Recent Progress in the Chemistry of lndole Alkaloids and Mould Metabolites J. E. Saxton Department of Organic Chemistry The University of Leeds Leeds LS2 9JJ ~ ~~ ~ ~ ~~ Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of literature in Natural Products Reports 1984 Vol. 1 p. 2 1) 1 General 2 Simple Alkaloids 2.1 Non-t rypt amines 2.2 Non-isoprenoid Tryptamines 3 Isoprenoid Tryptamine and Tryptophan Derivatives 3.1 Ergot Alkaloids 4 Monoterpenoid A1 kaloids 4.1 Aristotelia Alkaloids 4.2 Corynantheine-Heteroyohimbine-YohimbineGroup and Related Oxindoles 4.3 Sarpagine-Ajmaline-Picraline Group 4.4 Strychnine Group 4.5 Ellipticine-Uleine-Apparicine Group 4.6 Aspidospermine-Vincamine Group 4.7 Catharanthine-Ibogamine Group 5 Bisindole Alkaloids 6 Biogenetically Related Quinoline Alkaloids 6.1 Cinchona Group 6.2 Camptothecin 7 References 1 General During the past twelve months a monograph on the monoterpenoid indole alkaloids'" and two further volumes in the series that was founded by Manske (now edited by A.Brossi) have been published.Ib Volume 21 in the Manske- Brossi series includes chapters on the evodiamine-rutaecarpine group and camptothecin and Volume 22contains references to indole alkaloids in chapters on (a)Ipecac alkaloids and their p-carboline congeners (b) the elucidation of alkaloid structures by X-ray diffraction and (c) the application of enamide cyclizations in alkaloid synthesis.Of general interest is a compilation of 13C n.m.r. spectral data for indole alkaloids in which substituent-induced chemi- cal shifts have been calculated for various types of ar-hydroxy- and methoxy-substituted indole alkaloids.* Me2NCONH2 + ClCOSCl -2 Simple Alkaloids 2.1 Non-tryptamines Evidence for the presence of 3-indolylmethylglucosinolateand its 1-methoxy-derivative in the roots of the horseradish (Armoracia rusticana P. Gartner B. Meyer et Scherb.) has been ~btained.~ An improved preparation of 1-methoxyindoleacetonitrile which has been isolated from Brassicu pekinensis Rupr. that is infected by Plasmodiophora brassicue Woronin has been reported. Dendrodoine (l) a metabolite of the marine tunicate Dendrodoa grossularia has been very simply synthesized by 1,3-dipolar cycloaddition of indole-3-carbonyl cyanide and NN-dimethylaminoformonitrileN-sulphide itself prepared by thermolysis of 5-(NN-dimethylamino)-1,3,4-oxathiazol-2-one (2)(Scheme l).5 7-Methoxygramine and 5,7-dimethoxygramine have been isolated from the roots of twelve-day-old seedlings of the pasture grass Phalaris aquatica L.;evidence for the presence of 5-methoxygramine was also obtained.'j None of these gramine derivatives has previously been found in Nature. New carbazole alkaloids continue to be found in species of the genus Murraya. Mukonicine isolated from the leaves of M. koenigii is a pyranocarbazole of structure (3),' and is therefore an isomer of koenigicine. The stem bark of the same plant has yielded mukonal (4);this is simply 3-formyl-2-hydroxycarba-zole a probable biogenetic precursor of the pyranocarbazoles found in the plant.* Mukoline and mukolidine which occurs in the roots are 6-hydroxymethyl-1 -methoxycarbazole (5) and 6-formyl-1-methoxycarbazole(6) respectively ;9 both structures were confirmed by synthesis.Murrayaquinone-B a new alkaloid from the root bark of Taiwanese M. euchrestijiolia Hayata has the structure (7) and is the first carbazole quinone to be isolated from natural sources.1o Another new carbazole derivative in which 0-methylation has blocked pyran ring- closure is clausenapin (8) a constituent of the leaves of Clausena heptaphylla.' The micro-organism that elaborates carbazomycins A and B,' 2o provisionally designated as strain H 1051-MY10 has now been identified as Streptoverticillium ehimense.OY-0 ?NANMe2 (2) Dendrodoine (1) Reagents i DMF at 145-150°C for a few minutes %heme I 50 NATURAL PRODUCT REPORTS 1985 H Mukonal (4) Mukonicine (3) 0 Mukoline (5) R=CH20H Mukolidine (6) RXHO Murrayaquinone-B (7) In a notable series of papers Steyn and his collaborators have given details of the structure eludication of the tremor- genic mycotoxins penitrems A-F;14 a correction to the relative stereochemistry of penitrems A B E and F compared with that reported initially,12b is now made and the absolute configuration of the penitrems has been determined. On the basis of nuclear Overhauser effects (n.0.e.) between the proton at C-24 and those at C-39 and between the proton at C-24 and H at C-21 rings H and I must be cis-fused and the complete relative configuration of penitrem A is as shown in (9).The absolute configuration again as expressed in structure (9) was determined by application of Horeau's partial resolution method involving esterification of the hydroxy-group at C-25 by means of (f)-a-phenylbutyric anhydride. Penitrems B (lo) E (13) and F (14) similarly have an a-epoxide function. The absolute configuration of penitrem D (12) was also determined by Horeau's method and the absolute configuration of the other penitrems (B C E and F) by detailed comparison of the n.m.r. spectra with those of penitrems A and D.14 The mass spectrum of penitrem A is discussed briefly in the first of these papers,14 but has been discussed in greater detail together with the mass spectra of penitrems B-E by other workers.15 The janthitrems are a related series of tremorgenic mycotox- ins that have been isolated from Penicillium janthinellum a micro-organism which with several other Penicilliumspecies is associated with ryegrass staggers [a neuromuscular disease which affects livestock that graze on pastures in which perennial ryegrass (Lolium perenne) is predominant].In another impressive and detailed n.m.r. study,16 the structures and relative stereochemistry of janthitrems E F and G [(15)-( 17)] were deduced with the exception of the configurations at C-22 and C-23. The absolute stereochemistry implied in structures (15)-( 17) has not yet been established.The penitrems and janthitrems show an obvious biosynthetic relationship the major difference between the two series being the structure of the monoterpenoid unit and its mode of attachment to the benzene ring. Lolitrems A B C and D form another series of tremorgens which have been isolated from toxic perennial ryegrass and which are also suspected of being responsible for ryegrass staggers in livestock. In lolitrem B (18) the monoterpenoid unit has yet another structure and mode of attachment to the benzene ring and the degraded diterpene component has been extended by the incorporation of an additional mevalonate unit with formation of the tenth ring (ring 1).17 Lolitrem C (a minor metabolite) appears to be the 40,41-dihydro-derivative of lolitrem B.The exact origin of the lolitrems has yet to be established but it is relevant to note that an endophytic fungus of the genus Acremonium which infects ryegrass has recently been shown to be associated with the production of the neurotoxins that cause ryegrass staggers. 2.2 Non-isoprenoid Tryptamines Bufotenine has been shown to be a constituent of the stem bark of Umbellulariu culifornica Nutt. the leaves of which provide OyJ OMe Clausenapin (8) Penitrem A (9) Ri=C1 RZ=OH Penitrem B (10) R1=R2=H Penitrem E (13) R1=H RZ=OH Penitrem F (14) R1=Cl R2=H Penitrem C (1 1) R=Cl Penitrem D (12) R=H Janthitrem E (15) R'=H R2=OH Janthitrem F (16) R1=Ac RZ=OH Janthitrem G (17) R1=Ac Rz=H U Lolitrem B (18) some of the components of laurel bay oi1.18 Whereas aporphine alkaloids are normally encountered in the family Lauraceae this is the first report of the presence of bufotenine.The 0-methyl ether of bufotenine has been shown to be the major base in the dart poison used by the YanoSma Indians of Brazil; this appears to confirm earlier reports that the poison is concocted from extracts of species of the genus vir~la.~~= The aerial parts of Melicope leptococca (Baill.) Guillaumin (a shrub endemic to New Caledonia) contain alkaloids belonging to the furoquinoline acridine and indole groups. The four indole bases isolated were shown to be 5-methoxy-NN-dimethyltryptamine and its N,-oxide 6-methoxy-2-methyl- tetrahydro-P-carboline and a hitherto unknown alkaloid 3- dimethylaminoacetyl-5-methoxyindole(19a) whose structure NATURAL PRODUCT REPORTS 1985 -J.E. SAXTON MeooT?!!JMe2 H was confirmed by its reduction to 5-methoxy-NN-dimethyltryp-tamine and by synthesis. 9b An efficient five-stage synthesis of lespedamine (19b) from methyl 2-nitrophenylacetate has some unusual features but proceeds in 24% overall yield (Scheme 2).20 The I3C n.m.r. spectrum of physostigmine has been re- analysed with the aid of the high-resolution proton-coupled spectrum and selective proton-irradiation experiments.2 Norharman is the simplest of the eighteen alkaloids isolated from the leaves of Rauwolja caflra;22a this is claimed to be the first report of its occurrence in a member of this genus.Two of the three anhydronium bases extracted from the root bark of Strychnos usambarensisproved to be melinonine F (20a) and normelinonine F (20b); of these the latter has not previously been isolated from natural sources. 22b Melinonine F has been shown to exhibit cytotoxic activity at relatively high concentrations in normal cancer cells.22c 4,8-Dimethoxy- 1 -(2-met hoxyet hyl)-&car boline (~OC) 3- methylcanthine-2,6-dione(20d) 4,9-dimethoxy-l-vinyl-P-car-boline (20e) and two bis-P-carboline bases (4.v.) are new alkaloids that have been found in the wood of Picrasma quassioides Bennet together with the known bases 1-acetyl-P- carboline 1-e t hyl-4,8-dime thoxy-fl-carboline 1-e thyl-4-me th- oxy-P-carboline 4-methoxy-l-vinyl-~-carboline, 4,8-dimeth-oxy-1-vinyl-P-carboline,canthin-6-one and 5-methoxycan-thin-6-0ne.~~& In other hands extracts of the root stem twigs and bark of the same plant have yielded 4,8-dimethoxy- 1-vinyl-l)-carboline together with 1-carbomethoxy-P-carboline 4,5-dimethoxycanthin-6-one(methylnigakinone) and 5-hydroxy-4-methoxycanthin-6-one (nigakin~ne).~~ A number of bioactive P-carboline derivatives including four with the previously unreported oxathiazepine ring system have been isolated from the Caribbean tunicate Eudistoma olivaceum which is reported to exhibit activity against Herpes simplex Eudistomins C E K and L which show the most potent antiviral activity have structures (21)-(24) and presumably originate from tryptophan and ~ysteine.~~~ The remaining eleven eudistomins are relatively simple P-carboline deriva- tives with structures (25)-(35) and include five bases (eudistomins G H I P,and Q) which contain the previously unreported 1-(2-pyrrolinyl)-P-carboline ring system.In these metabolites C-1 and the pyrrole (or pyrroline) ring are assumed to be derived from glutamic acid. The structures of eudistomins D and N were confirmed by synthesis.25b Three new P-carboline derivatives have been isolated from the fruit bodies of the gilled agaric Cortinarius infractus (Pers. ex Fr.) Fr.26 Infractine (36) is l-(2-methoxycarbonylethyl)-~-carboline and the second alkaloid is its 6-hydroxy-derivative (37). The third alkaloid infractopicrine is quaternary and was isolated as its chloride (38); it is reported to be responsible for the bitter taste of this toadstool.Four new P-carboline derivatives have also been found together with 1-methoxycanthin-6-one and two monoterpenoid indole alkaloids in the roots of Hannoa klaineana Pierre et Engl. (a tree endemic to tropical Africa). Decoctions from the roots of this plant are used locally against fever and intestinal disorders. The new bases are ethyl P-carboline-1-propionate(39) [cf infractine (36)] and its N,-oxide and 1-ethyl-0-carboline and its N,-~xide.~' It remains to be proved unequivocally that these ethyl esters are present in the plant and are not artifacts derived from the corresponding acid during the extraction and isolation procedure.Indeed this acid has recently been bH OMe OMe bMe Lespedamine (19b) Reagents i Zn NH,Cl MeOH; ii CH2N2; iii BrCH2CH2Br NaH; iv Me2NH Me,NH.HCl H20 DMF; v LiAlH4; vi HCl H20 Scheme 2 (20a) R=Me (20b) R=H OMe D1 R1 R2 R3 Eudistomin C (21) H OH Br Eudistomin E (22) Br OH H Eudistomin K (23) H H Br Eudistomin L (24) H Br H R' R1 R2 R3 R4 Eudistomin A (25) H OH Br 2-pyrrolyl Eudistomin D (26) Br OH H H Eudistomin J (30) H OH Br H Eudistomin M (31) H OH H 2-pyrrolyi Eudistomin N (32) H Br H H Eudistomin 0 (33) H H Br H R1 R2 Dl D2 n~ Eudistomin G (27) H Br Infractine (36) H Me Eudistomin H (28) Br H 6-Hydroxyinfractine (37) OH Me EudistominI (29) Eudistomin P (34) OH Br (39) H Et Eudistomin Q (35) OH H NATURAL PRODUCT REPORTS 1985 c1-Y %' 0' Infractopicrine (38) (42) R' = H R2 = COCF3 (46) R' = Br R2 = C02Me isolated together with 1-carbamoyl9-carboline l-carbometh- oxy-fbcarboline and two new alkaloids in a re-investigation of the constituents of the root bark of Ailanthus altissimu Swingle.28 The new bases are l-(2-hydroxy-l-methoxyethyl)-4-(43) R1 = H R2 = COCF3 (47) R1= Br R2 = C02Me ii [on (43)] iv [on (47)) 1 (44) R = H (48) R = Br methoxy-p-carboline (40) and 5-hydroxymethylcanthin-6-one (41).Canthin-6-one and 1-methoxycanthin-6-one were ob-tained in an investigation into the production of cytotoxic canthin-6-one derivatives in callus and cell suspension cultures of A.alti~sima.~~ Bergman's synthesis of rutaecarpine' 2c has now been extended to the synthesis of evodiamine and 13b 14-dihydro- rutae~arpine,~~ but full details are not yet available. In connection with biosynthetic studies complete assign- ments of the I3C n.m.r. signals of eight naturally occurring chaetoglobosins have been made.31 3 lsoprenoid Tryptamine and Tryptophan Derivatives The occurrence of flustramine A and flustramine B in Flustru folipcea L. has again been noted and the alkaloid content of specimens from Danish and Swedish waters has been compared. * Syntheses of (+)-debromoflustramine B (45)33 and (+)-flustramine B (49)34 have recently been reported. The two syntheses followed broadly similar lines the crucial stage being bis-alkylation of suitably N,-protected tryptamine derivatives [(42)or (46)] at N,and position 3 with formation of the pyrrolo- indoles (43) or (47).Some difficulty was experienced in both syntheses with the removal of the Nb-protecting group to form (44) and (48) (Scheme 3). Since bromine could not be introduced directly into position 6 in tryptamine the starting material [6-bromo-Nb-methoxycarbonyltryptamine(46)] for the synthesis of flustramine was itself prepared by an indirect multi-stage route.34 Two syntheses of borrerine (50)have also been rep~rted.~~~~~ A Debromoflustramine B (45) R = H Flustramine B (49) R = Br Reagents i Me2C=CHCH2Br acetate buffer; ii NaBH,; iii CH20 NaBH3CN; iv 10% NaOH EtOH boil for 100 h; v MeI K2C03 MeCOMe Scheme 3 I __+ a-bMe N' Y Isoborrerine (51) 1ii 111 t Borrerine (50) vi Since the direct Pictet-Spengler synthesis from tryptamine and senecioic aldehyde failed the French group prepared borrerine by an indirect isomerization of isoborrerine (5l) previously synthesized3'0 (Scheme 4).A more direct synthesis was achieved by preparation of the borrerine precursor (52) by a modified Pictet-Spengler cyclization of the Schiff s base (53) by means of methyl chloroformate and pyridine (Scheme 4).36 The structure of meleagrin (54) a metabolite of Penicillium meleagrinum Biorge IF0 8143 obtained during the process of screening Penicillium species for antimicrobial metabolites has been determined by X-ray crystal structure analysis of its 9-0-p-bromobenzoate m~nohydrate.