14 ALKALOIDS By J. A. Joule (Chemistry Department University of Manchester Manchester M13 9PL) THEvolume' of 'The Alkaloids' published this year is devoted to updating previous chapters on steroidal (Solanurnand Veratrurn) Erythrophleurn Taxus Lycopodiurn benzylisoquinoline (tricyclic-monomeric and cularine types) papaveraceae u-naphthaphenanthridine and simple indole alkaloids and on the alkaloids of the Calebar bean Picralirna nitida Mitragayna and Ouruparia species together with a compilation of alkaloids of as yet unknown structures. Two books2V3 deal with alkaloids and reviews have appeared devoted to bisc~claurine,~ ipecac,6S~larnander,~ Rau ~ol$a,~ calebash curare,8 ~trychnine,~ and proaporphine" alkaloids. Pyrrolizidine Alkaloids.-Two bases nilgirine (1 ; R = H) and axillarin (2) from Crotalaria rnuoonata' 'and C.axzllarisl2 respectively with new variations in the necic acid portions of their structures have been isolated and character- ised. Nilgirine lacks the one-carbon unit [R = Me or CH20H in (l)] which Me ,OH I C0,Me b' (3) R H. F. Manske 'The Alkaloids,' Academic Press New York 1968 vol. X. W. Dopke 'Einfuhrung in die Chemie der Alkaloide,' Akademie-Verlag Berlin 1968. G. A..Swan 'An Introduction to the Alkaloids,' Blackwell Oxford 1967. J. Sakakibara Nagoya Shiritsu Daigaku Yakugakubu Kenkyu Nempo 1966 14,l. S. C. Pakrashi and B. Achari J. Sci. Znd. Res. 1968,27,58. C. Szanthy Recent Developments Chem. Natural Carbon Compounds 1967,2,65. ' G. Habermehl Progr. Org. Chern.1968,7 35. H. Schmid Bull. Schweiz. Akad. Med. Wiss. 1967,22,415. R. N. Chakravarti J. Inst. Chemists (India) 1968,40 85. lo K. L. Stuart and M. P. Cava Chem. Reo. 1968,68,321. C. K. Atal R. S. Sawhney C. C. J. Culvenor and L. W. Smith Tetrahedron Letters 1968 5605. l2 D. H. G. Crout Chem. Comm. 1968,429. 490 J. A. Joule when present in other related bases it is suggested,' is methionine-derived. The necic acid portion of axillarin it is proposed," may be biogenetically derived from valine and isoleucine (with loss of carbon dioxide). The pyrrolizidine ester (3) obtained from Chysis bracte~cens'~displays an intriguing U.V. absorption at 290 nm. (E 40),the cause of which is not known. Neither the corresponding sodium salt nor the lithium aluminium hydride reduction product (identical with the alkaloid lindelofidine) show this pheno- menon.Pyridine and Piperidine Alkaloids.-A detailed e~amination'~ of hemlock (main alkaloids coniine and y-coniceine) has shown that the alkaloids present in the living plant occur in part in bound forms with the remainder as simple salts. The concentration and location within the plant of bound forms varies during the day and according to the stage of the plant's development. These findings have suggested that in this plant at least the alkaloids may be intimately involved in the metabolism perhaps in some oxidation-reduction sequence resembling the role of the pyridine nucleotides. It is intriguing to speculate whether other alkaloid-bearing plants utilise their alkaloids whether of greater or lesser complexity in a metabolically more fundamental way than has hitherto been believed.The trimer (4) has been isolated'' from Nicotiana tabacum and the dimer (9,named hystrine and isolated'6a from Genista hystrix has been obtained by partial synthesis16b from ammodendrin. RD Myosmine (6;R = 3-pyridyl) and apoferrorosamine (6;R = 2-pyridyl) have been neatly synthesisedl' by acid-catalysed isomerisation of a cyclopropyl imine (7; R = 2-or 3-pyridyl) derived in turn by addition of the appropriate pyridyl lithium to cyclopropanecarbonitrile. Two intriguing variations on the monoterpene-pyridine theme are jasminine (8) from Jasminum speciesI8 and gentiaflavine (9) from Gentiana species.'' The B.Liining and H. Tranker Actu Chem. Scud. 1968 22,2324. l4 J. W. Fairbairn and A. A. E. R. Ali Phytochemistry 1968,7 1593,1599. Is T. Kisaki S. Mizusaki and E. Tamaki Phytochemistry 