Tephrosia vogelii,’12 but the (6aS 5’RS 12aS)-Scheme 27 alcohol (137) was not significantly utilized as a precursor. A NATURAL PRODUCT REPORTS 1988 -P.M. DEWICK 93 4' 5' v (137) HO OMe Rot-Z'-enonic acid (136) \ b\ OMe (139) Deguelin (138) Scheme 28 (+)-Maackiain (140) (1411 (+) -Pisatin (142) Scheme 29 crude enzyme preparation from the seedlings and a purified deguelin cyclase enzyme from seeds of T. vogelii efficiently converted (136) into deguelin requiring 0 as cofactor. No stable intermediates could be detected and (1 37) was similarly not converted by the enzyme. These results appear to rule out the epoxide sequence but leave the ortho-quinone methide (139) as a plausible intermediate. An interesting observation from the studies was the relatively high efficiency of seedlings of T. vogelii for carrying out the later stages of biosynthesis of deguelin contrasting with the rather poor incorporation of phenylalanine.This observation indicates that the biosynthesis of rotenoids de novo is very slow. After (6aS 12aS)-rot-2'-enonic acid (136) that was labelled with 13C at C-4' was incubated with the enzyme preparation from seeds of T. vogelii 13C-labelled deguelin was isolated and analysed by 13C n.m.r. ~pectro~copy."~ The label was located in both methyl groups of the dimethylchromene though prefer- entially (73%) at C-8' [i.e. in the (pro-R) position]. Thus the enzymic cyclization with respect to the prochiral methyl groups is stereoselective but not stereospecific. No stereo-chemical bias occurred if the same change was achieved by using a chemical conversion so these effects are enzyme-mediated.Whatever the precise nature of the electrocyclization of (139) to deguelin an anticlockwise rotation is apparently favoured relative to a clockwise one (Scheme 28). Experiments in which precursors were fed to the pea (Pisum sativum) had established that the later stages in the biosynthesis of the pterocarpan phytoalexin (+)-pisatin (142) were 6a-hydroxylation of (+)-maackiain (140) followed by methylation of the phenolic group (Scheme 29). This sequence has been con- firmed by studies in which it was found that extracts from pea seedlings were able to methylate (+)-6a-hydroxymaackiain (141) to (+)-pisatin using S-adenosylmethionine as the methyl donor.l14 Although some enzyme activity was present in healthy seedling tissue infection with a microbe or treatment with CuCl (each of which can elicit the synthesis of pisatin) resulted in a much greater activity.The extract showed no methyltransferase activity towards either (-)-maackiain or (-)-6a-hydroxymaackiain though slow methylation of (+)-maackiain (140) was detectable. This suggests that the ability of CuC1,-treated pea tissue to transform (-)-maackiain and (-)-6a-hydroxymaackian into (-)-pisatin as reported in other studies is dependent on a new enzymic pathway that is induced by these precursors and is not present in seedlings that have been treated with CuCl alone. Enzymes that are involved in the biosynthesis of glyceollins [which are phytoalexins of soybean (Glycine max)] were shown to be induced rapidly after the plants had been infected with Phytophthora megasperma f.sp.glycinea only if an incompatible race of fungus was used that did not lead to successful colonization of the ~1ant.l'~ The activities of PAL chalcone synthase isoflavone synthase and dihydroxypterocarpan 6a-hydroxylase all increased markedly after the plant had been infected with an incompatible race of the fungus but they were not particularly different after it had been infected with a compatible race to which the host plant was susceptible. C.H ,OR (143)R = C(O)CH,CO,H (144) R = H c'pp (0 OH k H+ TPP -I Isochorismate (147) R (146) 4 J. 4 q 0 OSB (148) (R = CH,CH,CO,H) (TPP = thiamin diphosphate) Scheme 30 A specific isoflavone 7-0-glucoside-6"-malonatemalonyl-esterase activity has been detected and purified from roots of chickpea (Cicer arietinurn).ll6 This enzyme hydrolysed sub- strates such as biochanin A 7-0-glucoside 6"-malonate (143) to the isoflavone 7-0-glucoside (144) but it had extremely low activity with a range of synthetic esterase substrates and was also insensitive to typical inhibitors of esterases.The mal- onyltransferase thus appeared to differ greatly from other known esterases and it may have a biological function in C. arietinum of releasing isoflavone materials from malonate hemiesters of isoflavone 7-0-glucosides that have accumulated in this plant so that they may be available for the