~~ Melea-grin thus appears to be the 9-0-demethyl derivative of oxaline (53 but although p-bromobenzoylation esterified the 9-hydroxy-group methylation gave only the 14-methyl derivative rather than oxaline.Four metabolites olivoretins A-D which exhibit pro-nounced vesicant activity have been isolated39 from the mycelia of Streptoverticillium olivoreticuli in addition to the derivatives of pimprinine recorded earlier.40u Olivoretin D (56) is identical with teleocidin B,40b and olivoretin A is its 0-Tryptamine Reagents i ButOCl;ii CF3C02H at 20 "C; iii NaBH, MeOH; iv Me2C=CHCH0 4A molecular sieves CH2C12; v ClCO,Me py CH2C12; vi LiAIH, THF Scheme 4 methyl ether (57).39 The structure and relative configuration of olivoretin D and its identity with teleocidin B were revealed by X-ray crystal structure analysis.The absolute configuration follows from comparisons of the c.d. spectrum of teleocidin B (56) with those of the model indole-lactam (58) and its NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON Me I Meleagrin (54) R Oxaline (55) R = H = Me Olivoretin D (56) R Olivoretin A (57) R (ZTeleocidin B) = H = Me (58) B-CHMe2 at C-14 (59) a-CHMe at (2-14 Agroclavine-I (60) &H i-iv - H 0 L Ts v-xd xi xii - H xiii-xv J 2Me xviii xvi xvii -L / II \ H Clavicipitic acid I (61) a-H Clavicipitic acid I1 (62) P-H Reagents i TsCI K,CO, MeCOEt; ii MeMgI; iii rn-chloroperbenzoic acid CH,CI,; iv NaN, dioxan H,O; v Me2C(OMe), TsOH; vi H, Pt; vii TsCI NEt, CICH2CH,Cl heat; viii BrCH2C02Me K,C03 DMF; ix KOH MeOH H20, DME; x CH,N2 MeOH Et,O; xi POCl, DMF Et20; xii DBU PhH heat; xiii 1% HC1 MeOH THF H,O; xiv S=CC12 DMAP CH2C12; xv P(OMe), heat; xvi NaBH, N, hu at -7O”C Na2C03 MeOH DME H20 xvii separation of diastereoisomeric racemates; xviii KOH MeOH H,O at r.t.Scheme 5 diastereoisomer (59).41 It should be noted that in previous communications the stereochemistry at C-16 and C-19 in teleocidin B was incorrectly ill~strated.~~ The correct relative and absolute configuration for this metabolite are as depicted in (56). 3.1 Ergot Alkaloids Fumigaclavine A has been shown43 to be the major alkaloid produced by a strain of Aspergillus tamarii Kita which was found as a contaminant of the seeds of Paspalum scrobiculatum L.This plant is cultivated in some parts of India and used as a staple food by the poor. However consumption of the grains is often associated with symptoms of mycotoxin poisoning characterized by nausea vomiting delirium and unconscious- ness. Fumigaclavine may well be responsible at least in part for this toxicity. A study44 of the appropriate coupling constants in the proton n.m.r. spectrum of agroclavine-I (60) a metabolite of Penicillium k~puscinskii,~~ has revealed that ring c must have an envelope conformation ;epoxyagroclavine-I is its P-epoxide. The first total synthesis of (+)-clavicipitic acid I (61) and clavicipitic acid I1 (62) follows a lengthy and largely unexcep- tional route (Scheme 5).46 However the product of reduction and detosylation of the unsaturated ester (63) gave a mixture of products from which the two diastereoisomeric esters (64)and (65) were separated.Saponification then gave (f)-clavicipitic acid I (61) and (+Aavicipitic acid I1 (62). The suffixes I and I1 are proposed to denote these diastereoisomers which have not previously been obtained pure (albeit racemic). Natural clavicipitic acid is a mixture of the optically active acids I and 11 ar.d a mixture of racemates was also the end-product of Kozikowski’s ~ynthesis.~5 A shorter synthesis of clavicipitic acid (stereochemistry unspecified) has been briefly reported but details are not yet a~ailable.~’ Details of Kozikowski’s synthesis4OC of (+)-paliclavine and (+)-paspaclavine have now been published.48 Also published in detail are Rebek’s synthese~~~~.~~ of setoclavine lysergine and lysergic acid,49 and Oppolzer’s syntheses’ 2d of chanocla- vine and iso~hanoclavine.~0 This last synthetic approach has been extended by making use of the previously synthesized’ 2d trans- and cis-aldehydes (66) and (67) to afford new syntheses of (+)-6,7-secoagroclavine (68) and ( f)-paliclavine (69) (Scheme 6) and of (f)-costaclavine (70) (Scheme 7).50 Synthesesof (f)-lysergene (71) (k)-agroclavine (72),51 (+)-isolysergol (73) and (i-)-elymoclavine (74)52 have been the subject of recent Japanese reports (Schemes 8 and 9).Both routes involve the construction of the required tetracyclic framework by photocyclization of an enamide and require no further comment except to note that these are the first reported syntheses of all four bases.Isomerization of ergoline-8@carboxylic acid esters (75) to the thermodynamically unfavoured 8a-epimers (76) can be achieved in good yield by formation of the corresponding lithium enolate by means of LiNPri in tetrahydrofuran followed by decomposition with water or dilute aqueous acid.53 This opens up a route to the pharmacologically active 8a- carboxylic esters and several such compounds have been prepared for pharmacological evaluation. 54 Other compounds that have been prepared for this purpose include a series of 6- methylergolin-8-ylpropionic acid derivatives; of these the cyano-amide (77) exhibits the most potent antihypertensive activity.55 NATURAL PRODUCT REPORTS 1985 CHO CO~BU' -@Me i + epimer HN (66) (67) J ii iii Me Me 1 I 1 C02Me $ # @ -q$Mec02Bu1 H O S iii iv MeC02Bu1 HMe + epimer \ \ HN I HN Paliclavine (69) 1ii HN Iv Costaclavine (70) 6,7-Secoagroclavine (68) Reagents i Me3SicMeC02Me; ii H2 Pd A1203; iii CF3C02H; iv Reagents i H,C=CMeMgBr; ii CF3C02H; iii Ph3P=CMe2 Me,AI; v LiAlH Scheme 6 Scheme 7 cH20H CH20H -H -@ + \ Me i.ii @e iv v MbsN MbsN MbsN Me Me I Me ... Vlll ix v viii f---4 MbsN Agroclavine (72) + Lysergene (71) epimer (Mbs = p-methoxybenzenesulphonyl) Reagents i MeNH,; ii furan-3-carbonyl chloride; iii hv NaBH, PhH MeOH; iv 03,CH2C12 at -60 "C; v LiAlH,; vi MesC1 py; vii KOBu DMSO; viii PhSeSePh; ix Birch reduction.Scheme 8 An improved preparation of the clinically useful prolactin deduced ;57 the absolute configuration implied in structure (78) inhibitor 2-bromo-a-ergocryptine which involves bromination follows from comparison of the c.d. spectra of (78) and of a-ergocryptine by means of pyrrolidone hydrotri bromide or aristoteline of known absolute configuration. piperidone hydrotribromide has been described ;56 the method Peduncularistine triabunnine and aristolarine are three is also applicable to other peptidic ergot alkaloids. new alkaloids that have been isolated from Tasmanian Aristotelia pedunculari~.~~ The structure and absolute confi- 4 Monoterpenoid Alkaloids guration of peduncularistine (79) follow from its spectral data 4.1 Aristotelirz Alkaloids (unconjugated indole carbonyl and Z configuration of X-Ray crystal structure analysis of aristoserratine (78) has disubstituted alkene groups) and its hydrogenation to aristoser-confirmed the structure and relative stereochemistry previously ratine.Triabunnine (80) is the related hydroxyindolenine and NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON 55 SH~OAC CH20H 1 ii-vi vii-ix 9PMe HN AcN Elymoclavine (74) Ivii xi xii CH20Ac CH2OH I xiii ix x viii ix -___) \ ~ &Me \ Me AcN AcN Lysergene (71) (major product) Isolysergol (73) Reagents i hv NaBH, PhH MeOH; ii 0,; iii LiAlH,; iv separation of epimers; v H2 Pd/C; vi Ac20 py at 0 "C; vii SOCl2 PhH heat; viii HCI MeOH (on minor product); ix PhSeSePh; x DBU; xi MesC1 py; xii base; xiii deacetylation Scheme 9 lv (77) qqHi OT-lH Me Me - Aristoserratine (78) Peduncularistine (79) lii Aristolarine (8 1) Triabunnine (80) Reagents i H2 Pd; ii 02,hv Rose Bengal MeOH HC104 at 0 "C Scheme 10 was prepared by photochemical oxidation of aristoserratine (78) (Scheme 10).Aristolarine is unique among Aristoteliu alkaloids in being yellow owing to the presence of an indolin-3-one chromophore. The molecule contains only two methyl groups the third one normally encountered in the Aristoteliu alkaloids being (+)-Aristoteline (86) (-)-Hobarthe (82) Reagents i Br, Et20; ii HN3 BF3.Et20 PhH; iii LiAlH,; iv indole-3-acetaldehyde PhH; v HC02H at r.t.; vi 20% HCI H20' Scheme 11 replaced by a primary alcohol function attached (as expected) to a fully substituted carbon atom.If the monoterpenoid residue has the usual Aristoteliu skeleton a possible structure for aristolarine is (81); this is consistent with all of the available evidence but cannot yet be regarded as being unequivocally established. If furthermore aristolarine arises by rearrange- ment of a 3P-hydroxyindolenine [cJ:(80)] the relative stereo- chemistry in structure (81) would also result.s8 A short and efficient synthesiss9 of (-)-hobartine (82) relies on a neat preparation of (S)-(p-menth-l-en-8-yl)amine (83) of high optical purity from (S)-wterpineo1(84).Condensation of (83) with 3-indolylacetaldehyde gave an imine (85) which was cyclized to (-)-hobartine (82) in 64% yield by means of formic acid (Scheme 11). This synthesis establishes the absolute configuration of (-)-hobartine previously unknown ; further confirmation was obtained by its cyclization to (+)-aristoteline (86). 4.2 Corynantheine-He tero yohimbineYohimbine Group and Related Oxindoles 5,6-Dihydroflavopereirineis one of three anhydronium bases that have been isolated from the root bark of Strychnos usurnburensis.22b Flavopereirine itself is the simplest of eleven alkaloids that have been extracted from the stem bark of S. longicaudata Gilg. from ZBire.60 A glucosidic alkaloid from the leaves of Pauridiantha lyallii Brem.proves to be 21-epi-pauridianthoside (87)f1 this is the first example of a naturally occurring epimer of secologanin and presumably arises by enzymic hydrolysis of the glucose unit followed by epimerization at C-21 in the hemiacetal thus released and re-formation of the glucosidic linkage. Desoxycordifolinic acid (88) the parent diacid related to desoxycordifoline was obtained as the major alkaloid of the heartwood of Nauclea diderrichii (De Wild.) Merr.;62 in the extractions the use of ammonia and strong acids was avoided in an attempt to reduce the possible production of artifacts. It is thus of interest to note that no alkaloids containing a pyridine ring were encountered. The dried legumes of Rhazya stricta from which the seeds had been removed have been shown to contain isovallesiachotamine.63 The Oriental drug 'chotoko' [the dried climbing hooks and stems of a species of the genus Uncaria (possibly U.sinensis Oliver)] is reputed to have sedative and hypotensive properties.A methanol extract of this drug did in fact elicit a strong long-lasting hypotension when injected into rats and on fractionation it yielded cadambine 3a-dihydrocadambine and 3P-i~odihydrocadarnbine.~~~ The pharmacological activity of the extract appears to be due mainly to the last two of these a1 kaloids. The presence of cadambine in the leaves of Anthocephalus chinensis (Lamk.) A. Rich. ex Walp. known in India as 'wild cinchona' has been confirmed,64b and the high-field proton and 13C n.m.r.spectra of this alkaloid have been recorded and analysed. Guettardine a new alkaloid from the bark of Guettarda heterosepala has the structure (89) which was established by correlation with dihydrocorynantheol(90) (Scheme 12).65 This alkaloid may well be a biogenetic intermediate in the conversion of b-carboline alkaloids into the cinchonamine 21 -epi-Pauridianthoside (87) Desoxycordifolinic acid (88) i ii __* 1 OH bH / Guettardine (89) OH Dihydrocorynantheol (90) Reagents i TsCl CH2C12 at 0 "C;ii DMF heat; iii LiAlH, THF heat Scheme 12 NATURAL PRODUCT REPORTS 1985 group a possibility which is underlined by the presence of Cinchona alkaloids in the same plant. If so it indicates that fission of the 4-5 bond in an intermediate of the corynan- theine-geissoschizine type probably precedes formation of the quinuclidine ring.-A new alkaloid isolated from the leaves of Catharanthus roseus and Rhazya stricta66 is tentatively formulated as 16-epi- (2)-isositsirikine (91). This base was not identical with either of the two (a-isomers that were obtained by reduction of geissoschizine but the n.m.r. data were certainly consistent with those of structure (91) which had been prepared earlier (together with its stereoisomers) by reduction of 4,21-di-de hydrogeissosc hizine hydrochloride. In an extensive investigation into the constituents of Guyanese Aspidosperma marcgravianum Woodson no fewer than 46 alkaloids were isolated from the stem bark leaves and root bark.68 This tree is apparently not used locally for medicinal purposes but its wood finds extensive use.Twelve of the alkaloids that were isolated are new; these include 16-epi- isositsirikine Nb-oxide isositsirikine Nb-oxide 18,19-dihydro- antirhine isogeissoschizol 10-methoxyisogeissoschizol isoantirhine and 3,4,5,6-tetradehydro-18,19-dihydrocory-nantheol from this group. In addition tetrahydroalstonine dihydrocorynantheol Nb-oxide antirhine deplancheine (1 6R)- 18,19-dihydrositsirikine (1 69-1 8,19-dihydrositsirikine and 16-decarbomethoxy-16,17-dihydro-17-hydroxy- 19-epi-ajmali-cine were isolated for the first time from any species of the genus Aspidosperma. Thirteen other alkaloids had already been encountered in this genus; these include dihydrocorynantheol aricine reserpiline reserpinine isoreserpiline isositsirikine 16-epi-isositsirikine geissoschizol 1 0-methoxygeissoschizol P-yohimbine yohimbine 0-acetylyohimbine and 10-methoxy- di hydrocorynantheol .68 A similarly thorough investigation has also been carried out on the seeds of Aspidosperma oblongum (A.DC.) Pichon the aerial parts having been examined on previous occasions.69 Like A.marcgrauianum this species is also endemic to Guyana; it appears to have no local medicinal use but is prized for its wood. In all 35 alkaloids were isolated from the seeds; these included thirteen new ones all of which belong to this group; these are 1O-methoxy- 17-epi-alloyohimbine 19,20-didehydr@- yohimbine 3,4-didehydro-P-yohimbine(as the perchlorate) p-yohimbine oxindole P-yohimbine pseudoindoxyl P-yohimbine N,,-oxide 1 0-met hox y-& yohim bine 1 0-me thox y-a-yo him bine 19,20-didehydro-a-yohimbine, aricine pseudoindoxyl an ar- methoxyantirhine 10-methoxysitsirikine and 3,4,5,6-tetrade- hydrositsirikine.One other alkaloid 17-epi-alloyohimbine had already been prepared by partial synthesis and has now been isolated from natural sources for the first time. In addition antirhine vallesiachotamine neo-oxygambirtannine alloyo- himbine corynanthine and 3,4,5,6-tetradehydro$-yohimbine are among those isolated from any species of the genus Aspidosperma for the first time and P-yohimbine yohimbine aricine tetrahydroalstonine a-yohimbine 10-methoxycory- nanthine isositsirikine 16-epi-isositsirikine (16R)-sitsirikine (16R)-18,19-dihydrositsirikine,(16R)-lO-methoxy-18,19-dihy-drositsirikine and 10-methoxyisositsirikine were already known in this genus.69 Sitsirikine has also been found in the leaves of Rauwolfia cafra22a and yohimbine a-yohimbine and alloyohimbine in the seeds.70 Tetrahydroalstonine occurs in roots of Kopsia o_tfcinalis7 and in Alstonia yunnanensis Diels the roots of which are used in Chinese folk medicine for the treatment of headaches fever and hyperten~ion.