1968,7,,323. l6 (a)E. Steinegger C. Moser and P. Weber Phytochemistry 1968 7,849; (b)E. Steinegger and P. Weber Helv. Chim. Actu. 1968 51 206. '' R. V. Stevens M. C. Ellis and M. P. Wentland J. Amer. Chem. SOC., 1968.90 5576. Alkaloids 491 isolation of jasminine did not involve the use of ammonia and so one may be sure that this base containing two nitrogen atoms occurs naturally. The yellow alkaloid gentiaflavine has been ascribed the novel 1,2-dihydropyridine structure (9) mainly on the basis of its n.m.r. spectrum. Of0 I 0 MeO,C 0HC.p CH ” N HH 0 (8) (9) (10) Lupin Alkaloids-Lamprolobine (10) from Lamprolobium fruticosum2 co-occurs with cytisine.A biogenesis from three moles of lysine is suggested for the new base. Structurally useful mass spectral studies,’ have been made on the cytisine and lupanine types. When deoxyangustifoline (11; R = H,) was treated with formaldehyde in the presence of acid a salt (13) was formed,22 from which a crystalline perchlo- rate was obtained. The salt was stable to hot water and cold sodium hydroxide and required treatment with hot alkali to hydroryse it back to starting material. When boiled in acetic acid it was converted into 13-epiacetoxylupanine (12; R = H,) [the analogous amide (1 1 ;R = 0)gave a cyclised product (12 ;R = 0) directly on reaction with formaldehyde and acid].An X-ray analysis of the perchlorate of (13) showed that the bonds N(1&C( 17) and C(17)-N( 12) were not equal in length. The former is ascribed a bond order of 0.86 and the latter 1.13. The suggestion which is to be tested is that the methylene group in this salt may behave biologically like the ‘active formaldehyde’ of hydroxymethyl- tetrahydrofolic acid. N. K. Hart S. R. Johns and J. A. Lamberton Austral. J. Chem. 1968 21,1321. l9 N. L.Marekov and S. S. Popov Tetrahedron 196% 24,1323. ’O N.K.Hart S. R. Johns and J. A. Lamberton Austral. J. Chem. 1968 21,1619. ” D.Schiimann N. Neuner-Jehle and G. Spiteller Monatsh. 1967,98,836; 1968,9!9,390; M. Silva M. V.Medina and P. G. Sammes Phytochemistry 1968,7,661. 22 G. I. Birnbaum K.K. Cheung M. Wiewiorowski and M. D. Bratek-Wiewiorowska J. Chem. Soc. (B),1967 1368. 492 J. A. Joule Neat synthesesz3 of lupinine continue to appear ;onez3' involved the reaction of methyl pyridine-2-acetate with carbon suboxide to give a methoxycarbonyl- quinolizinone system suitable for elaboration. Isoquinoline Alkaloids.-The powerful combination of g.1.c. and mass spectrometry has been applied to extracts of Peyote cactusz4 and of Lophophora wiEliamsii2 and Trichocereus pa~hanoi.~ In this way it was possible to demon- strate the presence of minute quantities of partially methylated and oxygenated intermediates2' on the biosynthetic pathway from tyrosine to mescaline and the isoquinoline alkaloids. The presence of small quantities of many compounds for example peyonine (14) derived by interaction of mescaline with acids of the Krebs cycle was dem~nstrated.~~ From Cryptostylis fulva a l-phenyl- 1,2,3,4-tetrahydroisoquinolinealkaloid has been isolated26 for the first time.::q -aq. HC1 PhCH C0,H PhCH 23 (a)Th. Kappe Monatsh. 1967,96,1853; (b)E. Wenkert K. G. Dave and R V. Stevens J. Amer. Chem. Soc. 1968,!W 6177. 24 G. J. Kapadia and H. M. Fales Chem. Comm. 1968 1688. 25 S. Agurell and J. Lundstrom Chem. Comm. 1968 1638. 26 K. Leander and B. Luning Tetrahedron Letters 1968 1393. Alkaloids 493 In support of a suggestion27 that the biosynthesis of isoquinoline alkaloids involves peptide chains-the head turning and biting its tail-a model sequence (15) -+ (19) designed to simulate this process has been in~estigated.