biosynthesis of pterocarpan phytoalexins. The biosynthesis elicitation and biological activities of isoflavonoid phytoalexins have recently been reviewed."' NATURAL PRODUCT REPORTS 1988 6 Quinones Many natural naphthoquinones and anthraquinones including menaquinone (vitamin Kz) are biosynthesized via the shiki- mate-derived intermediate o-succinylbenzoic acid (OSB) (148).This compound arises from isochorismate (147) 2- oxoglutarate (145) and thiamin diphosphate (TPP) pre-sumably via the succinic semialdehyde-TPP anion (146) that is derived by decarboxylation of 2-oxoglutarate (Scheme 30). Evidence has been presented1lS that this decarboxylation is not a function of the oxoglutarate dehydrogenase complex [E.C. 1.2.4.21but is carried out by a separate activity. Thus cell-free extracts from Escherichia coli without added TPP lose o-succinylbenzoate synthase activity but retain all of the activities of the oxoglutarate dehydrogenase complex.Secondly o-succinylbenzoate synthase activity is inhibited by the addition of tetrahydrothiamin diphosphate but the activities of the oxoglutarate dehydrogenase complex are only slowly affected. In confirmation it has now proved to be possible to separate the two enzyme activities by chromatography. The naphthoquinone shikonin (1 52) is an example of another group of natural shikimate-derived quinones which originate via 4-hydroxybenzoic acid (149). The postulated biosynthetic pathway (Scheme 31) to shikonin and related materials is supported by the isolation of intermediates from shikonin- producing cell cultures of Lithospermum erythrorhi~on."~ Thus 3-geranyl-4-hydroxybenzoicacid (150) and geranylhydro-quinone (151) have been isolated for the first time.In non- shikonin-producing cultures the only intermediate that was detected was (150) suggesting that the important decarb- oxylation/ hydroxylation step is repressed in these cultures. Cultures that are capable of synthesizing shikonin but which are being grown in a medium that is not conducive to the production of this quinone were found to accumulate the glucoside of 4-hydroxybenzoic acid (1 53).lZo The concentration of this metabolite decreased rapidly when the cells were transferred to a production medium which stimulated the synthesis of shikonin. This suggested that the precursor 4- hydroxybenzoic acid was being stored in the form of the glucoside when the cells were not synthesizing shikonin and could be released when it was required for metabolism.Two reviews on the biosynthesis of quinones have been published.lZ1.lZ2 7 Miscellaneous Shikimate Metabolites 7.1 Cyclohexyl Fatty Acids A major component of the cellular fatty acids of Curtobacterium pusillum is 1 1-cyclohexylundecanoic acid (1 55). Trace amounts of 13-cyclohexyltridecanoicacid (1 56) together with other non- cyclohexyl fatty acids are also found. These acids are formed by fatty-acid synthase activity and involve extension of the chain of the appropriate starter units by malonate units. A variety of CoA esters of starter acids were accepted when acyl-carrier protein (ACP) and NADPH were added to a crude enzyme preparati~n,"~ though surprisingly acetyl-CoA itself was not satisfactory.Since acetyl-ACP could function as a starter the specificity of the system results from the initial acyl-CoA :[acyl-carrier-protein] S-acyltransferase activity rather than from subsequent chain-elongation reactions. The cyclohexane-con- taining fatty acids arise from cyclohexanecarbonyl-CoA (154) as the starter unit which in turn is formed from shikimic acid (Scheme 32) as demonstrated by feeding experiments in which labelled shikimic acid was used. This necessitates the reduction of the functional groups of shikimic acid and stereochemical aspects of the reduction of the double-bond have been investigated in further experiments.lZ4Labelled 11 -cyclohexyl- undecanoic acid (157) (from the feeding of ~-[6,6-'H,]-glucose to C. pusillum) was partially degraded (by using a combination of microbiological and chemical means) to give (9-cyclohexylphenylcarbinol,which was analysed by 'H n.m.r. spectroscopy. Most of the deuterium enrichment was located at NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK CO,H CO,H CO,H I 1 I geranyl d 1 phosphate OGlc OH (150) maIonyl -CoA C (0)-SCOA ++-.) ICH,I,&O,H [CH 1,,CO2H Ho-P-co2H HO -(154) (155) (156) Scheme 32 I HO' 0 OH (a) glycolysis; (b) pentose phosphate pathway Scheme 33 the axial proton on C-2 of the cyclohexyl moiety with smaller amounts at both 6-H, and 6-H, (157). Labelling at other positions was insignificant.This labelling pattern established that the reduction of the double-bond of shikimic acid had been stereospecific and involved syn addition of hydrogen at the re faces of C-1 and C-2 (Scheme 33). 