~~ I-r-Is A MeOzC l6 CH20H 16-epi-(Z)-isositsirikine (91) NATURAL PRODUCT REPORTS 1985 -J.E. SAXTON During a search for antimicrobial alkaloids in the root bark of Aspidosperma excelsum Benth. a number of inactive alkaloids including aricine yohimbine and O-acetylyohim- bine were isolated.73 The investigation into the variability of Thai specimens of the leaves of Uncaria elliptica R.Br. ex G. Don. previously noted,40d has been extended.74 A total of six samples has now been examined; from these seven of the eight possible diastereoisomers of the pentacyclic heteroyohimbine alkaloids were isolated. Only akuammigine was absent. Other alkaloids identified were 14P-hydroxy-3-isorauniticine,*tetrahy-droalstonine N,-oxide mitraphylline and isomitraphylline uncarine A and uncarine B and the four new natural products rauniticine pseudoindoxyl akuammigine pseudoindoxyl raun- iticine oxindole A and 3-isorauniticine pseudoindoxyl. The roxburghine alkaloids previously isolated from U.elliptica were not detected and in general this species seems to show considerably greater chemotaxonomic variation than had previously been suspected. The use of proton n.m.r. spectra in the identification of ajmalicine and its stereoisomers is e~emplified.~~ A South American species of the genus Uncaria U.guianensis (Aubl.) Gmel. appears to contain only oxindole alkaloid^.^^ The leaves contain rhynchophylline and isorhynchophylline and the roots yielded pteropodine speciophylline and mitra- phylline. Rhynchophylline and isorhynchophylline are also the two oxindole bases in the roots of Hannoa klaineana.27 A quantitative analysis of the tertiary bases in various organs of Uncaria rhynchophylla Miq. has been reported.76 Isocorynox-eine isorhynchophylline corynoxeine and rhynchophylline predominate in the hooks small stems and leaves whereas hirsuteine and hirsutine constitute 96% of the alkaloid content of the root bark. Little alkaloid is present in the wood but the proportion of the relatively rare alkaloids corynantheine and dihydrocorynantheine is somewhat higher than in the other parts. In the course of extracting the major alkaloids mitraphylline and isomitraphylline from the leaves of Bengali Mitragyna parvifolia (Roxb.) Korth. the N,-oxide of speciophylline was also isolated.77 Reserpic acid has been shown for the first time to be a natural product since it was isolated during an examination of the acidic constituents of the roots of Congolese RauwolJia oornit~ria.~~ It was shown not to be an artifact since the ester alkaloids in the roots remained intact.Pleiocarpamine is one of fourteen alkaloids that have been isolated from the stem bark and aerial parts of Melodinus guillauminii from New Caled~nia,~~ and it has also been obtained from the leaves of Catharanthusroseus together with fluorocarpamine and fluorocarpamine Nb-oxide.80 Cell suspension cultures of RauwolJia serpentina result in the formation of twelve indole alkaloids of which reserpine yohimbine ajmalicine 3-isoajmalicine serpentine and alston- ine belong to this group.81 Finally the pattern of distribution of alkaloids in the leaves stems and roots of ten African species of the genus RauwolJia has been summarized and the interrelationships of the alkaloid types have been discussed.82 Almost all of the alkaloids in these species belong to this group or to the ajmaline group although traces of akuammicine and its relatives in the strychnine group have been reported.Tetraphylline (92) Now known to be 14a-hydroxyrauniticine; for structure revision see later (ref. 96). (93) Melinonine E (94) \-xii OTQMe Ts H' TMe H H** iv v Ixiii. xiv GCOMe vii viii - (96) 3SR 19RS Mostueine (95) 3SR 19RS (+ 19-epimer) Reagents [Ref. 851 i HCO,Et NaH; ii N,-methyltryptamine AcOH THF at r.t.; iii H2S04 THF at 0 "C then at r.t. for 24 h; iv PhH Bu4N+ HSO, PhSO,CI 50%NaOH-H,O at r.t.; v MeMgI PhH; vi NaBH,; vii MesC1 NEt, THF at -20 "C; viii KOBu' THF 18-crown-6 at -20 "C; [Ref.861 ix N,-methyltryptamine toluene TsOH heat; x HCI MeOH; xi TsCI KOH glyme; xii MeLi LiBr THF at -78 "C; xiii LiAIH4 THF at -98 "C; xiv 10% KOH MeOH heat; xv HC(OMe),NMe, toluene heat. Scheme 13 NATURAL PRODUCT REPORTS 1985 It has been pointed that the absolute configuration at C-3 in heteroyohimbine alkaloids cannot be deduced unequivo- cally from the c.d. spectra since interaction between the indole ring and the chromophore in ring E can reverse the expected sign of the Cotton effect. Since the absolute configuration of yohimbane derivatives can be securely established by this method the chromophore in ring E in the heteroyohimbine series must first be removed e.g. by hydration reduction of the ester to a primary alcohol function or decarboxylation and hydration with formation of a ring E hemiacetal.The sign of the Cotton effect in the 270-300 nm region can then be safely used to deduce the configuration at C-3. Confirmation of the configuration that had been deduced for tetraphylline (92) was obtained by X-ray crystal structure determinati~n.~~ Melinonine-E a quaternary alkaloid of Strychnos melinoniana Baill. for which the structure (93) was earlier [19571 proposed on the basis of very limited evidence has now been re-in~estigated.~~ Its molecular formula determined by mass spectrometry is C,,H2 N20+,and the presence of nineteen carbon atoms [rather than twenty as in (93)] is confirmed by its I3C n.m.r. spectrum. Complete analysis of its proton and I3C n.m.r.spectra reveals that the alkaloid has the structure and relative stereochemistry shown in (94); melinonine-E thus contains a new skeleton. Biogenetically it could arise from an alkaloid such as antirhine in which case (94) would also show the correct absolute configuration. Two very similar synthese~~~~~~ of mostueine (95) (Scheme 13) serve to confirm the gross structure of this base from Mostuea brunonis but the conclusions concerning the stereo- chemistry of mostueine that have emerged are at variance. The French workersg5 established the relative stereochemistry of their intermediate (96) by X-ray crystallography and this leads to the opposite configuration at C-19 to that shown in (95) for mostueine if the final ring-closure involves a direct SN2 displacement on the 19-mesylate following deprotection of N,.However the American worked6 noted nuclear Overhauser enhancement of the signal owing to the axial proton at C-14 in mostueine when the signal of the methyl group C-18 was presaturated and of the signals of the protons at C-12 and C-21 when the signal of the proton at C-19 was presaturated. These observations are only consistent with the stereochemistry for mostueine that is shown in structure (99 i.e. 3SR,19RS. It therefore seems probable that cyclization of the mesylate derived from (96) involves overall retention of configura- tion at C-19. This may well be so,since the first part of the sequence to mostueine from (96) involves reaction conditions similar to those prescribed for the formation of chlorides from benzylic-type alcohols.Hence the resulting chloride may be the substrate for cyclization and the overall process from (96) to mostueine (95) involves double inversion at C-19. The structure of vinoxine (97) (Scheme 14) has also been confirmed by synthesis,87 and again this has led to revision of the stereochemistry. In an earlier investigation vinoxine was depicted as (98) on the basis of the chemical shift of the proton at (2-16. However the availability of both vinoxine and 16-epi- vinoxine from the synthetic work allowed comparison of J15 ,6 in these two bases with the reported values for pleiocarpamine and 16-epi-pleiocarpamine from which it was deduced that vinoxine has the stereochemistry shown in structure (97).87 A considerable amount of effort continues to be expended on the total synthesis of the mainstream yohimbine and heteroyo- himbine alkaloids.A reviewg8 of the methods available for the elaboration of the ethylidene side-chain in the ring-E-seco alkaloids shows how much attention has already been paid to this one structural feature. A new four-stage synthesis of flavopereirine (99) via 5,6-dihydroflavopereirine (loo) is claimed to be the most efficient yet reported (Scheme 15).89 1 'C02Me \C02Me MeO,Cm &I Me02C N CH~CH~OAC \ C02Me Me Vinoxine (97) R'=H R2=C0,Me 16-epi-Vinoxine (98) Rl=CO,Me R2=H Reagents i LiNPr', THF at -30 "C; ii HCl PhH at pH 3.5-4; iii 4M-HCl (on either epimer); iv 1.5M-HCl MeOH at r.t.; v NaBH, MeOH at 0°C Scheme 14 i ..... CHOEt / /o 5,6-Dihydroflavopereirine(100) Flavopereirine (99) Reagents i r.t.; ii Huang-Minlon reduction; iii LiAlH, THF; iv DDQ AcOH at 100°C. Scheme 15 NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON Details of McLean's synthesis45 of the diastereoisomers of (+)-decarbomethoxynauclechine have now been published.g0 Wanner's synthetic route involving the addition of ester anions to nicotinium salts has been applied in a very brief synthesis of nauclefine (101) (Scheme 16).91 The synthesis of (&)-corynantheidol by Imanishi et al. previously reported in brief has been described in detail.92 A new synthesis93 of (+)-dihydrocorynantheol (102) in- volves as its critical stage the alkylation-cyclization of 3,4- dihydro-a-carboline with the (a-lactone (103) which gave the tetracyclic lactam (104) in good yield and with a very high degree of stereoselectivity.Removal of the 0x0-group from the lactam and stereospecific reduction of the 3-14 double-bond was achieved by a two-stage sequence in which the second stage which presumably involves reduction of a 3-Nb immonium grouping by means of sodium borohydride occurs specifically at the 01 face owing to co-ordination of reagent with the free hydroxy-group attached to C-18. Reductive removal of this hydroxy-group and release of the hydroxy-group at C-17 then completed the synthesis (Scheme 17).93 Although several syntheses of (f)-ajmalicine are on record only partial syntheses of (-)-ajmalicine (105) have hitherto been reported.A total synthesisg4 of (-)-ajmalicine (Scheme 18) is therefore of considerable interest since this alkaloid is prescribed in some countries for the treatment of cardiovascu- lar disease. Pictet-Spengler cyclization of (+)-tryptophan- + 0-p -i,ii "H NH,*HCl \+ c1-amide with 4-formyl-2,2-bis(phenylthio)butyratehad earlier95 been shown to lead stereospecifically to the tetrahydro-a- carbbline derivative (106) from which the redundant carbox- amide group was then removed. Protection of N (to avoid lactam formation) and introduction of a double-bond conjugated with the ester group then gave an intermediate (107) which on reaction with methyl vinyl ketone followed by cyclization gave the tetracyclic keto-ester (108).Reduction of (108) gave the known lactone (109) in 7.5% overall yield from (-)-tryptophan. Conversion of (109) into (-)-ajmalicine by van Tamelen's route was then accomplished in 50% yield. A new partial synthesis77 of (-)-ajmalicine from mitraphyl- line (1 10) simply involves the reaction of mitraphylline methiodide with triethyloxonium fluoroborate followed by reduction (by sodium borohydride in acid solution) of the imino-ether (111) thus produced (Scheme 19). By use of the quaternary salt in this procedure the fission of the 3-Nb bond to give a ring-c-seco base was avoided and the stereochemistry at C-3 was preserved. Finally (-)-ajmalicine (105) was prepared by pyrolysis of the methiodide (1 12).77 The application of two methods for the introduction of a hydroxy-group into position 14 of the heteroyohimbine bases has allowed the structure of an alkaloid from Uncaria attenuata to be established.Originally postulated to be 1@-hydroxy-3- isorauniticine,12e this alkaloid has now been shown to be 14a- hydroxyrauniticine (1 13) since it can be prepared by hydro- H HGswCHzPh / J vi c- N auclefine (101 ) Reagents i NEt, MeCN; ii PhCH2Br MeCN heat; iii C:)-CO2Et Na+ EtOH then xylene heat for 30 minutes; iv Raney nickel TMF heat; v Pd/C Hz EtOAc MeOH HCl; vi 40% HBr-AcOH at 40°C. Scheme 16 vi vii viii (or ix) -OH bThp Dihydrocorynantheol (102) (Thp =tetrahydropyran-2-yl) Reagents i PhH; ii DMF at 80 "C under Nz for 30h; iii chromatography on silica gel; iv LiAlH, THF; v NaBH,; vi o-02NC,H,SeCN Bu3P THF under Nz; vii TsOH pyridine EtOH; viii Ph,SnH PhMe heat; ix W-2 Raney nickel EtOH Scheme 17 60 NATURAL PRODUCT REPORTS 1985 0Tj20NH2 H ( + )-Tryp tophanamide ii iii ii iv-vi + i -H H'* -TH H H* -SPh I OHCCH2CH2F'CozMe PhSpPh "C0,Me 0,Me SPh vii 1 HH t t t Me H** \ Me0,C 0,Me ( -)-Ajmalicine (1 05) 0 ( 108) ( 109) Reagents i PhH remove water azeotropically then CF,C02H CH2C12; ii trifluoroacetic anhydride; iii KBH, MeOH heat; iv PhSH NaH; v rn-chloroperbenzoic acid then PhMe heat; vi NaBH ; vii H,C=CHCOMe; viii pyrrolidine THF Scheme 18 A (-)-Ajmalicine (105) +\ H H-* jii 0;s- H' Et *-Me Mitraphylline (1 10) (1 11) Me0,C (1 12) Reagents i MeI THF; ii Et,O+ BF, CH,Cl2 under N,; iii NaBH, AcOH; iv heat in vacuo Scheme 19 "";Ix -< **' Me i-iii 1401-Hydroxyrauniticine (1 13) Me0,C Rauniticine (1 15) Hd (1 16) Reagents i Bu'OCl; ii HCl DME; iii KOH MeOH; iv BH, THF; v 3M-NaOH 30% H,O,; vi (PhCO,),; vii MeOH HCl; viii NaBH,; ix NaOMe Scheme 20 boration-oxidation of the enamine (1 14) prepared from and 1401-hydroxypseudoyohimbine(118).The initial products rauniticine (1 15) (Scheme 20).96The 3P-epimer 1401-hydroxy- from reserpine were 14a-benzoyloxyisoreserpine(1 19) and 14a- 3-isorauniticine (1 16) was the product of oxidation of the benzoyloxyreserpine (1 20) and no P-hydroxy-compounds ap- enamine (1 14) (by dibenzoyl peroxide) followed by reduction pear to be produced.p-Nitrobenzoyl peroxide gave analogous (by sodium borohydride). This latter method can also be used to products and 1401-hydroxyisoreserpine (122) was obtained introduce a hydroxy-group into position 14 in yohimbine and from 1401-p-nitrobenzoyloxyisoreserpine(121) by treatment reserpine;97 however the reaction appears to be less specific. with sodium methoxide followed by selective acylation with Yohimbine gives a mixture of l@-hydroxy-yohimbine (1 17) 3,4,5- trimet hoxy benzoyl chloride (Scheme 21) NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON MeO,C'* 6H (117) R'=OH R2=H; 3~-H (118) R'=H R2=OH; 3Q-H (1 19) R=OCOPh; 3~-H (120) R=OCOPh; 3Q-H (121) R&COC,H,NO,; 3a-H 'lii 122) R=OH ; 3a-H Reagents i NaOMe MeOH at r.t.; ii 3,4,5-trimethoxybenzoyl chloride pyridine DMAP at r.t.Scheme 21 A new ~ynthesis9*$~~ of (&)-yohimbine (123) and (&)-alloyohimbine (1 24) makes use of the reductive photocyclization of enamides in the direct synthesis of the desired pentacyclic system. The unconjugated enone (1 23 thus prepared,98 readily isomerizes to the normal enone (1 26a) or the allo enone (1 26b). Acylation of the lithium enolate from (126a) with chloroformic ester gave a mixture of products but the magnesium enolate gave the desired keto-ester exclusively in 67% yield. Hydrogen- ation of the double-bond then gave (&)-yohimbinone which was reduced to (+)-yohimbine (123) by means of sodium borohydride. An exactly analogous sequence of reactions on the allo enone (126b) afforded (&)-alloyohimbine (124) (Scheme 22).Details of SzBntay's syntheses of deserpidine 3-epi-17-epi- raunescine and several related compounds with the normal stereochemistry previously reported in brief O0 have been published. lo1 Ninomiya's group have also completed a new synthesis of (+)-deserpidine (128) (Scheme 23) again by use of the route involving the reductive photocyclization of enamides. lo2 The pentacyclic lactam (129) prepared (together with a regio-isomer) in an analogous manner to that of (127) was reduced and hydrolysed to the unsaturated methoxy-ketone (1 30) ; again this was accompanied by the formation of an isomer. Introduction of the ester group at C-16 was achieved preferably by acylation of the lithium enolate of (1 30) by means of methyl cyanoformate (Mander's method).Unexceptional stages then led to the ester (131) which has previously been converted into ( & )-deserpidine by Szantay et al. O A new synthesislo3 of (+)-deoxytubulosine (132) takes advantage of an ingenious preparation of the dihydropyran ester (1 33) which is essentially an analogue of 3,4-dihydroseco- loganin aglucon. Condensation of (1 33) with 3-hydroxy-4-methoxyphenylethylamine under reducing conditions gave the intermediate (1 34) which it was discovered suffered Pictet-Spengler cyclization two decarbomethoxylations and epimerization at C-5 when boiled with propionic acid. The synthesis was then completed using conventional stages (Scheme 24).lo3 Finally the microbiological hydroxylation of the heteroyo- himbine isomers ajmalicine tetrahydroalstonine 3-isoajmali- cine and akuammigine by seven micro-organisms has been studied.lo4 In many cases hydroxylation at C-10 was observed but in others (notably with the micro-organism MRRS 10-IBI w OMe .. ... 