~' The compound (15) was treated with the masked phenylpyruvate (16) to give the diamide (17) which cyclised easily to a tetrahydroisoquinoline derivative (18) hydrolysis of which gave (19).Presumably if nature does indeed take a course analogous to this laboratory model then carboxy-benzylisoquinoline corn-pounds like (19) may well exist in benzylisoquinoline-producingplants. As aids for the elucidation of structures mass spectrometric studies have been carried out on tetrahydroprotoberberine2* and cryptaustoline alkaloid^,^ an analysis3' of the effect of oxygen substitution on U.V. absorption in the benzylisoquinoline and tetrahydroprotoberberine alkaloids has been made and n.m.r. examinations have shown that because of proximity effects caused by the ring systems the chemical shifts of aromatic methoxy-groups on macro- cyclic bisbenzylisoquinoline alkaloids can aid in deciding the type of oxygen bridge present3' and that the stereochemistry at C-14 of the rh~eadine-type~~" of alkaloid can be deduced.33 The racemisation at C-13a of tetrahydroprotoberberine alkaloids like corexi- mine (20) when catalysed by metals involves exchange of the 13a-h~drogen~~ in contrast to the situation in the acid-catalysed epimerisation of the analagous C-3 position in tetrahydro-P-carboline alkaloids which can occur without exchange of the hydrogen.3s A certain degree of success36 has been achieved in attempts to make bisbenzyl- isoquinoline alkaloids by forming the ether links by oxidative coupling.27 G. E. Krejcarek B. W. Dominy and R. G. Lawton Chem. Comm. 1968 1450. 28 C.-Y. Chen and D. B. MacLean Canod. J. Chem. 1968,46,2501. 29 T.Kametani and K. Ogasawara Chem. and Pharm. Bull. (Japan) 1968 16,1498. 30 L. Hruban and F. SantavjS Coll. Czech. Chem. Comm. 1967 32 3414. 31 J. Baldas P. N. Porter I. R. C. Bick G. K. Douglas M. R. Falco J. X. De Vries and S. Yu. Yunosov Tetrahedron Letters 1968,6315. 32 Ann. Reports:(a)1965,378;(b)1966,506;(c) 1967,437; 1965,38O;(d)1956,247;(e)1960,290;(f) (9)1967,439;(h) 1966,511;(i)1965,384;(j)1962,355. 33 M. Shamma J. A. Weiss S. Pfeifer and H. Dohnert Chem. Comm. 1968 212. 34 T.Kametani and M. Ihara J. Chem. SOC. (C) 1968,191. 35 A.J. Gaskell and J. A.Joule Tetrahedron 1967,23,4053. 36 M. Tomita Y. Masaki K. Fujitani and Y. Sakatani Chem. and Pharm. Bull. (Japan),1968,16. 688; A. M. Choudhury I. G. C. Coutts A. K. Durbin K. Schofield and D. J. Humphreys Chem. Comm. 1968 1341 ;A. Rieker H. Kaufmann D. Briick R. Workman and E. Miiller Tetrahedron 1968 24 103. 494 J. A. Joule A neat synthesis37 of the erythrina skeleton has as its key step the enamine alkylation of (21) with methyl vinyl ketone. The first members of the homo- erythrina type3* have been obtained from Schelharnrnera pedunculata ; for example schelhammerine is (22). A homoerythrina skeleton has been synthe- ~ised~~ by oxidative coupling. investigation^^^ of the thebaine system continue to provide interesting chemistry for example the thebaine-iron tricarbonyl adduct gave4OU with acid a salt (23) which is the result of yet another new type of rearrangement in this series.Me0 / Me / Me0 / Fe (CO) (23) Morphinane derivatives have been obtained by use of oxidative coupling4' and by use of a Pschorr reaction42 to form the final bond. Thus reticuline (24) was converted4lU to isosalutaridine (25)by treatment with manganese dioxide- silica gel (a means of supplying the substrate to the oxidant at high dilution and thereby improving the yield by cutting down on competing polymerisation reactions). The amino-derivative (26)was converted42u into (27) by successive treatments with nitrous acid and heat. Me0 / $,NMe -Me0 MeO&,II NMe Me0 \ OH 0 37 R.V. Stevens and M. P. Wentland Chem. Comm. 1968 1104. 30 S. R. Johns C. Kowala J. A. Lamberton A. A. Sioumis and J. A. Wunderlich Chem. Comm. 1968,1102. '' T. Kametani and K. Fukumoto J. Chem. SOC.(C) 1968,2156. 40 (a)A. J. Birch H. Fitton M. McPartlin and R Mason Chem. Comm. 1968,531 ;(b)J. B. Taylor J. Chem. SOC.(C),1968,1506; Z. J. Barneis J. D. Carr R. J. Warnet and D. M. S. Wheeler Tetrahedron 196$,24,5053. 41 (a)B. Franck G. Dunkelmann and H. J. Lubs Angew. Chem. 1967,79,1066; (b)A. R. Battersby A. K. Bhatnagar P. Hackett C. W. Thornber and J. Staunton Chem. Comm. 1968,1214. 