7.2 Sporopollenin Sporopollenin is the general name for a group of C, polymers that are thought to be derived by oxidation of carotenoids and which are found as components in the walls of pollen and spores. Phenolic acids e.g. rn-hydroxybenzoic acid p-hydroxy- benzoic acid and protocatechuic acid result from the alkaline fusion of such materials. In recent it was shown that inhibitors of carotenoid formation had minimal effects on the biosynthesis of sporopollenin in the anthers of Cucurbita pepo. In the anthers of species of Tulipa tracer studies showed that phenylalanine was well incorporated whilst mevalonic acid was a poor precursor.Glucose malonic acid and p-coumaric acid were also utilized. These findings question the role of carotenoids as precursors but suggest that metabolism of phenolics may be an essential part of the biosynthetic sequence. @+OH 0 OHqOH S hikonin (152) (151) Scheme 31 8 References 1 P. M. Dewick Nut. Prod. Rep. 1986 3 565. 2 ‘The Shikimic Acid Pathway’ ed. E. E. Conn (Recent Advances in Phytochemistry Vol. 20) Plenum New York and London 1986. 3 H. G. Floss in ref. 2 p. 13. 4 S. Ahmad B. Rightmire and R. A. Jensen J. Bacteriol. 1986 165 146. 5 K. Shetty D. L. Crawford and A. L. Pometto Appl. Environ.Microbiol. 1986 52 637. 6 I. N. Olekhnovich N. P. Maksimova and Yu. K. Fomichev Mol. Genet. Mikrobiol. Virusol. 1986 No. 12 p. 34 (Chem. Abstr. 1987 106 64 168). 7 R. J. Ganson T. A. D’Amato and R. A. Jensen Plant Physiol. 1986 82 203. 8 J. E. B. P. Pinto J. A. Suzich and K. M. Herrmann Plant Physiol. 1986 82 1040. 9 G. Millar and J. R. Coggins FEBS Lett. 1986 200 11. 10 P. Le Marechal C. Froussios and R. Azerad Biochemie 1986 68 1211. 11 K. Duncan S. 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Mitsui Plant Cell Physiol.1986 27 677. 65 B. Laber H.-H. Kiltz and N. Amrhein Z. Naturforsch. Sect. C 1986 41 49. 66 I. A. Dubery and J. C. Schabort Biochem. hi. 1986 13 579. 67 J. M. Boniwell and V. S. Butt 2.Naturforsch. Sect. C 1986 41 56. 68 R. J. A. Villegas and M. Kojima J. Biol. Chem. 1986 261 8729. 69 B. Dahlbender and D. Strack Phytochemistry 1986 25 1043. 70 W. Grawe and D. Strack 2.Naturforsch. Sect. C,1986 41 28. 71 D. Strack R. Ruhoff and W. Grawe Phytochemistry 1986 25 833. 72 C. Andary and R. K. Ibrahim 2.Naturforsch. Sect. C 1986,41 18. 73 C. C. S. Chapple M. A. Walker and B. E. Ellis Planta 1986 167 101. 74 Y. Koezuka G. Honda and M. Tabata Phytochemistry 1986 25 2085. 75 F. C. Bradley S. Lindstedt J. D. Lipscomb L. Que A. L. Rowe and M.Grundgren J. Biol. Chem. 1986 261 11 693. 76 J. W. Reed and D. G. 1. Kingston J. Nut. Prod. 1986 49 626. 77 P. Proksch J. Palmer and T. Hartmann Planta 1986 169 130. 78 S. A. Brown Z. Naturforsch. Sect. C 1986 41 247. 79 B. Tal and D. J. Robeson Plant Physiol. 1986 82 167. 80 0.Hofer G. Szabo and H. Greger Monatsh. Chem. 1986 117 1219. 81 H. Wendorff and U. Matern Eur. J. Biochem. 1986 161 391. 82 K. D. Hauffe K. Hahlbrock and D. Scheel Z. Naturforsch. Sect. C 1986 41 228. 83 S. A. Brown in ref. 2 p. 287. 84 B. Moerschbacher B. Heck K. H. Kogel 0.Obst and H. J. Reisener 2. Naturforsch. Sect. C 1986 41 839. 85 E. Morelli R. N. Rej N. G. Lewis G. Just and G. H. N. Towers Phytochemistry 1986 25 1701. 86 W. M. Kamil and P. M. Dewick Phytochemistry 1986 25 2089.87 W. M. Kamil and P. M. Dewick Phytochemistry 1986 25 2093. 88 A. Pelter in ref. 2 p. 201. 89 W. Heller in ‘Plant Flavonoids in Biology and Medicine Biochemical Pharmacological and Structure-Activity Relation- ships’ ed. E. Middleton and J. B. Harborne (Progress in Clinical and Biological Research Vol. 213) Alan R. Liss New York 1986 p. 25. NATURAL PRODUCT REPORTS 1988 -P. M. DEWICK 90 W. Knogge E. Schmelzer and G. Weissenbock Arch. Biochem. 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ISSN:0265-0568    

DOI:10.1039/NP9880500073

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Errata In issue 6 of volume 2 (1985) some of the formulae in the article by D. M. Harrison were incomplete. Structure (121) on page 541 should have been (121) a;R'= RZ= ti ~3= OH b;R'=H,R2=R3=OH C;R'=Rs=OH,Rz=H d;R'= R3= H,R2= OH On page 542 the diagrams in Scheme 14 should have been (122b) (122a)

ISSN:0265-0568    

DOI:10.1039/NP9880500099

出版商:RSC    

年代:1988

数据来源: RSC