11 111 J (127) (126a) (1 26b) v-ix Iv-ix i bH OH Yohimbine (1 23) Alloyohimbine (124) Reagents i hv MeCN MeOH NaBH,; ii LiAlH,; iii HCl H,O; iv tartaric acid dioxan at 80 "C; v LiNPr', THF at -78 "C; vi MgBr,; vii CICOIMe; viii Hz PtO,; ix NaBH,; x silica gel Scheme 22 isolated from the roots of RauwolJia uomitoria) hydroxylation of C-11 occurred. 4.3 Sarpagine-Ajmaline-Picraline Group This group has recently been comprehensively reviewed.lo50 Normacusine B has been isolated from the seeds of RauwolJia cagra7Oand vomilenine strictamine akuammidine perakine raucaffrinoline normacusine B peraksine dihydroperaksine sarpagine macrophylline and three new bases have been isolated from the leaves.2za The three new bases were tentatively suggested to be 21 -deoxyvomilenine 2 1-acetyl-19,20-dihydrovomilenine,and 18,Na-didemethyl-19-hydroxy-N,-methylsuaveoline (1 35). Normacusine B has also been found together with sarpagine perakine vellosimine and vinorine in the roots of Alstonia yunnanensis Diel~;~~ this is the first reported occurrence of these alkaloids in the genus A lstonia. The root and stem barks of Strychnos angolensis Gilg.contain 1 1-methoxymacusine A (136),Iosb which like many quaternary alkaloids exhibits muscle-relaxant activity. Peri- vine and vobasine are two of the four major alkaloids of the leaves of Tabernaemontana dichotoma Roxb. and isornethuenine is one of the minor bases.lo6 The four alkaloids previously NATURAL PRODUCT REPORTS 1985 HOH2C liii iv QT%oMe-v vi Q%oMe HOH,CvCO,Me Me0,C MeO OH 0 vii-xi R9 H\ Rhazimol (137) R=H (EDeacetylakuammiline o'I '~ I oc~Me EErcinaminine) Ercinamine (140) R=OH HYC0,Me 16 Me0,C \OMe bMe 0 -0Me 11 Deserpidine (1 28) Reagents i LiAIH,; ii 10% HCl MeOH at r.t.; iii LiNPri2 THF at -78 "C; iv CNC0,Me; v H2 PtO, MeOH; vi NaBH,; vii BBr, CH2C12 at 0°C; viii 2M-NaOMe MeOH; ix NaOMe MeOH "3 heat for 72 h; x 3,4,5-trimethoxybenzoyl chloride pyridine; xi \ R3 epimerization at C-3 R' R2 R3 Scheme 23 10-Hydroxystrictamine (1 38) OH H H 1 1-Hydroxystrictamine (1 39) H OH H Gomaline (141) H H OH EtCH,CH=CHCO,Me -+ Me0,C 'Et isolated from the fruit stem bark and root bark have not so far been found in the leaves.Perivine and 16-epi-affinine are Me02CI\C0,Me among the bases in the bark of Peschiera fuchsiaefolia (DC.) Miers. and the presence of voachalotine and affinisine previously noted has been confirmed.lo7 The 13Cn.m.r. data for 16-epi-affinine and vobasinol were also recorded and analysed in this communication. Aspidodasycarpine is the only representative of this group to be encountered among the 35 alkaloids of the seeds of Aspidosperma ~blongum.~~ New extractions of Catharanthus roseus have yieldedIo8" rhazimol (1 37) which was first isolated108b from Rhazya stricta ; since this alkaloid is simply deacetylakuammiline the introduction of a new name is unnecessary.Strictamine Nb-oxide has been isolated from the leaves of Rhazya stricta.lo9 The two bases that were isolated earlier from Vinca erecta' lo and claimed to be 10- and 1i-hydroxypleiocarpamine have iv v nowlll been shown to be 10- and 11-hydroxystrictamine [(138) and (139)]. Two other bases from the same source are ercinamine and ercinaminine ;the former has been formulated as 10-hydroxydeacetylakuammiline (140) and ercinaminine vi vii -(another superfluous name) is its deoxy-derivative i.e.deacetyl- akuammiline (1 37). Yet another base has been isolated from the leaves of Catharanthus roseus;' the number isolated from the various organs of this prolific plant appears to exceed ninety. Deoxytubulosine (1 32) Gomaline an amorphous base is an indolenine whose proton Reagents i (C02Me)? KOMe; ii CH2(C02Me)2 KOMe; iii 3- n.m.r. and mass spectra are consistent with the presence of a hydroxy-4-methoxyphenylethylamine NaBH,CN; iv EtC02H strictamine skeleton carrying a hydroxy-group at C-i 8. Since heat; v CH,N,; vi Bui2AIH; vii tryptamine H+/H20 the methyl of the carbomethoxy-group is not shielded by the Scheme 24 indolenine ring system gomaline (141) is concluded to have the NATURAL PRODUCT REPORTS,1985 -J.E.SAXTON same stereochemistry as strictamine and it is therefore considered to be 18-hydroxystrictamine. A report' on the alkaloids of Gelsemium elegans [humanten- mine (gelsenicine?) humantenine humantenidine and hu- mantenirine] appears to duplicate one mentioned last year.45 Vomilenine ajmaline 17-O-acetylajmaline 17-0-acetylnor- ajmaline vinorine and sarpagine have been shown to be produced in cell suspension cultures of Rauwolfia serpentina;* of these only ajmaline had previously been found in cultured cells of this plant. The distribution of alkaloids is quite different from that observed in intact plants; in particular vomilenine which is the major alkaloid has not been found in R. serpentina and the yield is estimated to be 51 times that reported from R.vomitoria. Some new interrelationships in the corymine series have recently been reported. l4 Treatment of desformocorymine (142) with trifluoroacetic acid at room temperature gives a mixture of C-2 epimers (143) which presumably arise by protonation of N,in (142) fission of the bond between C-2 and Nb,proton exchanges to give (144) and recyclization. Proof of the structure of (143) was provided by its reduction to 2-epi-16- epi-cathafoline (149 which was further reduced and acetylated to give the base (146) also obtainable from picralstonine (147) (Scheme 25). This sequence constitutes the first interconver- sion of the corymine skeleton into the akuammiline skeleton and it also incidentally proves that C-16 suffers epimerization in the deformylation of corymine to give desformocorymine (142) and in the formation of picralstonine (147) by loss of the intermediate (149) analogous to (144) forms the hemiacetal (150); the alternative cyclization possible in (149) leads to the second product a highly unstable lactam which exists as a hydrated form (151).Treatment of the hemiacetal (150) with aqueous base also gives (151). The reaction of (150) or (151) with sodium methoxide leads to the formation of an indole base (152) whose structure was established by X-ray crystal structure analysis of its p-bromobenzoate. The fission of the 7- 16 bond in (150) and (151) is essentially the reverse of the process that has been postulated to occur in the biogenesis of the akuammiline group of alkaloids.In the course of purifying the hydrated lactam (151) a by- product was obtained whose molecular formula indicated the loss of two hydrogen atoms from dihydrocorymine (148). Its structure also determined by X-ray crystallography was shown to be (1 53) i.e. 17-hydroxymethylvincoridine,and it is presumably formed by oxidation of dihydrocorymine (1 48) in the reaction medium. Acylation of the 17-hydroxy-group in dihydrocorymine obviously blocks the formation of the hemiacetal (150). Consequently when dihydrocorymine trifluoroacetate (1 54) is treated with trifluoroacetic acid the reversible formation of (155) allows the equilibration of (154) and its C-3 epimer. Hydrolysis of the resulting mixture then gives predominantly 3- epi-dihydrocorymine [the C-3 epimer of (148)]; this affords a much more direct correlation of these C-3 epimers than has hitherto been achieved.Il4 Details of Husson's synthesis37b of the ervitsine ring system acetoxymethyl group from picraline.-9have been published. The rearrangement of di hydrocorymine (1 48) under similar The pharmacology of echitamine has been studied in some conditions follows a different course (Scheme 26).l14 Here the detail. ROH,C-C02Me ROH2C,,C02Me i Me Desformocorymine (1 42) (144) Dihydrocorymine (148) R=H (149) R=H (1 54) R=COCF3 (155) R-COCF3 1 / ii c- 9 HO' 2-epi- 16-epi-Cathafoline (145) iii iv I / AcoH2CYH iii v iv Picralstonine (147) Reagents i CF3C02H at r.t. for 40 h; ii Et,SiH CF,C02H; iii, LiAIH,; ivyAc20 NEt, CH,Cl,; v CH20 AcOH then NaBH (152) 17-Hydroxymethylvincoridine(153) Reagents i CF3C02H at r.t.; ii NaOMe MeOH Scheme 25 Scheme 26 NATURAL PRODUCT REPORTS 1985 4.4 Strychnine Group Akuammicine its N,-oxide and its 19,20-dihydro-derivative are among the leaf alkaloids of RauwolJia caflra.22a Stemma-denine occurs in the seeds of Tubernaemontana dichotomal and vallesamine in the seeds of Aspidosperma oblong~m.~~ 11-Methoxytubotaiwine is one of the antimicrobial alkaloids of the root bark of Aspidosperma excelsum ; compactinervine which is inactive is also present.73 Two new alkaloids Na-formylechitamidine (1 56) and Na-formyl-12-methoxyechitamidine(1 57) have been isolated together with echitamidine (158) from the bark of Nigerian Alstonia boonei De Wild.which is widely used locally as an antipyretic and in external application for rheumatic pains. The stem bark of Strychnos longicauduta Gilg. contains three new alkaloids [I ,2-didehydrodeacetylretuline(1 59) 18-ace-toxy-Na-deacetylisoretuline (1 60) and 23-hydroxy-2,16-dide- hydroretuline (161)] together with the Wieland-Gumlich aldehyde diaboline and N,-deacetyl-l 8-hydroxyisoretuline [Wieland-Gumlich diol (162)] from this group.60 The Wie- land-Gumlich aldehyde was also present in the root bark. The stem bark of S. ngouniensis Pellegrin yielded norfluorocurarine (1 63) and three new alkaloids i.e. 18-hydroxynorfluorocurarine (164) 18-acetoxynorfluorocurarine (1 65) and tubotaiwinal (166); this last base also occurs in the root bark.60 Norfluoro- curarine has also been obtained together with tubotaiwine and twenty alkaloids from the pseudoaspidospermidine-cleav-amine group from the leaves of Tabernaemontana eglandulosa Stapf.The stem bark of Strychnossoubrensis Hutch. et Dalz. a West African liana which has not previously been investigated has been shown to contain strychnobrasiline (1 67a) strychnofend- lerine isosplendine and a new base 14P-hydroxystrychnobra- siline (167b) whose structure was confirmed by an as yet unpublished X-ray crystal structure determination. 2oa The root bark of S. henningsii Gilg. which is used by the Zulus to relieve rheumatic pains has yielded diaboline holstiine Na-acetylstrychnosplendine(1 68a) and a new alka- loid which proves to be Na-acetyl-1 1 -methoxystrychnosplen- dine (168b).120b The stereochemistry of echitamidine (1 58) isolated recently from Indonesian Alstonia angustiloba and A.pneumatophora has been deduced from its n.m.r. spectrum and confirmed by X- ray crystal structure analysis of its trifluoroacetate. 21 Both C- 19 and C-20 have the S configuration; hence echitamidine (158) is (19S 20S)-19-hydroxy-19,20-dihydroakuammicine. An isomer (169) obtained from the same source is epimeric at C- 20 but the configuration at C-19 has not been established. Two other isomers [(170) and (171)l isolated from A. angustiloba belong to the tubotaiwine group but again their stereoche- mistry has not been completely elucidated. An attempt to prepare them by the hydroboration-oxidation of tubotaiwine resulted in the formation of the tertiary alcohol (172) by an anomalous reaction that has previously been observed in the akuammicine series.The very high positive optical rotations of (170) and (171) indicate that they belong to the enantiomeric series compared with akuammicine and echitamidine. Carbon-13 n.m.r. data have been recorded and analysed for norfluorocurarine vincanidine akuammicine and vinervin- ine,' 22 and for strychnine its ar-hydroxy- and ar-methoxy- derivatives and for members of the vomicine-icajine group. 23 On the basis of their proton n.m.r. spectra and comparison with model compounds rosibiline (1 73) has a trans B/C ring junction and the Wieland-Gumlich glycol formal (1 74) has a cis B/C ring fusion.' 24 Details of Ban's synthetic approach40e to the Strychnos alkaloids have been published.' 25 4.5 Ellipticine-Uleine-Apparicine Group (-)-Apparicine has been isolated from the leaves of Tabernae-montana dichotomal O6 and N,,N,-dimethyltetrahydroellipticin-ium hydroxide from Aspzdosperma gilbertii.26 The isolation and structure determination of ngouniensine which is the major alkaloid of the stem-and root-bark of Strychnos ngouniensis Pellegrin were reported earlier in brief;45 the full paper60 records the separation of thirteen alkaloids which include ngouniensine (1 75) 20-epi-ngouniensine (1 76) and / \OH N,-Formylechitamidine (1 56) R'=H R2=CH0 N,-Formyl-1 2-methoxyechitamidine (1 57) R'=OMe R2=CH0 1,2-Didehydrodeacetylretuline (159) (160) R=Ac Echitamidine (1 58) R1=R2=H; 19s (162) R=H H OH Norfluorocurarine (1 63) R=H (167a) R=H 18-Hydroxynorfluorocurarine (1 64) R=OH Tubotaiwinal (166) (167b) R=OH (161) 18-Acetoxynorfluorocurarine (165) R=OAc C02Me k02Me Echitamidine (1 58) 19S 20s (168a) R=H (170) (171) R'=H R2==OH (169) 20R (168b) R=OMe (172) R1=OH R2=H NATURAL PRODUCT REPORTS 1985 -J.E. SAXTON la I R Wieland-Gumlich glycol formal (174) R=OH; 16a-H Rosibiline (1 73) R=H ; 16P-H CH Ngouniensine (1 75) R=H ;20P-H 20-epi-Ngouniensine (1 76) R=H ; 2001-H Glucosylngouniensine (1 77) R=GlcO; 20P-H 20-epi-Glucosylngouniensine(1 78) R=GlcO; 20a-H their 10- (or 1 1-)glucosyloxy-derivatives(1 77) and (1 78).Owing to paucity of material the exact position of the aromatic substituent in (177) and (178) has not yet been determined. Details of the synthesis45 of derivatives of olivacine and of ellipticine by Wanner et al. have been p~blished.