42 (a)T. Kametani K. Fukumoto andT. Sugahara Tetrahedron Letters 1968,5459;(b)T.Kametani K. Fukumoto F. Satoh and H. Yagi Chem. Comm. 1968 1398. A lkaloids 495 PO 0Me (26) (27) A morphinan skeleton has been converted43 into a hasubanan skeleton32b and a totally synthetic route44 to a simple hasubanan compound has been developed.Kreysiginine (28) is a homomorphine type4' containing the carbon skeleton of andr~cymbine~~" with the additional ether bridge. This new alkaloid has an absolute configuration opposite to that of morphine.46 The carbon skeleton of these alkaloids has been produced both by ferricyanide oxidative coupling4' and the use of a Pschorr reaction.48 OMe Rb Rb HO (28) (29) A group of bases (29; R1.= R2= Me R3 = H OH) (29; R1= Me R2= H R3 = H OH) and (29; R1+ R2 = CH, R3 = 0)from Furnariu officinalis have structures49 allied to that of ochotensimine (29; R1= R2 = Me R3 = CH,).( f)-Ochotensimine has been synthesised." " T. Ibuka and M. Kitano Chem. and Phann. Bull. (Japan),1967,15,1944. 44 M. Tomita M. Kitano and T. Ibuka Tetrahedron Letters 1968,3391. '' A. R. Battersby M. H. G. Munro R. B. Bradbury and F. Santav); Chem. Comm. 1968 695; N. K. Hart S.R Johns J. A. Lamberton and J. K. Saunders Tetrahedron Letters 1968 2891 ; J. Fridrichsons M. F. Mackay and A McL. Mathieson ibid. 1968 2887. 46 A. F. Beecham N. K. Hart S.R.Johns and J. A. Lamberton Austral. J. Chem. 1968 21,2829. 47 T. Kametani K. Fukumoto M. Koizumi and A. Kozuka Chem. Comm. 1968,1605. '* T. Kametani K. Fukumoto F. Satoh and H. Yagi J. Chem. SOC.(C),1968 3084. 49 J. K. Saunders R. A. Bell C.-Y. Chen D. B. McLean and R H. F. Manske Canad.J. Chem.1968 46,2873,2876. 'O H. Irie T. Kishimoto and S. Uyeo J. Chem. SOC.(C) 1968,3051;S. McLean Mei-Sie Lin and J. Whelan Tetrahedron Letters 1968 2425. 496 J. A. Joule Amaryllidaceae Alkaloids.-Quantitative analysis5 of the alkaloidal content of Amaryllidaceous plants can be carried out by g.1.c. of their tetramethylsilyl ethers. This technique makes easy a progressive analysis of the alkaloidal content of a plant throughout its growth cycle. Two new alkaloids isolateds2 from many varieties of daffodils are narciclasine (30) and narciprimine (31). Ta~ettine~~~ is in fact an artifact produceds3 from pretazettine (32) during work-up. Lycorine has been converted5 into hippea- trine.^^^ OMe (32) 0 0 MeoG7 N.CO CF CO * CF3 I Me0d \ OH OH OH (33) (34) A biogenetically patterned oxidative coupling route (33) + (34) has been employed to produces5 a crinine ring system.Indole Alkaloids.-Simpler alkaloids. Brevicolline (35) from Carex brevi- c01Iis~~" have been assigned the and nitrarine (36) from Nitraria ~choberi~~' novel structures shown. Elaeocarpidine (37) from Elaeocarpus archbo1dianuss7 is also clearly different in type to previously isolated indole bases. Dasycar- pidone (38 ;R = 0)58 and uleineS8" and their C-3 epimersS8 have been synthe- 51 S. Takagi T. Katagi and K. Takebayashi Chem. and Pharm. Bull. (Japan) 1968 16 1116 1121. 52 F. Piozzi C. Fuganti R. Mondelli and G. Ceriotti Tetrahedron 1968,24,1119. 53 W. C. Wildman and D. T. Bailey J. Amer.Chem. Soc. 1967,89,5514. 54 K. Kotera Y. Hamada and R. Nakane Tetrahedron 1968,24,759. s5 B. Franck and H. J. Lubs Angew. Chem. 1968,80,238. 56 (a) P. A. Vember I. V. Terent'eva and A. V. Ul'yanova Khim prirod. Soedinenii 1968 4 98 (b)M. Normatov and S. Yu Yunosov ibid. p. 139. " S. R. Johns J. A. Lamberton and A. A. Sioumis Chem. Comm. 1968,410. 