12. ALKALOIDS By J. A. Joule (Chemistry Department University of Manchester Manchester 13) A FURTHER volume' of 'The Alkaloids' series has appeared containing reviews of the Salarnandra Nuphar mesembrine Tylophora and Galbulimirnaalkaloids all of which are new to the series. This volume also contains supplements to earlier chapters on the alkaloids of the lupin quinoline (not Cinchona) iso-quinoline (various) tropane steroid (Apocynaceae and Buxaceae) Erythrina and Sternona groups. Reviews have appeared devoted to oxindole,' Czo-diterpene~,~ and pyrrolizidine4 alkaloids to the stereochemical aspects of ephedrine pyrrolizidine granatane and tropane chemistry5 and yohimbine heteroyohimbine oxindole and Arnaryllidaceae alkaloids6 A review7 of the mass spectral behaviour of quaternary nitrogen compounds deals mainly with indole alkaloid N(b)-methosalts.Pyrrole Pyridine and Lupin Alkaloids.-Liparis species* and Malaxis congesta,' members of the Orchidaceae have yielded interesting new pyrrolizi- dine alkaloids for which the structures [l R' = Glu.Ara R2 = CH,*CH:C-(Me), R3 = a-HI nervosine [l ; R' = Glu R2 = CH2-CH:C(Me)2 R3 = P-H methosalt] kumokirine and (1 ;R' = Glu R' = H R3 = P-H) malaxin have been proposed. n Me FH20C0 Me02C (1) HO (3) ' (2) R. H. F. Manske 'The Alkaloids' Academic Press New York 1967 vol. IX. G. B. Yeoh K. C. Chan and F. Morsingh Rev. Pure Appl. Chem. (Australia) 1967 17 49. S. W. Pelletier Quart. Rev. 1967 21 525. F. L. Warren Fortschr. Chem. org. Naturstoffe 1966 24 329.G. Fodor. Recent Developments Chem. Natural Carbon Compounds 1965 1 15. G.A. Morrison Fortschr. Chem. org. Naturstoffe 1967.25,269; See also W. F.Trager C. M. Lee. and A. H. Beckett Tetrahedron 1967 23 365; N. J. Dastoor A. A. Gorman and H. Schmid Hch. Chim. Acta 1967 50 213; M. Shamma R. J. Shine I. KompiS T. Sticzay F. Morsingh J. Poisson and J.-L. Pousset J. Amer. Chem. SOC. 1967 89 1739. ' M. Hesse Fortschr. chem. Forsch. 1967,8 608. K. Nishikawa and Y. Hirata Tetrahedron Letters 1967 2591 ; K. Nishikawa M. Miyamura and Y. Hirata Tetrahedron Letters 1967 2597. K. Leander and B. Luning Tetrahedron Letters 1967 3477. 426 J. A. Joule The quaternary species (2) a new variation of the actinidine type has been obtained from Valerianu oficinulis.Fontaphilline (3) from Fontanesia philfyreoides is a related alkaloid of the same series as gentianine." A third variant on the theme is the base (4) from Rauwolfia uerticillutd2 which lacks the 3-substituent and a fourth permutation the pyridine (5)from Gentiana tibetica,' which is formally derivable from the gentianine type by ring opening rotation ring formation and loss of the 3-substituent. All these compounds almost certainly arise from loganin or some other similar monoterpenoid precursor. It is interesting that the cleavage necessary to produce (3) and (9,the loss of the carboxyl carbon necessary to form (4) and (3,and the rotation necessary for (5) are all processes recognised in the biogenesis of various indole alkaloids from a terpenoid precursor.Two more hydroxyskytanthines have been ob- tained from Skytanthus actus. l4 The relative stereochemistry of clivonine and clivimine has been revised on the basis of n.m.r. spectroscopy.15 The simple base (6)occurs in pomegranate. l6 Piperlongumine (7) has been obtained from Piper longum. Iso-orensine has been