~~ Husson's synthesis' 2f of 20-epi-uleine (1 79) via 2-cyano-A3-piperideines has been modified and improved and 20-epi-uleine can now be prepared in four steps from the N-oxide (1 80) (Scheme 27). The latest synthesis of ellipticine (181) involves as its critical stage the intramolecular 1,4-addition of an ester anion on an unactivated pyridinium salt (Scheme 28).12' In previous syntheses of this type the pyridinium ring has been activated by carbonyl groups at position 3. A very neat and efficient synthesis of 17-oxoellipticine (182) takes advantage of the greater reactivity of the ketone carbonyl than the amide carbonyl group in (183) towards alkyl-lithium reagents.The reaction of (1 83) with 2-lithio-2-trimethylsilyl-1,3-dithian followed by methyl-lithium gave the pyridocarba- zole derivative (1 84) which was converted into 17-oxoellipti- cine (182) in 25% overall yield (Scheme 29).128a The various approaches to the synthesis of ellipticine and its relatives up to the end of 1982 have been reviewed.128b A clue to the possible mode of action in uivo of the antitumour alkaloid 10-hydroxy-N-methylellipticiniumacetate (185) has been provided by a study of its reaction with adenosine and with methanol. 29 The reaction with adenosine in the presence of hydrogen peroxide and horseradish peroxidase gave a ketal of structure and stereochemistry (186) (Scheme 30) ; this presumably originates from two successive oxidations of (185) to a quinone imine followed by nucleophilic addition of adenosine.The reaction with methanol in the presence of copper(1) chloride-pyridine and oxygen gives an exactly analogous keto-ketal. In uivo 1O-hydroxy-N-methyl-ellipticinium acetate may well react after oxidation with the terminal nucleotide of mRNA or tRNA and hence inhibit the early stages of protein biosynthesis.' 29 4.6 Aspidospermine-Vincamine Group There continues to be a considerable amount of activity in this large group of alkaloids. Several new extractions and the isolation of several new alkaloids have been reported and a number of synthetic approaches have come to fruition.Aspidosperma marcgravianum Woodson the most prolific of the species recently examined contains among its 46 alkaloids two new ones from this group 18-oxohaplocidine (1 87) and 2- ethyl-3-[2-(3-acetyl-N-piperidino)ethyl]indole ( 188). Aspido- carpine limapodine haplocidine (1 89) aspidolimidine (190) rhazinilam tetrahydrosecodine (191) and decarbomethoxy- tetrahydrosecodine (192) were also isolated.68 N,-Acetylaspido- spermidine and 0-demethylaspidospermine are two of the Me ,O-Me Me i ii 111 Et0-Et4) -Nc-Q CN Etd CN (180) iv/ vi or v\ 20-epi-Uleine (1 79) Reagents i trifluoroacetic anhydride CH,CI,; ii Et,AICN PhH; iii KCN CH2C12 H20; iv indole AgNO, AcOH HzO at 60 "C for 24 h; v MeLi Et,O under argon; vi TsOH CHCI, heat; vii camphorsulphonic acid CHCI, heat.Scheme 27 CH, II ii-v Me Me Ellipticine (1 81) Reagents i 3-Acetylpyridine HBr MeOH; ii H, Pd/C MeOH; iii MeI; iv NaOMe MeOH; v ethyl nicotinate methiodide; vi NaAl(OCHZCHZOMe)2H,, xylene at 130 "C; vii PhSNa DMSO Scheme 28 (1 83) (182) Reagents i THF at -100 "C; ii MeLi; iii NaBH, EtOH heat; iv AgN03 H,O acetone Scheme 29 AcO-Me li (186) Ade = adeninyl Reagents i H202 adenosine horseradish peroxidase Scheme 30 -. R* H 18-Oxohaplocidine (1 87) R'=OH R2=Ac R3=0 Haplocidine (1 89) R'=OH R2=Ac R3=H2 Aspidolimidine (190) R'=OMe R2=Ac R3=H2 uN?R' H (188) R'=H R2=AC (191) Ri=C02Me R2=Et (192) R'=H R'=Et antimicrobially inactive alkaloids of A.ex~elsum.~~ The seeds of Tabernaemontanu dichotoma Roxb. contain tabersonine voaphylline and voaphylline hydroxyindolenine,l but 12- methoxyvoaphylline is one of the major alkaloids in the NATURAL PRODUCT REPORTS 1985 (+)-isoeburnamine] (-)-12-methoxy-N,-methoxycarbonyl-kopsinaline (203) (-)-Na-methoxycarbonyl-1 1,12-methylene- dioxykopsinaline (204) (-)-11 12-dimethoxy-Na-methoxycar-bonylkopsinaline (205) (-)-11,12-methylenedioxykop-sinaline (206) and (-)-I 2-methoxykopsinaline (207). The bases (204) and (206) are rare examples of indole alkaloids containing a methylenedioxy-group ; the only other species in which this structural feature has been encountered is Schizozygia caflaeoides.It is possible that alkaloids (203) and (204) are identical with kopsilongine and kopsamine from Kopqia longflora Merril1,l3l but this identity has not yet been established. Vindolinine N-oxide and 16-epi-(19S)-vindolinine N-oxide have been isolated from the leaves of Catharanthus roseus under conditions which it is claimed could not result in the formation of N-oxide artifacts,80 and a rapid procedure for the isolation of vindoline catharanthine and vinblastine from this source has been described.132 Details of the isolation and oxidative fragmentation of I6-epi-(19S)-~indolinine~~ have been published.133 Hyderabadine a new base isolated134a from the leaves of Ervatamiu coronaria is formulated as the pentacyclic ether (208) (stereochemistry undefined) on the basis of its n.m.r.and mass spectra. This structure bears an obvious relationship to that of voaphylline which occurs in the same plant. Mehranine another new alkaloid from the same plant is regarded as the epoxide (209) (stereochemistry again unspecified). 34b Finally three new alkaloids have been extracted from the bark of Microplumeria anomala (M. Arg.) Mgf. from the banks of the Rio Negro that are closely related to aspidocarpine (210). Anomaline (21 1) is 1 Sa-hydroxyaspidocarpine,and the other two bases are demethoxyanomaline (212) and 12-0-methylanomaline (21 3). * 35 These structures were deduced leaves.Io6 Voaphylline is also one of the constituents of the leaves twigs and stem bark of T. eglandulosa.l9 Fourteen alkaloids have been found in the stem bark and aerial parts of Melodinus guilluuminii Boiteau ;79 these include four new ones [~-oxo-14,15-seco-kopsinal (193) 11-meth~xy-A~~-vincamenine (1 94) 1 1 -meth~xy-A~~-vincanol (199 and 3-oxohydroxykop- sinine] and eight known bases [l 1-hydroxytabersonine 11-methoxytabersonine venalstonine (1 96) venalstonidine (1 97) 3-oxovenalstonine (198) 3-oxohydroxykopsinine kopsinine (1 99) 15a-hydroxykopsinine and 19P-hydroxyvenalstonine (200)l. In the novel alkaloid 3-oxohydroxykopsinine the position of the hydroxy-group was not determined owing to lack of material. Hexacyclic alkaloids are also a feature of the constituents of Melodinus reticulatus Boiteau from New Caledonia. 30 Tabersonine and 1 1 -methoxytabersonine occur in the fruits; the stems and leaves contain tabersonine venalstonine (196) and its 3-0x0-derivative (198) venalstoni- dine (197) and kopsinine (199) together with the three new alkaloids 19P-hydroxyvenalstonine (200) 19P-hydroxyvenal- stonidine (201) and 3-oxovenalstonidine (202).Kopsiu officinalis Tsiang et P. T. Li enjoys a reputation in Chinese popular medicine for the alleviation of gout and rheumatism and as an analgesic in pharyngitis and tonsillitis. The roots of this species have yielded nine monomeric alkaloids from this group including kopsinine 5,22-dioxokopsane and (-)-q~ebrachamine,~l and six new alkaloids which were shown to be (-)-isoeburnamine [the enantiomer of the familiar kO,Me (194) R1=H; 16,17-didehydro (1 93) (195) R'=H R2=OH A C0,Me (196) R'=HI RLH; (197) R'=H2 RLH; 14,15-epoxy (198) R'4 RZ=H; AI4(l5) (199) R'=H2 R'=H (200) R'=H2 R2=OH; (201) R1=H2 RLOH; 14,15-epoxy (202) Rl=O RLH; 14,15-epoxy NATURAL PRODUCT REPORTS 1985 -J.E. SAXTON Me Mehranine (209) Aspidocarpine (210) R'=R3=H R2=OMe Anomaline (21 1) R1=H R2=OMe R3=OH Demethoxyanomaline (21 2) R1=R2=H R3=OH 12-0-Methylanomaline (21 3) R1=Me R2=OMe R3=OH mainly by comparison of proton and 13C n.m.r. data with those of appropriate models; in this connection the 13C n.m.r. data of refractine and cylindrocarpine were reported and analysed. The absolute stereochemistry (7S,20R,21 S) that was deduced for vincatine last yeaP5 has been contradicted in a new investigation.36 The Italian authors agree with Pakrashi's group concerning the relative stereochemistry (from n.m.r. evidence) but on the sound basis of a partial synthesis (see Scheme 31) of vincatine (214) from (-)-vincadifforrnine (219 in which C-20 remains unaffected they conclude that vincatine has the absolute configuration 7R,20S,21R. In fact vincatine (214) and Pakrashi's base give enantiomeric c.d. curves. Because of the possibility of a reversible Mannich fission of the 7-21 bond in vincatine equilibration with its three diastereo- isomers is facile and all four bases were obtained in the partial synthesis from (-)-vincadifformine. This epimerization at C-7 and C-21 will even take place in chloroform solution at 35 "C; hence values of optical rotation for vincatine tend to be variable and any conclusions based on them are suspect.Trichophylline a novel alkaloid isolated (together with lochnerine) from the roots of Cutharanthus trichophyllus (Baker) Pichon has the structure (216) according to X-ray crystal structure analysis. Reduction of trichophylline with sodium borohydride gives an unsaturated lactone formulated as (217). 37 Oxidative fission of the C/D ring system in derivatives of vincadifformine has been previously observed ; hence trichophylline may arise by oxidation at C-21 of an appropriate precursor e.g. a 14,15-didehydrominovincinine(218) followed by fission of the 20-21 bond and simultaneous migration of C-18 (Scheme 32). The chromatographic behaviour of the enantiomers of a number of Aspidosperma alkaloids on a stationary phase composed of a polyether-type P-cyclodextrin bead polymer has been studied.38 In favourable circumstances resolution could be achieved; e.g. (f )-vincadifformine and ( f )-quebracha-mine were resolved in very good yield on a preparative scale simply by passing their weakly acidic solutions through the chromatographic column of polymer. A number of further rearrangements and transformations in this area have been reported. Deamination of 1,2-didehydro- aspidospermidine (21 9) affords the hemiacetal (220) (Scheme 33); this result is not exceptional and can be explained by any one of three simple mechanisms. 39 Desethyltabersonine (221) synthesized by the Kuehne rearranges in boiling acetic acid to a mixture of products which includes 3.4% of desethylcoronaridine (222); this presumably arises by reverse Diels-Alder fission of ring c in (221) followed by a 4n + 2n cycloaddition in an alternative sense (Scheme 34).The desired rearrangement product dese t hy lca t haran t hine could not be detected. The purely thermal rearrangement of some aspidospermi- dine derivatives can give rise to products containing the vincane ring system. Thus pyrolysis of (-)-I ,2-didehydroaspi- dospermidine (21 9) at 200 "C affords (-)-aspidospermidine ?-9-Me iii ( -)-Vincadifformine N-oxide (215) 1 ?-(-)-Vincatine (214) Reagents i 302,ButOK Bu'OH; ii Me2S0,; iii (Me0)2P(0)-CH2C02Me NaH DME; iv KOLCN=NC02K MeOH AcOH; v W-2 Raney nickel DME at r.t.Scheme 31 I __+ H C02Me c- II (217) Trichophylline (2 16) Reagents i oxidation; ii NaBH Scheme 32 Reagents i NaN02 SM-HCl at 0°C Scheme 33 Desethy Itabersonine (221 ) Ill a$-& Me02C Desethylcoronaridine (222) Reagents i AcOH under argon heat for 15 h Scheme 34 NATURAL PRODUCT REPORTS 1985 x2 __+ Q-pEt ' N' + O'N -pEt HH Scheme 35 Et Et (227) (223) and (-)-eburnamenine (224).141 This is not a simple intermolecular oxidation-reduction process but probably proceeds via a dimeric species (225) which undergoes two 1,5- sigmatropic shifts to form an intermediate (226); this frag- ments to (223) and (224) (Scheme 35). Et Under flow thermolysis conditions (580 "C),1,2-didehydro-k02Me aspidospermidine (2 19) gives vincane (227) again via two consecutive sigmatropic shifts.16-Hydroxyvincadifforine indolenine (228) on pyrolysis or I flow thermolysis rearranges to a mixture of vincamine (229) and 16-epi-vincamine (230) possibly via an obvious variant of the same mechanism (Scheme 36).I4I A new method for the introduction of a double-bond adjacent to a lactam carbonyl group has been devised;142 this may well prove valuable as an alternative route to the formation of Al4(ls) Aspidosperma alkaloids. The reaction of a ring D thiolactam [(231) or (232)] with an arylsulphinyl chloride (229) 16P-OH in the presence of base gives an unsaturated thiolactam [(233) (230) 1601-OH or (234)] which can then be desulphurized [+(235)] or Scheme 36 hydrolysed [-+(236)] (Schemes 37 and 38).This process is not considered to involve an a-phenylsulphoxide elimination since The microbiological oxidation of dihydrovindoline by means the conditions are too mild but it probably involves a of Streptomyces griseus UI 1158 gives four products which are sulphinylation on sulphur encouraged by the relative acidity of 3-oxodihydrovindoline 3-hydroxydihydrovindoline and the the protons at C-14,adjacent to the thiolactam function; phenol that is obtained by demethylation of its ll-methoxy- elimination of a proton from C-15 in the intermediate (237) group and 14-acetyl-l7-O-deacetyl-14,15-dihydro-3,14-didehy-so formed and the departure of an effective leaving group drovindoline (238e).143b (ArSO-) then gave the unsaturated thiolactam.142 Magnus and his collaborators have reviewed their highly The oxidation of 16-0-acetylvindoline (238a) by means of successful indole-2,3-quinodimethane strategy for alkaloid enzymic (laccase and human caeruloplasmin) microbiological and the synthesis of Hunteria alkaloids eburna- (Streptomyces griseus) or chemical (DDQ)reagents gives the 3- mine vincamine and their relatives has also been reviewed.14s Nbimmonium derivative (238b). Hydrolysis of the 16-0-acetyl A synthesis of desethylvincadifformine by the fJ-acylpyridine group in (238b) gives the dimer (238c) (previously identified45 reduction-yclization route has been described in detail. 146 as a product of the microbiological transformation of Several alkaloid syntheses previously reported in brief vindoline) presumably via the intermediate enamine communications have now been published in detail.These (2384). 