58 (a)A. Jackson A. J. Gaskell N. D. V. Wilson and J. A. Joule Chem. Comm. 1968 364 584; (b)L. J. Dolby and H. Biere J. Amer. Chem. SOC.,1968,90 2699 Alkaloids 497 rNM. (35) NMe R (37) sised in two different ways. Both methods involved as a key step a formation of the C-ring ones8' by cyclisation on to the indole P-position and the other58b by cyclisation on to the indole a-position.YohirnbP and related alkaloids. This year has seen the isolation (or detection) of two compounds (39 epimers at C-3) vincoside and isovincoside (together with the N-acetyl derivative59c of vincoside) from Vinca and strichto- sidine [same overall structure as (39) and probably identical stereochemically with one of the vincosides] from Rhazia~tricta,~~~ which lie even closer than tryptamine ~ordifoline~~f to the biogentic pathway from loganin to the indole alkaloids. One of the isomers vincoside has been shownsgc to be a direct precursor of the three main indole alkaloid skeletal types and both are formed in vitro when secologanin (40)is treated with tr~ptamine.'~" 59 (0)A. R. Battersby,A. R Burnett. and P. G. Parsons,Chem Comm. 1968 1282; (b)G.N.Smith ibid. 1968 912; (c) A. R. Battersby A. R. Burnett E. S. Hall and P. G. Parsons ibid. 1968 1582. 498 J. A. Joule Adina cordqolia has now yielded another P-carboline alkaloid adifoline (41),60 which retains the carboxy-group derived biogenetically from tryptophan. The novel seven-membered ring in this alkaloid is formed by linkage of the terpenoid part of the molecule to the aromatic nitrogen instead of as is more usual to the aliphatic nitrogen atom. Quinine has been transformed6' via a series of degradations including a von Braun cleavage into indole alkaloids of the dihydroantirhine [42; R' = CH(Et)*CH,OH,R2 = H] and dihydrocorynantheol(42 ;R' = CH2*CH2*OH R2 = Et) types. The key steps involved the treatment of the requisite dihydro- quinolones e.g.(43) with dihydropyran in acetonitrile when the hexahydro- quinolizones (44) were formed in high yield. Standard procedures then allowed closure to the required indoloquinolizine systems and removal of the aromatic oxygen function. THP = tetrahydropyranyl Synthetic ( & )-akuammigine and ( f)-tetrahydroalstonine each having cis D/E ring junctions have been obtained62 via the product [45; R = CH(CO,Me),] ofkinetically controlled Michael addition of dimethyl malonate to (45; R = H 15,20-dehydro). More examples of the utility of the synthetic approach to indole alkaloids which uses partial hydrogenation of 3-acyl-pyridinium species have appeared.63 6o R. T. Brown K. V. J. Rao P. V. S. Rao and L. R. Row Chem. Comm. 1968,350. 61 Y.K. Sawa and H. Matsumura Chem. Comm. 1968,679. '* E. Winterfeldt H. Radunz and T. Korth Chem. Ber. 1968 101,3172. 63 E. Wenkert K. G. Dave C. T. Gnewuch and P. W. Sprague J. Amer. Chem. SOC. 1968 90 5251; E. Wenkert K G. Dave R G. Lewis and P. W. Sprague ibid. 1967,89,6741; for a review see E. Wenkert Accounts Chem Res. 1968 1 78. A lkaloids 499 (45) A study of the mass spectral fragmentati~n~~ type has been of the voba~ine~’~ carried out. Another alkaloid of the vobasine class is taberpsychine (46) from Tabernaemontana psychotri$olia.65 Strychnos and related alkaloids. A study66 has shown that care is needed in the interpretation of 0.r.d. curves of indolines and N-acylindolines of the Strychnos and Aspidosperm series if the molecule also contains an aliphatic carbonyl group.An analysis of the mass spectral fragmentation of the strychnine type67 helped the elucidation of the structure of rindline from Strychnos henningsii. 4-Hydroxystrychnine has been isolated from S. icaja6’ and brucine has been obtained6’ by a series of oxidative steps from strychnine. (47) ii-iv 1 0 Reagents:i (EtCHCl-CO),O ;ii NaOH ;iii MnO ;iv NaOC(Me),Et. 64 T. Shiori T. Nakashima and S. Yamada Tetrahedron 1968.24,4177. 65 P. R Benoin R. H. Burnell and J. D. Medina Tetrahedron Letters 1968 807. 66 W. Klyne R. J. Swan A. A+ Gorman A. Guggisberg and H. Schmid Helv. Chim. Acta 1968,51 1168. 67 M. Spiteller-Friedmann and G. Spiteller Annalen 1968,711 205. 68 F. Sandberg K. Roos K. J. Ryrberg and K.Kristiansson Tetrahedron Letters 1968,6217. 69 P. Rosenmund W. H. Haase and K. Kaiser Chem. Ber. 1968,101,2754; E. Tedeschi S. Dukler P. Pfeffer and D. Lavie Tetrahedron 1968,24,4573. 