synthesised from isotripiperidine. ' The structure and absolute stereo- chemistry of an alkaloid (8) from Euphorbia atoto have been demonstrated.lg Two macrocyclic bases (9; x = y = 5) and (9; x = 5 y = 7) isolated from Azirna tetracantha are similar in type to carpaine (9;x = y = 7).20The dihydro- derivative of cassine has been obtained from Cassia carnauuL2 Lythranidine (10) is another macrocyclic piperidine base. This alkaloid is obtained from Lythrum anceps.22 lo L.K. Torssell and K. Wahlberg Acta Chem Scand. 1967,21 53. l1 H. BudzikiewicG C. Hortsmann K. Pufahl and K. Schreiber Chem. Ber. 1967,100,2798. l2 H. R. Arthur S.R. Johns J. A. Lamberton and S. N. Loo Austral. J. Chem. 1967,244 2505. F. Rulko L.DolejS A. D. Cross J. W. Murphy and T. P. Toube,Roczniki. Chemii 1967 41 56 7. l4 G. Adolphen H. H. Appel K. H. Overton and W. D. C. Warnock Tetrahedron 1967,23,3147. W. Dopke M. Bienert A. L. Burlingame H. K. Schnoes P. W. Jeffs and D. S. Farrier Tetra-hedron Letters 1967,451; See also W. Dopke and M. Bienert Arch. Pharm. 1966,299,994. l6 M. F. Roberts B. T. Cromwell and D. E. Webster Phytochem 1967,6 711. l7 A. Chatterjee and C. P. Dutta Tetrahedron 1967,23 1769. C.Schopf and W. Merkel Annalen 1967,701 180. l9 A. F. Beecham S. R. Johns and J. A. Lamberton Austral J. Chem. 1967,#) 2291; N. K. Hart S. R. Johns and J. A. Lamberton ibid. p. 561. 2o G. J. H. Rali T. M. Smalberger H. L. de Wad and R. R Amdt Tetrahedron Letrers 1967 3465. 21 D. Lythgoe and M. J. Verenengo Tetrahedron Letters 1967 1133. l2 E. Fujita K. Fuji K. Bessho and A. Sumi Tetrahedron Letters 1967 4595. Alkaloids 427 Oo co co 0 CH:CH oorLe 0 co (7) ‘’OMe Me I I cH2YgTcH2 v (10) 11-0xotetrahydrorhombifoline has been isolated from Ormosiu coutinhoi and a study made of its mass spectral beha~iour.~~ Two methods have been developed for the synthesis of lupinine in optically active form without resolu- tion at the last step.24 Qainoline Alkaloids.-Studies of the Cinchona alkaloids have been con-cerned with the relative stereochemistry at C-9,25 and with the application of 0.r.d.and c.d. to this series based on the quinoline or 4-acylquinoline chromo- phore.26 The quinolone (11)27 and acridone (12)28have been isolated from Evodia species and the furanoquinoline (13)from Choisya tern at^.^^ A synthesis of flaiamine (15)30makes a neat use of a Claisen rearrangement. The reaction was carried out in acetic anhydride which enabled the first product to be trapped (14) thereby preventing the subsequent undesired abnormal Claisen reaction. A synthesis of acronycine3’ employs as starting material 3,4-dihydro-5,7- dimethoxy-2-quinolone which contains the requisite side chain tied as the ” S.McLean,A. G. Harrison and D. G. Murray Canad. J. Chem. 1967,45,751. 24 T. Kunieda and S. Yamada Chem. and Pharm. BUM.(Japan) 1967,15,240; S. I. Goldberg and I. Ragade J. Org. Chem. 1967,3& 1046. 25 G. G. Lyle and L. K. Keefer Tetrahedron 1967,23 3253. 26 G. G. Lyle and W. Gaffield Tetrahedron 1967 23,51. ” R. Tschesche and W. Werner Tetrahedron 1967 23 1873. J. A. Diment E. Ritchie and W. C. Taylor Austral. J. Chem. 1967,20 1719. 29 S. R. Johns J. A. Lamberton and A. A. Sioumis Austral. J. Chem. 1967 20 1975. 30 T. R. Chamberlain and M. F. Grundon Tetrahedron Letters 1967 3547. 31 J. R. Beck R. W. Booher A. C. Brown R. Kwok and A. Pohland J. Amer. Chem. SOC. 1967 89,3934. 