43u include syntheses of N,-methylsecodine (N.B. the preliminary NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON AkO 1ii iii P S-SOAr S-SOAr a:$! \ I ArSO S iv v __+ Reagents i Lawesson's reagent (MeOC6H,P2S,C6H40Me) HMPA at 85 "C for 20 h; ii MeC6H,SOCl EtNPri at 0 "C; iii H20 AcOH; iv MeI THF at 50°C; v NaBH, MeOH at r.t. Scheme 37 1ii iii R R (236) (234) (R = p-MeOC&S02) Reagents i Lawesson's reagent toluene at 90 "C ;ii p-MeC,H,SOCl PriNEt2 CH2CI2 at 65°C; iii H20 AcOH; iv Et,O+ BF, CH2CI, at 25 "C; v KOH H20 THF at 25 "C Scheme 38 communication is not cited here) 47 a~pidospermidine,~~~ N,- acetylaspidospermidine and quebrachamine 25 taberson-10,22-dioxokopsane and kopsanone and eburnamonine.' s1 Kuehne's synthetic approach to the anilinoacrylate alkaloids has been applied to the first synthesis of minovincine (239).52a Two syntheses were in fact completed (Scheme 39). In the first AcO AcO (238a) (238b) J (238d) 1 OMe QNMe Me H I C02Me (238c) py-fcoMe H H (238e) of these the indolo-azepine (240) was condensed with the chloroaldehyde ketal (241) the end-product of the fragmenta- tion-recyclization reaction of the quaternary ammonium ior! (242) being minovincine ketal(243). Acid hydrolysis then gave minovincine (239).Since the original chloroaldehyde ketal (241) is not readily accessible and the final hydrolysis stage [(243)-+(239)] proceeds poorly an alternative route was sought. Two variants of the new route were eventually developed. The more efficient route involves the reaction of the indolo-azepine (240) with the sodium salt of formylacetone which gave a vinylogous amide (244). Cyclization was achieved in a separate stage and benzylation of the product (245) followed by fragmentation and recyclization gave (246). The remaining stages are unexceptional (Scheme 39). The immediate biogenetic precursor of minovincine could be 20,21-didehydro-19-oxosecodine(247) and the synthesis of such a base is therefore of considerable interest. Yet another application of Kuehne's synthesis has resulted in the prepara- tion of (247); this constitutes the first example of a stabilized secodine intermediate and it affords another synthesis of minovincine (Scheme 40).l 52b Basically the route follows that illustrated in Scheme 39 and proceeds via the vinylogous amide (248) and (249) [cf (244) and (245)].Quaternization and fragmentation of (249) gave 20,21-didehydro-l9-oxosecodine (247) which is a stable base of m.pt. 155-156 "C.Subsequent NATURAL PRODUCT REPORTS 1985 HI C02Me QyQA H Me CO,Me eOzMe (243) CH,COMe 1 iii viii ix a-$l +\ \ %OMe NCHzPh xii xiii COtMe / -COMe Minovincine (239) C0,Me Reagents i THF heat; ii NEt, MeCN heat for 24 h; iii 20%H2S0, HzO MeOH for 18h at r.t.; iv NaOCH=CHCOMe HCl Et,O THF (or HCECCOMe MeCN); v HCl THF; vi Cl[CHzJ31 THF for 48 h at r.t.; vii NEt, PhMe heat for 26 h; viii NaI MeCOMe; ix KOBu' at r.t.; x PhCH2Br THF; xi NEt, MeOH heat for 2 h; xii Hz Pd/C AcOH; xiii Cl[CH,],I KzC03 PhH heat for 7 h Scheme 39 Ll iv-vi 0 \ viii -H CO,Me ___* 1 I ,COMe %OMe \ c1-H H C0,Me H COzMe COzMe (247) Minovincine (239) Reagents i 20% HCl EtzO MeOH for 4 h; ii TsOH PhH for 2 h remove water azeotropically; iii PhSH NEt, CHCI, at 0 "C; iv N-chlorosuccinimide CCl, at O "C; v NEt, CHC13 heat for 1.5 h; vi NaIO, MeOH HzO; vii K2C03 THF at 20 "C for 4 days; viii THF HCl; ix THF for 48 h; x NEt, MeOH at 67 "C for 45 minutes; xi xylene heat for 24 h Scheme 40 NATURAL PRODUCT REPORTS 1985 -J.E. SAXTON thermal cyclization then afforded minovincine (239) in 77% yield. A total synthesis of (k)-l 1-methoxytabersonine (250) fol- lows an ingenious and conceptually original approach to the construction of the pentacyclic aspidospermine framework which makes use of an aza-Cope rearrangement in its critical stage.153 Thus the intermediate (251) which contains the desired cis ring-junction reacts with paraformaldehyde to give an oxazolidine (252) which rearranges thermally without added acid and subsequently cyclizes to 11-methoxy-1,2,14,15-tetradehydroaspidospermidine (253) in a very high-yielding completely stereospecific process. It is suggested that traces of formic acid in the reaction mixture catalyse the formation from the oxazolidine (252) of (254); this undergoes an aza- Cope rearrangement with formation of an enol-immonium ion (255) which is ideally set up for an intramolecular Mannich reaction.Imine formation completes the sequence of reactions to the observed product (253). Finally methoxycarbonylation with LiNPrj? and methyl chloroformate gives 1l-methoxytaber-sonine (250) (Scheme 41).l 53 An extension of earlier work by Szhntay and his collabora- tors has resulted in two further stereoselective syntheses of vincamine and related alkaloids. l 549 55 In both routes C-16 and C-17 originate from methylenemalonic ester which is added to an appropriate enamine. In the first of these syntheses the substrate was Wenkert's enamine [the base corresponding to (256)] and the cis Michael adduct (257) was elaborated as far as the oximino-ester (258) which was then resolved.Trans- esterification followed by hydrolysis and cyclization then gave (+)-vincamine (259) and (+)-apovincamine (260) (Scheme 42).154 By means of X-ray crystal structure analysis the (-)-oximino-ester (258) was shown to exist in the oxime form as illustrated rather than the cyclic form which is preferred in the corresponding keto-esters e.g. vincamine. V ___t 71 In the second synthesis,' 55 stereochemical control was achieved by use of an enamine [the base from (261)] that is related to Wenkert's enamine but derived from L-tryptophan. Addition of methylenemalonic ester was almost completely stereospecific; hydrolysis and decarboxylation then gave an immonium salt (262) which lost the carboxyl group from the tryptophan moiety comparatively readily.Further elaboration of the product gave the pentacyclic lactam (263) which has previously been converted into (+)-vincamine (259) and apovincamine (260). 55 For this last transformation an improved procedure has been developed (Scheme 42). 56 Three new preparations of Oppolzer's aldehyde (264) constitute three more formal syntheses of vincamine. 57 58 Two of these syntheses have been contributed by Langlois et al. and one of them is summarized in Scheme 43. Here the important lactam (265) is neatly obtained by a regiospecific photochemical rearrangement of a spiro-oxaziridine (266) prepared by oxidation of the imine derived from tryptamine and the simple keto-ester (267).57 4.7 Catharanthine-Ibogamine Group Voacangine hydroxyindolenine has been isolated from the ground bark of Peschiera fuchsiaefolia (DC.) Miers and the presence of voacangine has been confirmed. O7 Voacristine hydroxyindolenine occurs in Anacampta angulata (Mart.) Mgf. which is a species whose botanical classification seems to be in dispute.lS9 However the presence of this alkaloid is not inconsistent with its inclusion in the tribe Tabernaemontaneae of the family Apocynaceae. Examination of the leaves of Tabernaemontana dichotoma has revealed the presence of 19-epi- iboxygaine and 19-epi-voacristine ;lo6 the seeds of this species contain coronaridine ibogamine and voacangine.vi -SMe Et -SOPh + vii-ix ONHCoBu' OMe doSiMe3 NHCOBu' x xi 1 0"". OMe (251) xii xiii t t- ONH2 OMe (252) \ (253) 0,Me (250) Reagents i PhSCHCICH2CH2Cl ZnBr2 CH2C12 at 25°C; ii NaI MeCOEt under argon heat; iii NH, CHCl, at r.t. for 2 days; iv CIC02Me PhNEt, PhMe; v rn-chloroperbenzoic acid CHCl,; vi o-C6H4Cl2 CaC03 at 165 "C; vii BuLi THF at -78 "C; viii HCl H20 Et20( at 0 "C; ix Li80H MeOH at r.t.; x Ph,PMe+ Br- BuLi THF; xi 40%KOH MeOH heat for 8 h; xii (CH20), PhMe Na2S04; xiii heat for 6 h; xiv LiNPr'* ClC0,Me; THF at -78 "C. Scheme 41 NATURAL PRODUCT REPORTS 1985 (257) iv v I +- H H ( + )-Apovincamine (260) EtO,C-C-CH 11NOH i kt (261) (258) ii viii ix vi vii 1 C-3 epimer Reagents i H,C=C(CO,Et), KOBu' CH,CI,; ii H2 10% Pd/C DMF; iii KOH H,O EtOH at r.t.; iv NaNO, AcOH; v D-dibenzoyltartaric acid CH,CI,; vi NaOMe MeOH under nitrogen heat for 4 h; vii 5% H2S04 AcOH H20 heat for 2 h; viii 10% HCI H,O EtOH heat for 24 h; ix NaOH EtOH H20 at r.t.; x decalin at 16&170 "C for 30 minutes; xi P0Cl3 at r.t.for 2-3 days; xii Bu'ONO Bu'OK PhMe under nitrogen; xiii TsOH AcOH (CH,O), heat for 5 h; xiv ButOK MeOH at r.t. for 2 h Scheme 42 i ii &:,Me -(266) Tacamonine (272) R=H 17-Hydroxytacamonine (273) R4H 1iii iv -viii .'Et OH Et C02Me H H (264) (265) 16,17-Didehydrotacamine (274) Reagents i Tryptamine PhMe 4A molecular sieves at 40 "C; ii M-chloroperbenzoic acid at 0°C; iii hv MeCN at r.t.; iv POCl, MeCN; v NaBH, MeOH at -70 "C; vi chromatographic separation; vii LiAIH, THF; viii SO3 pyridine NEt, DMSO under argon Scheme 43 1.(276) R'=H R2=Et (277) R'=Et R2=H (279) R=H (278) R'=Et R2=OH (280) R=OH 18 The presence of tacamine (268) in the leaves of Tabernaemon-tana egfandufosa Stapf has previously been noted.45 The full R3 paper' l9 records the isolation of a total of 22 alkaloids from the leaves twigs and stem bark of which twenty (including twelve Tacamine (268) R1=CO,Me R2=OH R3=H new ones) belong to this group. Seven of these new alkaloids 16-epi-Tacamine (269) R1=OH R2=C0,Me R3=H belong to the tacamine (pseudovincamine) sub-group and have (270) R'=OH R2=R3=H (271) R1=R3=H R2=OH structures (269)-(275). Three cleavamine derivatives were also (19S)-19-Hydroxytacamine (275) R1=CO,Me R2=R3=OH encountered; these are the known compounds (+)-(20R)- NATURAL PRODUCT REPORTS 1985 -J.E. SAXTON H H It H Dichomine (281) I (14S 20R)-Velbanamine (282) Scheme 44 15,2O-dihydrocleavamine (276) and (-)-(2OS)-l5,20-dihydro-cleavamine (277) and a new base tentatively identified as (14S,20R)-velbanamine (278). The pseudoaspidospermidine group was represented by (+)-(20R)-1,2-didehydropseudoaspi-dospermidine (279) and (208-20-hydroxy- lY2-didehydropseu- doaspidospermidine (280) (both new) and (20R)- and (2051- pseudovincadifformine. An iboga alkaloid of novel type whose structure was divulged later (see below) was also isolated and the list is completed by the known bases coronaridine 11- hydroxycoronaridine and ibogamine.The isolation of eight bases of the tacamine group in this study poses an interesting chemotaxonomic problem since they have not been found in previous extractions of this species nor in any other species of the genus Tabernaernontana.The reasons for this are not clear but it is suggested that the plant material that was used from Cameroun may belong to a different race from the Nigerian and Tanzanian plants that had previously been investigated or it may be that during twenty years of cultivation in the Netherlands the climatic conditions and different nature of the soil had induced some subtle changes in the biosynthesis of secondary metabolites. l9 The novel iboga alkaloid from Tabernaernontanaeglandulosa has also been found and in somewhat greater amount in the leaves of T.dichotorna and has been named dichomine.160 A complete analysis of its proton and 13C n.m.r. spectra reveals that it has the structure (281); this structure together with the relative stereochemistry shown here was confirmed by the coupling constants of all of the signals in the 300 MHz proton n.m.r. spectrum and by comparison with expected values derived with the aid of a Dreiding model. The absolute configuration was assumed to be 14s since all known Tabernaernontanaalkaloids have this configuration. Proof was obtained by reduction of dichomine (281) with lithium aluminium hydride which gave (14S,20R)-velbanamine (282) presumably by the mechanism shown in Scheme 44.The rather strained ring system in dichomine (281) may well originate from an alkaloid such as (20R)- 1,2-didehydr0-20-hydroxypseu-doaspidospermidine (283) [the epimer of (280)] by a series of simple Mannich processes and prototropic shifts as outlined in Scheme 44.6o A new alkaloid from Strychnos ngouniensis has been shown by X-ray crystal structure determination of its p-bromoben- zoate to be (+)-16-hydroxyalloibogamine(284) and is the first CHO Ngouniensine (175) (285) -n VY HO 16-Hydroxyalloibogamine (284) (286) Scheme 45 natural iboga alkaloid of the a110 series to be discovered;161 furthermore it is remarkable in being racemic. One possibility for its biogenetic origin is that it could be derived from ngouniensine (175) which is the major alkaloid of this plant.Oxidation of ngouniensine (1 75) could generate the aldehyde (285) in which both C-3 and C-16 are epimerizable. Oxidation of (285) to the enamine (286) followed by cyclization and reduction then gives 16-hydroxyalloibogamine (284) (Scheme 45).’6’ The oxidation of coronaridine (287) by a variety of oxidizing agents has been examined. 16* Oxidation with potassium permanganate proceeds rapidly and gives a mixture of six compounds namely 5-hydroxy-6-oxocoronaridine(288) 3-oxocoronaridine (289) 5-oxocoronaridine (290) coronaridine hydroxyindolenine (291) and its 3-0x0-derivative (292) and a neutral compound (lacking an indole ring) which was postulated to be (293). Oxidation with manganese dioxide is much slower and gives four products which are (288) and (292) and two bisindole bases identified as (294) and (295).Oxidation with iodine gave a mixture of (289) (290) and 3-hydroxycoronaridine (296) and selenium dioxide gave only 6- oxocoronaridine (297). Oxidation with hydrogen peroxide or NATURAL PRODUCT REPORTS 1985 R3 uR2 Coronaridine (287) R' = R2 = R3 = H2 (288) R' = H2 R2 = H,OH R3 = 0 (289) R' = 0 R2 = R3 = H (290) R' = R3 = H1 R2 = 0 (296) R' = H,OH R2 = R3 = H2 (297) R' = R2 = HZ,R3 = 0 Et H MeOX (291) R = H2 (292) R = 0 -(293) with rn-chloroperbenzoic acid gave the same three products which were shown to be coronaridine hydroxyindolenine (291) coronaridine N,-oxide and coronaridine hydroxyindolenine N,-oxide.62 The synthesis of cleavamine by Imanishi et al. has been described in detail149 and a new synthesis of desethylcathar- anthine has been reported.163 5 Bisindole Alkaloids The first bis-carbazole alkaloids to be isolated have been found in Murraya euchrestijolia Hayata. 64-65Murrafoline from the root bark is a racemic alkaloid of structure (298) which was determined by X-ray crystal structure analysis. Murrafoline is clearly composed of a girinimbine unit attached to cycloma- hanimbine two monomeric carbazoles that occur in the same plant. 64 Bismurrayafoline-A (299) and bismurrayafoline-B (300) are dimeric species derived from the monomers murrayafoline-A (301) and murrayafoline-B (302); these monomers also occur in M.euchrestijolia. Bismurrayafoline-A has an unsymmetrical structure which is cleaved by hydrogenolysis (Pd/C-H2 in MeOH/HC02H) to give solely murrayafoline-A (301). Bismur- rayafoline-B (300) is a symmetrical dimer. 165 In a search for mycotoxins in species of the genus Chaetomium three isomeric bisindolylbenzoquinones have been isolated. The structure of cochliodinol (303) from C. cochliodes Palliser and C. elatum Kunze ex. Fr. was elucidated earlier and it has now been shown that isocochliodinol from C. murorum Corda has the isomeric 6,6'-disubstituted structure (304) and that neocochliodinol from C. amygdalisporum Udagawa et Muroi is the 7,7'-disubstituted isomer (305). 