500 J. A. Joule The simple precursor (47)has been neatly utilised7' in a total synthesis of (+)-tubifoline (48;R1= a-H R2 = H R3 = Et) and (+)-condyfoline (48; R' = P-H R2 = Et R3 = H). The synthesis centred on the production of the medium sized ring intermediate (49) which after modification was oxidatively closed to give both alkaloids. Continuing concentration on the relative and absolute stereochemistries of the tetra-71 and penta-~yclic~~ oxindole alkaloids has clarified the use of the various spectral and chemical methods for such assignments.Even mass spectrometric fragmentation [the relative intensity of the peak at m/e 180 (50) derived from the pentacyclic series] can have stereochemical ~ignificance.~ Aspidosperma alkaloids. An X-ray analysis74 of (-)-kop~anone~~~ methio-dide shows it to have the absolute configuration opposite to that of (+)-aspidospermine. Two intriguing bases from Aspidosperma dispermum7' Me0,C-0 provisionally assigned structures (5 1;R = H) and (51 ;R = OH) are the first known alkaloids of this group not to have an ethyl side chain in these bases replaced by a hydroxy-group. Q~ebrachamine~~~ by a route in which the nine- has been ~ynthesised~~ membered ring was created by acid-catalysed intramolecular acylation3 2g of the indole a-position. Iboga alkaloids.Much has been achieved this year in the synthesis of this class of alkaloid. Two more syntheses77a* of (_+)-ib~gamine~~' have appeared together with two for (+)-epi-ib~gamine~~~*' and syntheses of ~oronaridine~~ and ~elbanamine.~'? 32j One of the appro ache^'^" to the ibogarnine system utilised the cis-enedione (52) as starting material. The seven-membered 6-ring of the alkaloids was produced by monoacetalisation oxime formation and Beckman rearrangement (53). Next the double bond was used to introduce a 70 B. A. Dadson J. Harley-Mason and G. H. Foster Chem. Comm. 1968 1233. '' W. F. Trager C. M. Lee J. D. Phillipson R. E. Haddock D. DwumaBady and A. H. Beckett Tetrahedron 1968,24 523. 72 A. F. Beecham N. K. Hart S. R. Johns and J. A. Lamberton Austral.J. Chem. 1968,21,491. 73 M. Shamma and K. F. Foley J. Org. Chem. 1967,32,4141. 74 B. M. Craven B. Gilbert and L. A. Paes Leme Chem. Comm. 1968,955. 75 M. Ikeda and C. Djerassi Tetrahedron Letters 1968 5837. 76 F. E. Ziegler and P. A. Zoretic Tetrahedron Letters 1968,2639. " (a)S. 1. Sallay J. Amer. Chem. SOC.,1967,89,6762; (b)W. Nagata S. Hirai T. Okumura,and K. Kawata ibid. 1968 90 1650; (c) Y. Ban T. Wakamatsu Y. Fujimoto and T. Oishi Tetrahedron Letters 1968 3383. S. Hirai K. Kawata and W. Nagata Chem. Comm. 1968,1016. 79 G. Biichi P. Kulsa and R. L. Rosati J. Amer. Chem. SOC.,1968 90 2448. Alkaloids 501 i-iii - vii-xiii - (55) Reagents i HOCH,.CH,OH; ii H,NOH; iii TsC1-pyridine; iv PhC0,H; v LiAlH,; vi CrO pyridine; vii Ph,PCH,; viii B,H,-H,O,; ix LiAlH,; x PhCH20COCl; xi TsCl ; xii HBr-HOAc ; xiii heat.carbonyl group at C-7 (54 ;R = 0),whence by Wittig reaction and hydrobora- tion the corresponding hydroxymethyl compound (54; R = CH,OH) was obtained. A series of standard steps culminating in the formation of the isoquinuclidine ring system by intramolecular N-alkylation gave (55) which when subjected to a Fischer indole synthesis gave (-t-)-ibogamine. The relationship between yohimbk/strychnos aspidosperma and iboga skeleta. Although it has been known for some time that all of the three main skeletal types of indole alkaloid are derived from a common precursor which in a pre-alkaloid stage would be represented by a secologanin (40)and at an alkaloid level by vincoside (39) the manner in which this yohimbk/strychnos skeleton becomes rearranged to the two other types and indeed which of the yohimbk and strychnos types if either comes first in the biogenetic sequence is not certain.However this year considerable evidence". 