428 J. A. Joule heterocyclic ring which is later opened.The first step of the synthesis involves reaction with o-iodobenzoic acid-cuprous iodide to give (1 6). The subsequent steps to the acridone (17) suitable for further elaboration to a tetracyclic intermediate (1 8) are detailed. CH (1 3) M d0 O?L e I -& l2 Me (14) Me Me QtKT:: Reagents I Ac20-NMe piperidine 2 HBr-HOAc (15) OMe mOMe 1,2 (17) (18) Me Reagents 1 -PPA ;2 MeOH-HCl ;3 BCl ;4 MeLi ;5 Pyridine . HCI A Ikaloicis 429 Isoquinoline Alkaloids.-The structures of two simple halucinogenic bases (19) and (20; R' = Me R2 = OH R3 = Me) from species of cacti have been e~tablished.~~ Corypalline (20; R' = R2 = H R3 = Me) dimerises to (21) on electrolytic or photochemical oxidation.33 Sendaverine (alkaloid F 28) (20; R' = R2 = H R3 = CH2-Ph) from Corydalis aurea is a new type of isoquinoline alkaloid.34 When papaverine is photolysed in methanol or ethanol cleavage of the benzyl group occurs with the concomitant introduction of the alcohol alkyl residue at C-l.35The absolute stereochemistry of arge- monine [the (-) form (22) is shown] has been thoroughly e~tablished~~ by chemical correlation with L-aspartic acid and by 0.r.d.measurements. HO R2 Cryptowoline has been synthesised by routes which employ the formation of a benzyne as a last step.37 Stepharanine (23 ;R' = OMe R2 = OH R3 = H) has been obtained from Stephunia glabr~.~* Berberine has been transformed into columbamine thus completing a formal total synthesis of this widely distributed alkal~id.~' Irradiation of the amide (24) provides a novel approach to the synthesis of a methyl protoberberine system (23; R' = R2 = H R3 = Me).40 32 J.E. Hodgkins S. D. Brown and J. L. Massinghill Tetrahedron Letters 1967 1321. 33 J. M. Bobbitt J. T. Stock A. Marchand and K. H. Weisgrabar Chem. and Ind. 1966,2127. 34 T. Kametani and K. Ohkubo Chem. and Pharm. Bull. (Japan) 1967 15 608. 35 F. R. Stermitz R. Pua and H. Vyas Chem. Cornm. 1967 326. A. C. Barker and A. R. Battersby J. Chem SOC.(C),1967 1317; R. P. K. Chan J. Cymerman Craig R. H. F. Manske and T. Soine Tetrahedron 1967 23,4209; 0.brvinka A. FkbryovA and V. Novhk Tetrahedron Letters 1966 5375; M. J. Martell T. 0.Soine and L. B. Kier J. Pharm. Sci. 1967 !% 973. " F.Bennington and R. D. Morin J. Org. Chem. 1967,32,1050;T. Kametani and K. Ogasawara J. Chem. SOC.(C),1967 2208. R. W. Doskotch M. Y. Malik and J. L. Beal J. Org. Chem. 1967,32 3253. 39 M. P. Cava and T. A. Reed J. Org. Chem. 1967,32 1640. *' G. R. Lenz and N. C. Yang Chem. Comm. 1967 1136. 430 J. A. Joule Accounts of extensive investigations of the synthesis of protoberberine alka- loids using the Eschweiler-Clarke approach have been p~blished.~' Several more alkaloids based on the rhoeadine skeleton have been el~cidated.~~ including one in which the hemiacetal hydroxyl is linked to Crypto-pine can be converted into the berberinium ion by irradiati~n.~~ Macrocyclic bisbenzylisoquinoline alkaloids have been isolated from T.~implex,~~' Thalictrum fendleri,44a T.Dasyca~pum,~~~ and Cissampelos p~reira.~~~ Considerable efforts have been expended on the synthesis of this POCI, I 41 T.Kametani I. Noguchi S. Nakamura and Y.Konno,J. Pharm. SOC. Japan 1967 87 168; et seq. ; T. Kametani and T. Kikuchi Chem. and Pharm. Bull. (Japan) 1967,15,879; T. Kametani and M. Ihara J. Chem. SOC. (C) 1967 530. 