166 Murrafoline (298) QJ-DMe I OMe CH, / Bismurrayafoline-A (299) A Bismurrayafoline-B (300) OH Cochliodinol (303) R' = CH2CH=CMe2 R' = R3 = H Isocochliodinol (304) R' = R3 = H R2 = CH2CH=CMe2 Neocochliodinol (305) R' = R2 = H R3 = CH2CH=CMe2 Two alkaloids that are found in the wood of Picrasma quassioides Bennet prove to be dimeric P-carboline bases and are the first to be encountered from natural sources.The structures were shown to be (306)23a and (307),23b mainly on the basis of a detailed analysis of their n.m.r. spectra and by comparison with those of monomeric P-carbolines found in the same plant. New extractions of the leaves of Strvchnos usambarensis have resulted in the isolation of two novel quaternary alkaloids,16' which were separated and purified by the technique of droplet countercurrent chromatography for polar compounds.These two alkaloids were identified from their spectra and by comparison with authentic samples as the N,-methyl quater- nary derivatives (308) and (309) of 10-and 11-hydroxy-usam barine. NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON OMe OMe (307) (306) (308) R' = OH,R2 = H (309) R' = H,R2 = OH Several bases of the usambarensine group have been found among the 46 alkaloids of Aspidosperma marcgravianum.68 (17R)-4',5',6,17-Tetrahydrousambarensine N-oxide (3 10) and (17R)-N4'-carbomethoxy-4',5',6' 17-tetrahydrousambarensine (311) and the corresponding ethyl ester (312) are new and usambarensine (1 7R)-4,5',6' 17-tetrahydrousambarensine (3 13) (1 7S)-4',5',6',17-tetrahydrousambarensine (3 14) 5',6'-dihydrousambarensine (3 13 and ochrolifuanine A were found in the genus Aspidosperma for the first time.68 The root and stem barks of Strychnos longicaudata Gilg.and S. ngouniensis Pellegr. contain a number of Corynanthe+-carboline Strychnos-Corynanthe and bis-strychninoid alka- loids. The presence of longicaudatine in these and several other species of the genus Strychnos was recorded earlier ;45 recently eight other bisindole bases have been found four in each of these species.60 The alkaloids of S. ngouniensis are the two epimers 4',17-dihydro-l7PH-tchibangensine (3 13) and 4',17- dihydro-l7aH-tchibangensine(3 14) together with their 10'- hydroxy-derivatives [(3 16) and (3 17)]. Those from S. longicau-data are longicaudatine Y (3 18) and longicaudatine F (3 19) (which are new) nordihydrotoxiferine (320) and bisnor C- alkaloid H (321).60 Matopensine (322) (a new alkaloid from S.matopensis S. Moore and S. kusengaensis De Wild from Zaire) is a symmetrical dimer presumably resulting from the formation of a bis-carbinolamine from two molecules of the desoxy-Wieland-Gumlich aldehyde followed by dehydration. 16* Com-plete decoupling experiments and the identification of J values for the protons in the central oxygen-containing rings reveal that the configurations of the atoms in these rings are 2P-H 16P-H 2'P-H 16'P-H 17S and 17's. The molecule possesses a C2 axis of symmetry; the presence of a centre or plane of symmetry is excluded by the optical rotation [aID +lo5 O (MeOH).Matopensine is obviously very closely related to bisnordihydrotoxiferine (320) which also occurs in these Strychnos species. However it has not so far proved possible to interconvert these alkaloids ;prolonged treatment of matopen- sine (322) with an acid not surprisingly gives desoxy- Wieland-Gumlich aldehyde. 168 Acetylation of N in one of the molecules of desoxy- Wieland-Gumlich aldehyde would of necessity prevent the formation of a second N,-C-17 bond. Formation of a carbinolamine followed by dehydration would then give (323) which is the structure that has been deduced for a new alkaloid isolated from the root bark of S. variabilis de Wild. also from (310)R' = R2 = H; 17R;N,t-oxide (311) R1 = CO,Me R2 = H; 17R (312) R' = C02Et R2 = H; 17R (313) R' = R2 = H; 17R (314)R' = R2 = H; 17s (315) R2 = H;4',17-didehydro Longicaudatine Y (318)R = H (316) R' = H R2 = OH; 17R Longicaudatine F (319)R = OH (317)R' = H R2 = OH; 17s Nordihydrotoxiferine (320)R = H Bisnor C-alkaloid H (321)R = OH Matopensine (322) 16,17-Didehydroisostrychnobiline (323) Zaire.169a On the basis of a detailed lH n.m.r.analysis the configuration that has been deduced for 16,17-didehydroiso-strychnobiline (323) is 16'R,17'S. As expected from this formulation acid hydrolysis gives retulinal (324) and isoretu- linal (its C-16 epimer) together with their deacetyl derivatives. 12'-Hydroxystrychnobiline(325) is a new alkaloid from the same plant which is hydrolysed to deacetylretuline (326) and a mixture of 12-hydroxyretulinal and 12-hydroxyisoretulinal.69b Clearly C-16 has the Sconfiguration in 12'-hydroxystrychnobi- line; the configuration at the other centres deduced from the proton n.m.r. spectrum is 16S,17'R. A new type of bisindole alkaloid is represented by vobparicine (327) a minor constituent of the root bark of Tabernuemontanu chippii (Stapf) Pichon. 70 This molecule arises by union of apparicine (328) with vobasinol(329) and a partial synthesis by this route was carried out as proof of its structure (Scheme 46). The configuration at C-22 follows from the observation of nuclear Overhauser effects between the proton at C-22 and that at N,' and between the proton at C-3' and that at N,; no n.0.e. was observed between the proton at C-3' and 14a-H as would be expected on the basis of the structure and stereochemistry shown in structure (327).Fl H+yN* H Ac H \NW Deacetylretuline (326) 12'-Hydroxystrychnobiline (325) Vobasinol (329) r-i Apparicine (328) Reagents i 1.5% HCI MeOH under nitrogen heat for 2 h Scheme 46 Five of the six antimicrobial alkaloids of Aspidosperma excelsum are bisindole bases and were identified as ochro- lifuanine A tetrahydrosecamine 16-decarbomethoxytetrahy-drosecamine 16-hydroxytetrahydrosecamine,and 16-hydroxy- 16-decarbomethoxytetrahydrosecamine.73 The bark of Peschieru fuchsiuefoliu contains decarbomethoxy- voacamine demethylvoacamine and voacamidine and the presence of voacamine has been confirmed.107 Three new alkaloids have been isolated from the alkali- soluble fraction of extracts of Huplophyton cimicidum.17 Cimilophytine (330) represents a new type of bisindole alkaloid in which a dehydrocimicidine unit is attached to an unrear- ranged canthiphytine component.' la In norisohaplophytine (33 1) and haplocidiphytine (332) the dehydrocimicidine unit is attached to a rearranged canthiphytine unit as in haplophytine itself.lb Norisohaplophytine differs from haplophytine only in the absence of the N,-methyl group and in the position of the isolated double-bond in the Aspidospermu unit. Haplocidiphy- tine is the counterpart of cimilophytine in the rearranged haplophytine group the two bases exhibiting the same substitution pattern in the Aspidospermu unit.The stereoche- mistry of these alkaloids has not yet been fully elucidated; that depicted here is based on the stereochemistry of the other alkaloids of the Aspidospermu-canthinone group. 71b A new alkaloid (+)-kopsoffine from the roots of Kopsiu oficirzulis has the structure (333) and was partially synthesized by condensation of (+)-eburnamine (334) (contaminated with 16-isoeburnamine) and (-)-kopsinine in the presence of acid (Scheme 47).172 As in the case of vobparicine the monomers involved in this partial synthesis co-occur with the bisindole alkaloid in the plant; however the condensation conditions are such that in both cases it is considered extremely unlikely that the bisindole bases are artifacts. It should be noted that the eburnane component in (+> kopsoffine has the opposite configuration to that in (-> pleiomutine.172 NATURAL PRODUCT REPORTS 1985 Me HO' MeO\ \ HO rh COEt nR' Norisohaplophytine (331) R' = R2 = Me R3 = H Haplocidiphytine (332) R1 = R2 = H R3 = COEt (+)-Eburnamine (334) I H+V+d ,/' it ___+ + H H E02Me 60,Me (-)-Kopsinine (335) (+)-Kopsoffine (333) Reagents i 2% HCl MeOH heat for 4 h Scheme 47 %C02Me "p Me0 H u Callishiline (336) Guillauminine (C40H48N402) is a bisindole alkaloid of Melodinus guilluuminii which very probably belongs to the Aspidospermu-Eburneu group but its structure has not yet been elucidated.79 The structure of callichiline (336) which was first isolated in 1959 from Cullichiliu subsessilis Stapf has at last been revealed by X-ray crystal structure analysis; its 13Cn.m.r.spectrum has also been studied in detail and all of the signals have been assigned.173 Callichiline may well arise in the plant from a bisindole base derived from beninine and 1 l-demethoxy-vandrikine by rearrangement of the beninine-derived unit to the andrangine-like component of (336).l 73 NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON Although plant cell suspension cultures are an excellent source of monomeric monoterpenoid alkaloids the formation of bisindole alkaloids in cultured cells appears not yet to have been uniquivocally established. The isolation of voafrine A (337) and voafrine B (338) from the cell suspension culture of Voacanga africana Stapf is therefore of considerable interest.74 These bases are 3’-epimers and are probably biosynthesized from tabersonine via the coupling of the isomeric A3(14)-enamine with the corresponding immonium salt. In passing it may be noted that a dimer of tabersonine was isolated from the root bark of Crioceras dipladeniiJorus in 1973,175 but nothing is known of its structure beyond the fact that the union of the tabersonine components appears not to involve aromatic positions. It is possible that this ditabersonine is identical with one of the voafrine epimers but this remains to be proved. -/ H *‘Et \/ ‘ N‘ H &O,Me Voafrine A (337) 3’a-H Voafrine B (338) 3’b-H H‘ Roseadine (339) (V = 10-vindolinyl) Reagents i 40% H2S0, H20 at r.t.for 30 minutes Scheme 48 CICO[CH,],C02Me Me3SiC-CCO[CH2],C0,Me I ii-v A rapid procedure for the extraction of vinblastine from the leaves of Catharanthus roseus has been described. 32 Three new alkaloids of the vinblastine group have been isolated from the leaves of C. roseu~.~~~ Roseadine (339) however is not an entirely new compound since it had been prepared earlier by Wenkert and his collaborators1 77 by rearrangement of leurosine (340) with aqueous sulphuric acid (Scheme 48). The structure that was proposed by Wenkert et al. has been confirmed mainly on the basis of a detailed analysis of the mass and n.m.r. spectra of roseadine but the 2 configuration of the double-bond as depicted in (339) is now preferred.76 Similarly on the basis of a detailed examination of the 13Cn.m.r. spectra the structures of pleurosine (leurosine N,’-oxide) and vindolicine were also confirmed. The structures of the other two alkaloids that were isolated in this study i.e. roseamine and pericathidine have not yet been divulged. The cytotoxic activity of pleurosine was assayed in several anti-cancer test systems and it was shown to be particularly active in two systems in vivo these being P-388 lymphocytic leukaemia and B-16 melanocarcinoma. Roseadine was also active in the P-388 test system but was not tested further. 76 A detailed study of the proton n.m.r. spectra of (20S)-20’-deoxyvinblastine and its N,’-borane complex has also been published.’ 78 6 Biogenetically Related Quinoline Alkaloids 6.1 Cinchona Group Quinidine and dihydroquinidine are among the 46 alkaloids of Aspidosperma marcgravianum;68 although these alkaloids are demonstrably monoterpenoid in origin it appears to be the first time that they have been found co-occurring with typical monoterpenoid alkaloids.Quinidine one of the minor constituents of the bark of Cinchona ledgeriana which is used in the treatment of cardiac ailments can be prepared in 50% yield by the microbiological reduction of quininone using Hansenula anomala var. schneg-gii. 79 Only two organisms out of 450 that were tested were able to achieve this conversion; of these the Hansenula species gave the better conversion. 6.2 Camptothecin Details of Kametani’s synthesis45 of ( f)-camptothecin by the double enamine annelation route have been published.180 The latest formal synthesis of ( & )-camptothecin (341) was developed during an exercise to demonstrate the utility of an ingenious new route to indolizin-5-ones (Scheme 49). l8 This GN*iMe 0 0 (344) VIII ix 1.. Camptothecin (341) (345) Reagents i Me3SiC-CSiMe3 AICl, CH2C12 at 0 “C,ii HOCH2CH20H,TsOH PhH heat; iii NaOH H20 MeOH; iv (COCI), PhH DMF at r.t.; v NaN, MeCN heat for 0.5 h; vi Me,SiC-CCHzCH2Me (343) CpCo(CO), rn-xylene hv heat for 3-5 h; vii Et,CO, KH PhMe; viii (CO,H), EtOH H,O; ix o-H2NC6H4CH=NC6H4Me-p TsOH PhMe Scheme 49 18 NATURAL PRODUCT REPORTS 1985 involves the [2 + 2 + 21 cycloaddition of a 5-isocyanatoalkyne 26 W.Steglich L. Kopanski M. Wolf M. Moser and G. Tegtmeyer (342) to disubstituted alkynes e.g. (343) catalysed by cyclopen- Tetrahedron Lett. 1984 25 2341. tadienylcobalt dicarbonyl. The product in this particular 27 L. Lumonadio and M. Vanhaelen Phytochemistry 1984 23 453. reaction consisted of 68%of the indolizinone (344) and only 5% 28 T. Ohmoto and K. Koike Chem. Pharm. Bull. 1984 32 170. of its regio-isomer in which the propyl and trimethylsilyl groups 29 L. A. Anderson A. Harris and J. D. Phillipson J. Nut. Prod. 1983 46 374. are reversed. The orientation observed in structure 30 J. Bergman Heterocycles 1984 21 404. (349 with the trimethylsilyl group a to the amide linkage was 31 S. Sekita K. Yoshihira and S. Natori Chem. Pharm. Bull. 1983, preferred in all of the reactions that were investigated even 31 490.when the other alkyne substituent was the sterically demanding 32 T. Sjoblom L. Bohlin and C. Christophersen Acfa Pharm. Suec. tertiary butyl group; this appears to point to the operation of a 1983 20 415. stereoelectronic effect that is peculiar to silicon. Elaboration of 33 P. Muthusubramanian J. S. CarlC and C. Christophersen Acta (344) by unexceptional methods then gave the tetracyclic Chem. Scand. Ser. B. 1983 37 803. pyridone (349 which is a pivotal intermediate in several 34 T. Hino T. Tanaka K. Matsuki and M. Nakagawa Chem. earlier syntheses of camptothecin (341).’* Pharm. Bull. 1983 31 1806. 35 M. D& de Maindreville J. Levy F. Tillequin and M. Koch J. Nut. Prod. 1983 46 310.7 References 36 E. Yamanaka N. Shibata and S. Sakai Heterocycles 1984 22 1 (a) ‘The Monoterpenoid Indole Alkaloids‘ ed. J. E. Saxton 371. Wiley-Interscience New York 1983; (b)‘The Alkaloids’ ed. A. 37 J. E. Saxton in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Brossi Academic Press New York 1983 Vols. 21 and 22. Periodical Reports) The Royal Society of Chemistry London 2 R. Verpoorte T. A. van Beek R. L. M. Riegman P. J. Hylands 1981 Vol. 11 (a) p. 153; (b) p. 173. and N. G. Bisset Org. Magn. Reson. 1984 22 328. 38 K. Kawai K. Nozawa S. Nakajima and Y. Iitaka Chem. Pharm. 3 J. Helmlinger T. Rausch and W. Hilgenberg Physiol Plant. Bull. 1984 32 94. 1983 58 302. 39 S. Sakai N. Aimi K. Yamaguchi Y. Hitotsuyanagi C. 4 R. M. Acheson G. N. Aldridge M. C. K. Choi J.0.Nwankwo Watanabe K. Yokose Y. Koyama K. Shudo and A. Itai Chem. M. A. Ruscoe and J. D. Wallis J. Chem. Res. 1984 (5‘) 101;(M) Pharm. Bull. 1984 32 354. 1301 40 J. E. Saxton in ‘The Alkaloids’ ed. M. F. Grundon (Specialist 5 I. T. Hogan and M. Sainsbury Tetrahedron 1984 40 681. Periodical Reports) The Royal Society of Chemistry London 6 D. P. Mulvena K. Picker D. D. Ridley and M. Slaytor 1983 Vol. 13 (a)p. 205; (b)p. 213; (c)p. 216; (d) p. 224; (e)p. 243. Phytochemistry 1983 22 2885. 41 Y. Endo K. Shudo K. Furuhata H. Ogura S. Sakai N. Aimi Y. 7 M. Mukherjee S. Mukherjee A. K. Shaw and S. N. Ganguly Hitotsuyanagi and Y. Koyama Chem. Pharm. Bull. 1984,32,358. Phytochemistry 1983 22 2328. 