82a has appeared which ''9 suggests that rearrangement occurs at an alkaloid level and which gives an inkling as to the sort of mechanisms which may be involved. The secamines (56; together with 15,20- or 15',20'-dihydro- and 15,15',20,20- tetrahydro-; the alternative structures with C-2' and its accompanying ester attached to C-17' are much less likely) a series ofnovel dimeric alkaloids isolated from Rhazya stricta" and Rhazya orientalis and an alkaloid (57)from Taber-namontana cumminsii,*' may well represent the species which lie on the pathway D.A. Evans G. F. Smith G. N. Smith and K. S. J. Stapleford Chem. Comm. 1968,859. P. A. Crooks B. Robinson and G. F. Smith Chem. Comm. 1968 1210. 82 (a) A. A. Qureshi and A. I. Scott Chem. Comm.,1968,945,947; (b)cf E. Wenkert J. Amer. Chem. SOC. 1962,84,98 (c)Doubts have been expressed on the reproducibility of those experiments; Alka- loids Conference Manchester Univ. April 1969. 502 J. A. Joule dfiN\ H dfiN Meocw Q-Jy (57) between the alkaloid types in these cases removed from the interrelationship pathway by some other irreversible process. The structure of (57) followed simply from its mass spectrum and the base has been synthesised.8' The struc- tures of the secamines were elucidated" (stereochemistry as yet unspecified) by an elegant combination of mass spectrometry labelling and chemical studies.The most relevant results are as follows. Hydrolysis of tetrahydrosecamine led to a didemethoxycarbonylated product (58) which suggested the presence of two a-indolylacetic ester units and to the fission product (59),which was identi- fied by synthesis. The latter arises by a reverse Mannich reaction from the bottom half of the molecule. Reductive didemethoxycarbonylation gave (60) which was synthesised. The positions of the double bonds in the less reduced members were established by Hofmann degradation and identification with the known 3-ethyl-l-methyl-l,2,5,6-tetrahydropyridine. These alkaloids are the first recognised members of a new class with the (monomeric) skeleton of (61).82b Their existence is a strong indication that the alkaloid rearrangement could occur through an intermediate with the (61) type of structure.Thus for example a species of the form (61) could clearly be reversibly derivable (see Scheme) from any of the three types of skeleton and could thereby become the crucial go-between.82 A series of in uitro experimentss2" have provided striking evidencesZc in sup-port of these ideas. When (-)-tabersonine (62)(an aspidosperma alkaloid with A lkaloids 503 C0,Me C0,Me Aspidosperma series (62) 11 Stemmadenine 11 Strychnos series (63) CbzMe Iboga series SCHEME the appropriate oxidation level) was simply heated in acetic acid there were obtained as well as starting material ( +)-catharanthine (63)(12%) and pseudo- catharanthine (28%)(which is in any case formed from catharanthine under these conditions).Even more remarkable when ( +)-stemmadenine (64) (with double bond at 19,20) was heated under reflux in acetic acid ( f)-tabersonine (12 %) and consequently ( *)-catharanthine (9 %) and pseudocatharanthine OH 504 J. A. Joule (16 %) were formed. When the yohimbk alkaloid geissoschizine (65) were treated with hot acetic acid under nitrogen catharanthine (5 %) and pseudo- catharanthine (15 %) were formed. These rearrangements almost certainly proceed through a ring-opened intermediate of the (61) type and constitute strong support for the idea that the in vivo processes OCCUTby analogous routes.Steroidal Alkaloids.-The 0.r.d. of steroidal amines has been studied by use of the aliphatic amino-absorption as the asymmetric chromophore. The highly poisonous batrachotoxinine-A from the Columbian arrow poison Me \ MeCHOH n v (66) (67) frog has the novel structure (66).84 Spiropachysine (67) is yet another variant of the pachysandra alkaloid theme.85 Lycopodium Alkaloids.-Annopodine (68) another alkaloid from Lycopo-dium annotinum has a novel ring structure.86 Two elegant syntheses8’ of (-I-)-lycopodine (73; R = H,) have appeared. One of these87“ utilised the cyclo- hexanone (69) which was converted into the hexahydroquinoline derivative (70) (and its unwanted isomer methyl and benzyl interchanged) by reaction of the corresponding pyrrolidine enamine with acrylamide.Acid-catalysed intra- molecular alkylation of the aromatic ring gave (71). The aromatic ring was then destroyed by a sequence of reactions leaving only the desired functionalities (72). Removal of the N-protecting group then gave a keto-lactam (73; R = 0) which was reduced and re-oxidised to (-t )-lycopodine (73 ; R = H2). Miscellaneous Alkaloids.-Several macrocyclic polyamino-bases have figured in the literature this year. Palustrin from Equisetum palustre88probably has the structure (74) and two bases from Oncinotis nitZda8’ have been assigned the structures (75) oncinotine and (76) iso-oncinotine. Homaline from Homalium alni$oliumgOhas been given the working structure (77) and pithecolobine from 83 J.Parello and F. Picot Tetrahedron Letters 1968 5083. 84 T. Tokuyama J. Daly B. Witkop I. L. Karle and J. Karle J. Amer. Chern. SOC.,1968,90 1917. 85 T. Kikuchi T. Nishinaga M. Inagaki and M. Koyama Tetrahedron Letters 1968,2077. 86 W. A. Ayer G. G. Iverach,J. K. Jenkins and N. Masaki Tetrahedron Letters 1968,4597. 87 (a)G. Stork R. A. Kretchmer and R. H. Schlessinger,J. Amer. Chem. SOC.,1968 90 1647; (6) W. A. Ayer W. R. Bowman T. C. Joseph and P. Smith ibid. p. 1648. 88 C. Mayer W. Trueb J. M. Wilson and C. H. Eugster Helv. Chim. Act4 1968,51,661. 89 M. M. Badawi A. Guggisberg P. van den Broek M. Hesse and H. Schmid Helv. Chim. Acta 1968,51,1813. 90 M. Pais G. Rattle R. Sarfati and F.-X. Jarreau Compt. rend..1968 266 C 37. Alkaloids 505 OMe 70,Me CH,Ar i ii 0aMe -\/CO,Me ix x] Me -\/COz Me xi R' u (73) Reagents i C,H,N; ii CH = CH*CO.NH,; iii H,PO,-HC0,H; iv LiAlH,; v Li-NH,-Bu'OH; vi Bu'O- ; vii CCl,*CH,.O*COCl; viii 0,;ix Se0,-H,O,; x Me0 -;xi Zn. Pithecolobiurn sarnan91 seems to have the structure (78) despite the difficulty in definitely establishing the absence of a third oxygen atom suggested by earlier analyses. The novel imidazolium salt (79)has been isolated92 from Dendrobium anosmum and D. parishii. Novel indolizidines have been obtained from Elaeocarpus species (see also under simple indole alkaloids). Elaeocarpine (80; R = a-H) and isoelaeocarpine (80; R = P-H) occur in E. polyda~tylus,~~" and their dihydroaromatic counterparts elaeocarpiline (81; R = a-H)and isoelae-carpiline (81; R = p-H) in E.doli~hostilis.~~~ Borohydride reduction of iso- elaeocarpiline gave (82).93b Slaframine a fungal alkaloid has been reformulated as (83).94 91 K. Wiesner D. M. MacDonald C. Bankiewicz and D. E. Orr Cad.J. Chem. 1968,46,1881. 92 K. Leander and B. Liining Tetrahedron Letters 1968,905. 93 (a)S. R. Johns J. A. Lamberton A. A. Sioumis and J. A. Wunderlich Chem. Comm 1968,290; (b)S. R. Johns J. A. Lamberton and A. A. Sioumis ibid. 1968 1324. 506 J. A. Joule Et NH [dH] CO 1;JHY (74) (75) PhCH Me[CH,],-CH[CH,],. CO I CO-CH-NMe I I CCHzI3 'N' [CH2]4. N [CH,] 3 I I NH* [CH,I4. NH MeN-CH-CO I (79) PhCH (78) (77) OMe Ar 0ge Me Me (85) Alkaloids 507 Borohydride reduction of isoelaeocarpiline gave (82).93bSlaframine a fungal alkaloid has been reformulated as (83).94 Several different waysg5 of synthesising the mesembrine (84) system have come to light this year.Three groups have used the reaction of an arylpyrroline (85) as an enamine (see also under erythina alkaloids). Thus for exampleg5" the appropriate aryl cyclopropyl nitrile was converted into the corresponding imine which was rearranged (see also under pyridine alkaloids) to (85). Reaction of (85) with methyl vinyl ketone gave mesembrine. 94 R. A. Gardiner K. L. Rinehart J. J. Snyder and H. P. Broquist J. Amer. Chem. SOC. 1968,90 5639. 95 (a) S. L. Keely and F. C.Tahk J. Amer. Chern. SOC.,1968,90 5584; (b)R. V. Stevens and M. P. Wentland ibid.,p. 5580; T. J. Curphey and H. L. Kim Tetrahedron Letters 1968 1441 ;M. Shamma and H. R. Rodriguez Tetrahedron 1968 24 6583; T. Oh-Ishi and H. Kugita Tetrahedron Letters 1968. 5445; H. Taguchi T. Oh-Ishi and H. Kugita ibid. p. 5763.