42 See for example N. Sakabe H. Harada Y. Hirata Y. Tomiie 8 P. Bhattacharyya and A.Chakraborty Phytochemisrry 1984 23 and I. Nitta Tetrahedron Lett. 1966 2523. 471. 43 K. K. Janardhanan A. Sattar and A. Husain Can. J. Microbiol. 9 S. Roy L. Bhattacharyya and D. P. Chakraborty J.Indian Chem. 1984 30,247. Soc. 1982 59 1369. 44 V. G. Sakharovsky and A. G. Kozlovsky Tetrahedron Lett. 1984 10 T. S. Wu T. Ohta H. Furukawa and C. S. Kuoh Heterocycles 25 109. 1983 20 1267. 45 J. E. Saxton Nat. Prod. Rep. 1984 1 21. 11 P. Bhattacharyya and B. K. Chowdhury Chem. Ind. (London) 46 H. Muratake T. Takahashi and M. Natsume Heterocycles 1983 1984 301. 20 1963. 12 J. E. Saxton in ‘The Alkaloids’ ed. M. F. Grundon (Specialist 47 S. Nakatsuka T. Masuda K. Yamada and T. Goto Hetero-Periodical Reports) The Royal Society of Chemistry London cycles 1984 21 407.1982,Vol. 12,(a)p. 163;(b)p. 168;(c)p. 170;(d)p. 175;(e)p. 184; 48 A. P. Kozikowski Y. Y. Chen B. C. Wang and 2. B. Xu (r> p. 213. Tetrahedron 1984 40 2345. 13 K. Yamasaki M. Kaneda K. Watanabe Y. Ueki K. Ishimaru S. 49 J. Rebek D. F. Tai and Y. K. Shue J.Am. Chem. Soc. 1984,106 Nakamura R. Nomi N. Yoshida and T. Nakajima J.Antibiot. 1813. 1983 36 552. 50 W. Oppolzer J. I. Grayson H. Wegmann and M. Urrea 14 A. E. de Jesus P. S. Steyn F. R. van Heerden R. Vleggaar P. L. Tetrahedron 1983 39 3695. Wessels and W. E. Hull J. Chem. Soc. Perkin Trans. 1 1983 51 T. Kiguchi C. Hashimoto and I. Ninomiya Heterocycles 1984 1847; A. E. de Jesus C. P. Gorst-Allman P. S. Steyn F. R. van 22 43. Heerden R. Vleggaar P. L. Wessels and W. E. Hull ibid.p. 52 I. Ninomiya C. Hashimoto and T. Kiguchi Heterocycles 1984 1863. 22 1035. 15 P. A. Fellows N. Kyriakidis P. G. Mantle and E. S. Waight Org. 53 J. Benes A. Cerny V. Miller and S. KudrnaE Collect. Czech. Mass Spectrom. 1981 16 403. Chem. Commun. 1983 48 1333. 16 A. E. de Jesus P. S. Steyn F. R. van Heerden and R. Vleggaar J. 54 A. Cerny V. Zikan D. Vlckova J. Bene; J. Holubek K. Chem. Soc. Perkin Trans. I 1984 697. ReZabek M. AuSkova. and J. Kfepelka Collect. Czech. Chem. 17 R. T. Gallagher A. D. Hawkes P. S. Steyn and R. Vleggaar J. Commun. 1983 48 1483. Chem. Soc.. Chem. Commun. 1984 614. 55 L. Bernardi G. Bosisio S. Mantegani 0.Sapini A. Temperilli P. 18 B. Pech and J. Bruneton J. Nut. Prod. 1984 47 390. Salvati E. di Salle G. Arcari and G. Bianchi Arzneim.-Forsch.19 (a)C. Galeffi I. Messana and G. B. Marini-Bettolo J.Nat. Prod. 1983 33 1094. 1983,46,586;(b)A. L. Skaltsounis F. Tillequin M. Koch and T. 56 R. Rucman J. Korsic and M. Jurgec Farmaco Ed. Sci. 1983,38 Sevenet ibid. p. 732. 406. 20 M. Somei H. Sato and C. Kaneko Heterocycles 1983 20 57 I. R. C. Bick M. A. Hai V. A. Patrick and A. H. White Aust. J. 1797. Chem. 1983 36 1037. 21 A. 0.K. Nieminen H. Haataja M. Rautio and E. Rahkamaa J. 58 R. Kyburz E. Schopp and M. Hesse Helv. Chim. Acta 1984 67 Heterocycl. Chem. 1983 20 515. 804. 22 (a)A.M.A.G. Nasser and W. E. Court Phytochemistry 1983 22 59 T. Darbre C. Nussbaumer and H. J. Borschberg Helv. Chim. 2297; (b)M. Caprasse C. Coune and L. Angenot J.Pharm. Belg. Acta 1984 67 1040. 1983 38 135; (c)R.Bassleer J. M. Marnette P. Wiliquet M. C. 60 G. Massiot P. Thepenier M.-J. Jacquier J. Lounkokobi C. De Pauw-Gillet M. Caprasse and L. Angenot PIanta Med. 1983 Mirand M. Zeches L. Le Men-Olivier and C. Delaude 49 158. Tetrahedron 1983 39 3645. 23 T. Ohmoto and K. Koike Chem. Pharm. Bull. (a) 1982,30 1204; 61 J. Levesque R. Jacquesy and C. Merienne J. Nat. Prod. 1983 (b) 1983 31 3198. 46 619. 24 S. Luo and L. Mai Yaowu Fenxi Zazhi 1983,3 90 (Chem. Abstr. 62 A. 0. Adeoye and R. D. Waigh Phytochemistry 1983 22 2097 1983 99 136 824). 63 Atta-ur-Rahman and S. Malik J. Nat. Prod. 1984 47 388. 25 (a) K. L. Rinehart Jr. J. Kobayashi G. C. Harbour R. G. 64 (a) K. Endo Y. Oshima H. Kikuchi Y. Koshihara and H. Hughes Jr. S. A. Mizsak and T. A. Scahill J. Am. Chem. Soc.Hikino PIanta Med. 1983 49 188; (b)S. S. Handa R. P. Borris, 1984,104,1524;(b)J. Kobayashi G. C. Harbour J. Gilmore and G. A. Cordell and J. D. Phillipson J. Nat. Prod. 1983 46 K. L. Rinehart Jr. ibid. p. 1526. 325. NATURAL PRODUCT REPORTS 1985 -J. E. SAXTON 65 M. H. Brillanceau C. Kan-Fan S. K. Kan and H.-P. Husson Tetrahedron Lett. 1984 25 2767. 66 S. Mukhopadhyay A. El-Sayed G. A. Handy and G. A. Cordell J. Nut. Prod. 1983 46 409. 67 C. Kan S. K. Kan M. Lounasmaa and H.-P. Husson Acta Chem. Scand. Ser. B 1981 35 269. 68 G. M. T. Robert A. Ahond C. Poupat P. Potier C. Jollb A. Jousselin and H. Jacquemin J. Nut. Prod. 1983 46 694. 69 G. M. T. Robert A. Ahond C. Poupat P. Potier H. Jacquemin and S. K. Kan J. Nut. Prod. 1983 46 708.70 A. M. A. G. Nasser and W. E. Court PIanta Med. 1983,47,242. 71 X. Z. Feng C. Kan P. Potier S. K. Kan and M. Lounasmaa PIanta Med.. 1983 48 280. 72 W. M. Chen Y. P. Yan and X.T. Liang Planta Med. 1983,49 62. 73 R. Verpoorte E. Kos-Kuyck A. T. A. Tsoi C. L. M. Ruigrok G. de Jong and A. B. Svendsen PIanta Med. 1983 48 283. 74 J. D. Phillipson and N. Supavita Phytochemistry 1983,22 1809. 75 M. Lavault C. Moretti and J. Bruneton Planta Med. 1983 47 244. 76 E. Yamanaka Y. Kimizuka N. Aimi S. Sakai and J. Haginiwa Yakugaku Zasshi 1983 103 1028. 77 A. Chatterjee J. P. Dhara and J. Banerji J. Indian Chem. Soc. 1982 59 1360. 78 A. Malik and N. Afza J. Nut. Prod. 1983 46 939. 79 M. Ztches J. Lounkokobi B. Richard M. Plat L. Le Men- Olivier T.Sevenet and J. Pusset Phytochemistry 1984 23 171. 80 Atta-ur-Rahman and M. Bashir PIanta Med. 1983 49 124. 81 J. Stiickigt A. Pfitzner and J. Firl Plant Cell Rep. 1981 1 36. 82 W. E. Court Planta Med. 1983 48 228. 83 E. Seguin M. Koch A. Ahond J. Guilhem C. Poupat and P. Potier Helv. Chim. Acta 1983 66 2059. 84 R. P. Borris A. Guggisberg ind M. Hesse Helv. Chim. Acta 1984 67 455. 85 M. Onanga and F. Khuong-Huu Tetrahedron Lett. 1983,243627. 86 L. R. McGee G. S. Reddy and P. N. Confalone Tetrahedron Lett. 1984 25 2115. 87 J. Bosch M.-L. Bennasar E. Zulaica and M. Feliz Tetrahedron Lett. 1984 25 3119. 88 J. Bosch and M.-L. Bennasar Heterocycles 1983 20 2471. 89 V. S. Giri B. C. Maiti and S. C. Pakrashi Heterocycles 1984,22 233. 90 A.Shariff and S. McLean Can. J. Chem. 1983 61 2813. 91 M. J. Wanner G. J. Koomen and U. K. Pandit Tetrahedron 1983 39 3673. 92 T. Imanishi M. Inoue Y. Wada and M. Hanaoka Chem. Pharm. Bull. 1983 31 1551. 93 B. Danieli G. Lesma G. Palmisano and S. Tollari,J. Chem. Soc. Perkin Trans. 1 1984 1237. 94 G. Massiot and T. Mulamba J.Chem. Soc.. Chem. Commun. 1984 715. 95 G. Massiot and T. Mulamba J. Chem. Soc.,Chem. Commun. 1983 1147. 96 E. Yamanaka E. Maruta S. Kasamatsu N. Aimi and S. Sakai Tetrahedron Lett. 1983 24 3861. 97 E. Yamanaka M. Ono S. Kasamatsu N. Aimi and S. Sakai Chem. Pharm. Bull. 1984 32 818. 98 T. Naito Y. Tada Y. Nishiguchi and I. Ninomiya Heterocycles 1982 18 213. 99 0.Miyata Y. Hirata T. Naito and I. Ninomiya J. Chem.Soc. Chem. Commun. 1983 1231. 100 Cs. Szantay G. Blask6 K. Honty L. Szab6 and L. Toke Heterocycles 1977 7 155; Cs. Szantay L. Toke G. Blask6 K. Honty and L. Szabb Lect. Heterocycl. Chem. 1978 4 25; Cs. Szantay G. Blasko K. Honty L. Szab6 and L. Toke in ‘Indole and Biogenetically Related Alkaloids’ ed. J. D. Phillipson and M. H. Zenk Academic Press New York 1980 Ch. 11. 101 (a)Cs. Szantay G.Blasko K. Honty E. Baitz-Gacs and L. Toke Liebigs Ann. Chem. 1983 1269; (b) Cs. Szantay K. Honty G. Blasko E. Baitz-Ghcs and P. Kolonits ibid. p. 1278; (c) Cs. Szantay G. Blask6 K. Honty E. Baitz-Gh J. Tamas and L. Toke ibid. p. 1292. 102 0. Miyata Y. Hirata T. Naito and I. Ninomiya Heterocycles 1984 22 1041. 103 R. T. Brown and M. F. Jones Tetrahedron Lett.1984,25 3127. 104 G. Lesma G. Palmisano and S. Tollari J. Org. Chem. 1983,48 3825. 105 (a) A. Koskinen and M. Lounasmaa Fortschr. Chem. Org. Naturstofle 1983,43,267;(b)R. Verpoorte L. Bohlin D. Dwuma- Badu W. Rolfsen and J. Strombom J. Nut. Prod.. 1983,46 572. 106 P. Perera G. Samuelsson T. A. van Beek and R. Verpoorte Planta Med. 1983 47 148. 107 R. M. Braga H. F. Leitao Filho and F. de A. M. Reis Phytochemistry 1984 23 175. 108 (a)Atta-ur-Rahman I. Ali and M. Bashir J.Nut. Prod. 1984,47 389; (b) Y. Ahmad K. Fatima P. W. Le Quesne and Atta-ur- Rahman J. Chem. SOC.Pakistan 1979,1,69 (Chem. Abstr. 1980 92 177 386). 109 Atta-ur-Rahman and S. Khanum Phytochemistry 1984 23 709. 110 K. T. Il’yasova V. M. Malikov and S. Yu. Yunusov Khim.Prir. Soedin. 1970 717 (Chem. Abstr. 1971 74 95431); M. M. Khalmirzaev M. R. Yagudaev and S. Yu. Yunusov Khim. Prir. Soedin. 1980 426 (Chem. Abstr. 1980 93 146 303). 111 M. R. Yagudaev M. M. Khalmirzaev and S. Yu. Yunusov Khim. Prir. Soedin. 1983 483 (Chem. Abstr. 1984 100 99 867). 112 Atta-ur-Rahman I. Ali and M. Bashir Heterocycles 1984 22 85. 113 J. Yang and Y. Chen YaoxueXuebao 1983,18,104 (Chem. Abstr. 1983,99 102 248). 114 G. Massiot C. Lavaud J. Vercauteren L. Le Men-Olivier J. Levy J. Guilhem and C. Pascard Helv. Chim. Acta 1983 66 2414. 115 D. S. Grierson M. Harris and H.-P. Husson Tetrahedron 1983 39 3683. 116 J. A. 0. Ojewole Fitoterapia 1983 54 99. 117 P. Perera F. Sandberg T. A. van Beek and R. Verpoorte Planta Med. 1983 49 28.118 J. U. Oguakwa C. Galeffi I. Messana M. Patamia M. Nicoletti and G. B. Marini-Bettblo Gazz. Chim. Ital. 1983 113 533. 119 T. A. van Beek R. Verpoorte and A. B. Svendsen Tetrahedron 1984 40,737. 120 (a) F. C. Ohiri R. Verpoorte A. B. Svendsen J. Karlsen and A. Mostad J. Nut. Prod. 1983,46,369; (b)W. A. Chapya C. Galeffi M. Sperandei J. D. Msonthy M. Nicoletti I. Messana and G. B. Marini-Bettolo Gazz. Chim. Ital. 1983 113 773. 121 M. Ztches T. Ravao B. Richard G. Massiot L. Le Men-Olivier J. Guilhem and C. Pascard Tetrahedron Lett. 1984 25 659. 122 M. R. Yagudaev Khim. Prir. Soedin. 1983 210. 123 R. Verpoorte T. A. van Beek R. L. M. Riegman P. J. Hylands and N. G. Bisset Org. Magn. Reson. 1984 22 345. 124 T. A. Crabb and J. Rouse Org.Magn. Reson. 1983 21 683. 125 Y. Ban K. Yoshida J. Goto T. Oishi and E. Takeda Tetrahedron 1983 39 3657. 126 A. P. Duarte and E. C. Miranda An. Acad. Bras. Cienc. 1983,55 189 (Chem. Abstr. 1984 100 6911). 127 D. D. Weller and D. W. Ford Tetrahedron Lett. 1984 25 2105. 128 (a)M. G. Saulnier and G.W. Gribble Tetrahedron Lett. 1983,24 3831;(b)M. J. E. Hewlins A. M. Oliveira-Campos and P. V. R. Shannon Synthesis 1984 289. 129 V. K. Kansal S. Funakoshi P. Mangeney P. Potier B. Gillet E. Guittet and J. Y. Lallemand Tetrahedron Lett. 1984 25 2351. 130 H. Mehri C. Rochat S. Baassou T. Sevenet and M. Plat Planta Med. 1983 48 72. 131 W. D. Crow and M. Michael Aust. J. Chem. 1962 15 130. 132 Atta-ur-Rahman M. Bashir M. Hafeez N. Perveen J. Fatima and A.N. Mistry PIanta Med. 1983 47 246. 133 Atta-ur-Rahman M. Bashir S. Kaleem and T. Fatima Z. Naturforsch. Teil B 1984 39 695. 134 (a)Atta-ur-Rahman and N. Daulatabadi 2. Naturforsch. Teil B 1983 38 1310; (b) Atta-ur-Rahman A. Muzaffar and N. Daulatabadi ibid. p. 1700. 135 A. I. Reis Luz A. I. da Rocha B. Porter and E. Wenkert Phytochemistry 1983 22 2301. 136 B. Danieli G. Lesma G. Palmisano R. Riva and S. Tollari J. Org. Chem. 1984 49 547. 137 S. Mukhopadhyay G. A. Cordell G. A. Sim and P. J. Cox Tetrahedron 1983 39 3639. 138 B. Zsadon L. Decsei M. Szilasi F. Tudos and J. Szejtli J. Chromatogr. 1983 270 127 (Chem. Abstr. 1984 100 139 426). 139 J. Levy and F. Sigaut Tetrahedron Lett. 1983 24 4983. 140 R. Wen J. Y. Laronze and J. Levy Heterocycles 1984 22 1061.141 G. Huge1 and J. Levy Tetrahedron 1984 40 1067. 142 P. Magnus and P. Pappalardo J. Am. Chem. Soc. 1983,105,6525. 143 (a) F. S. Sariaslani F. M. Eckenrode J. M. Beale and J. P. Rosazza J. Med. Chem. 1984,27 749; (b) M. E. Eckenrode and J. P. Rosazza J. Nut. Prod. 1982 45 226; 1983 46 884. 144 P. Magnus J. Gallagher P. Brown and P. Pappalardo Acc. Chem. Res. 1984 17 35. 145 Atta-ur-Rahman and M. Sultana Heterocycles 1984 22 841. 146 E. Wenkert K. Orito D. P. Simmons N. Kunesch J. Ardisson and J. Poisson Tetrahedron 1983 39 3719; J. Org. Chem. 1983 48 5006. 147 Atta-ur-Rahman M. Sultana I. Hassan and N. M. Hasan J. Chem. Soc. Perkin Trans. I 1983 2093. 148 C. Exon T. Gallagher and P. Magnus J. Am. Chem.Soc. 1983 105,4739; T. Gallagher P. Magnus and J. C. Huffman ibid. p. 9750. 149 T. Imanishi H. Shin N. Yagi A. Nakai and M. Hanaoka Chem. Pharm. Bull. 1983 31 1183. 150 P. Magnus T. Gallagher P. Brown and J. C. Huffman J. Am. Chem. Soc. 1984 106 2105. 151 T. Imanishi K. Miyashita A. Nakai M. Inoue and M. Hanaoka Chem. Pharm. Bull. 1983 31 1191. 152 M. E. Kuehne and W. G. Earley Tetrahedron 1983 39 (a) p. 3707; (b) p. 3715. 153 L. E. Overman M. Sworin and R. M. Burk J. Org. Chem. 1983 48 2685. 154 L. Szabo J. Sapi G. Kalaus G. Argay A. Kalmin E. Baitz-Gacs J. Tamas and Cs. Szantay Tetrahedron 1983 39 3737. 155 L. Szabb J. %pi K. Nogradi G. Kalaus and Cs. Szantay Tetrahedron 1983 39 3749. 156 L. Szab6 G. Kalaus and Cs. Szantay Arch.Pharm. (Weinheim Ger.) 1983 316 629. 157 Y.Langlois A. Pouilhes D. GCnin R. 2. Andriamialisoa and N. Langlois Tetrahedron 1983 39 3755. 158 T. R. Govindachari and S. Rajeswari Indian J. Chem. Sect. B 1983 22 531. 159 J. Gamier J. Mahuteau and C. Moretti J. Nut. Prod. 1984,47 191. 160 P. Perera T. A. van Beek and R. Verpoorte PIanta Med. 1983 49 232. 161 G. Massiot M. J. Jacquier P. Thepenier J. LCvy L. Le Men- Olivier C. Delaude J. Guilhem and C. Pascard J. Chem. Soc. Chem. Commun. 1983 1018. 162 K. Rastogi R. S. Kapil and S. P. Popli Heterocycles 1983 20 2001. 163 Cs. Szantay T. Keve H. Bolcskei and T. Acs Tetrahedron Lett. 1983 24 5539. NATURAL PRODUCT REPORTS. 1985 164 A. T. McPhail T. S. Wu T. Ohta and H. Furukawa Tetrahedron Lett 1983 24 5377.165 H. Furukawa T. S. Wu and T. Ohta Chem. Pharm. Bull. 1983 31 4202. 166 S. Sekita Chem. Pharm. Bull. 1983 31 2998. 167 M. Caprasse D. Tavernier and L. Angenot J.Pharm. Belg. 1983 38,211. 168 J. Massiot B. Massoussa P. Thepenier M. J. Jacquier L. Le Men-Olivier and C. Delaude Heterocycles 1983 20 2339. 169 M. Tits L. Angenot and D. Tavernier (a)J.Pharm. Belg. 1983 38,241; (b) J. Nut. Prod. 1983 46 638. 170 T. A. van Beek R. Verpoorte and A. B. Svendsen Tetrahedron ' Lett. 1984 25 2057. 171 (a)A. A. Adesomoju V. H. Rawal M. V. Lakshmikantham and M. P. Cava J. Org. Chem. 1983,48 3015; (b) A. A. Adesomoju M. V. Lakshmikantham and M. P. Cava Heterocycles 1983,20 1511. 172 X.Z. Feng C. Kan H.-P. Husson P. Potier S.K. Kan and M. Lounasmaa J. Nut. Prod. 1984 47 117. 173 A. T. McPhail E. W. Hagaman N. Kunesch E. Wenkert and J. Poisson Tetrahedron 1983 39 3629. 174 J. Stiickigt K. H. Pawelka T. Tanahashi B. Danieli and W. E. Hull Helv. Chim. Acta 1983 66 2525. 175 J. Bruneton A. Bouquet and A. Cavk Phytochemistry 1973 12 1475. 176 A. El-Sayed G. A. Handy and G. A. Cordell J.Nut. Prod. 1983 46 517. 177 E. Wenkert E. W. Hagaman B. Lal G. E. Gutowski A. S. Katner J. C. Miller and N. Neuss Helv. Chim. Acta 1975 58 1560. 178 A. de Bruyn J. Sleeckx J. P. de Jonghe and J. Hannart Bull. Soc. Chim. Belg. 1983 92 485. 179 L. Ray C. Das Gupta and S. K. Majumdar Appl. Environ. Microbiol. 1983 45 1935. 180 M. Ihara K. Noguchi T. Ohsawa K. Fukumoto and T. Kametani J.Org. Chem. 1983 48 3150. 181 R. A. Earl and K. P. C. Vollhardt J. Am. Chem. Soc. 1983 105 6991.