42 (a) A. NemiXkovA A. D. Cross and F. Santavjr Naturwiss. 1967,54,45; (b) E. A. Guggisberg M. Hesse H. Schmid H. Bbhm H. Ronsch and K. Mothes Helv. Chim. Acta 1967,50,621; L. M. Maturovh H. PottiSilovA,F. Santavy A. D. Cross V. HanuS and L. DolejS Coll. Czech. Chem. Comm. 1967,32,419; D. W. Hughes L. Kiihn and S. Pfeifer J. Chem. SOC.(C),1967,444. 43 X.A. Dominguez and J. G. Delgado Tetrahedron Letters 1967 2493.** (a)M.Shamma R. J. Shine and B. S. Dudock Tetrahedron 1967,23 2887. (b)S. M. Kupchan T.-H. Yang G. S. Vasilkiotis M. H. Barnes and M. L. King .I.Amer. Chem. SOC. 1967,89 3075; (c) N. M.Mollov V. S. Georgiev D. Jordanov and P. Panov Compt. rend. Acad. bulg. Sci. 1966,19,491; (d)A. K. Bhatnagar and S. P. Popli Experientia 1967 23 242. Alkaloids 43 1 type of alkal~id.~’ illustrates the type of The synthesis of ~epharanthine~’” approach which is used. A di-amide macrocyclic intermediate (25)was built up from suitable ‘halves’. The amide-forming steps were used to construct the large ring. Phosphorus oxychloride treatment then caused ring closure in both halves to dihydro-isoquinoline rings and the molecule was finally modified as necessary.A basically similar approach has been used in the synthesis of the bisbenzylisoquinoline alkaloids magn~line,~~” and magnol- i~oliensinine,~~~ amine46‘ which have one ether link between the two units. Perhaps the most interesting bisbenzylisoquinoline alkaloid examined in the year under review was isolated from Daphnandra repandula. Repanduline has been assigned the novel structure (26) though the position of the spiro- linkage is not ~ertain.~’ Cleavage of the alkaloid with potassium-ammonia gave rise to hemirepanduline (27) which was synthesised. Co-occurring with repanduline is nortenuipine (28) and it seems reasonable to suppose that the (26) 45 (a) M. Tomita K. Fujitani and Y. Aoyagi Tetrahedron Letters 1967 1201 ;(b)T.Kametani 0.Kusama and K. Fukumoto Chem. Comm. 1967 1212; J. P. Sheth and 0.N. Tolkachev Tetra-hedron Letters 1967 1161; 0.N. Tolkachev L. P. Kvashnina and N. A. Preobrazhenskii Zhur. obshchei Khim. 1966. 37 1764. *6 (a) T. Kametani R Yanase S. Kano and K. Sakurai Chem. and Pharm. Bull. (Japan) 1967 15,56 ;(b)T. Kametani S. Takano and K. Satoh J. Heterocyclic Chem. 1966,3,546; (c)T. Kametani H. Yagi and S. Kaneda Chem. and Pharm. Bull. (Japan) 1966,14,974. 47 J. Harley-Mason A. S. Howard W. I. Taylor M. J. Vernengo I. R. C. Bick and P. S. Clezy J. Chem. SOC.(C) 1967 1948; I. R. C. Bick J. H. Bowie J. Harley-Mason and D. H. Williams ibid. p. 1951;K. Aoki and J. Harley-Mason ibid. p. 195?. 432 J. A. Joule novel base is derived biogenetically by a condensation involving the methoxyl carbon atom (marked *) of a nortenuipine-type precursor.Litsericine has a protoaporphine structure.48 Phenolic coupling routes have led to the syntheses of glazi~vine~~“ orientalinone corydine and iso- c~rytuberine.~~~ ( -)-Mecambrine has been transformed into ( +)-roemerine.” The widespread occurrence of plants containing aporphine alkaloids is illus- trated by the following list all of which have been reported in the year under review Lindera pipericarpa,’ la Phoebe clemensii,’ lb Croton wilsonii,5 le Fagara tinguassoiba,’ Id Papaver persicum and P. cancasium,’ le Thalictrum fer~dleri,~~“ Laurelia novae-zelandioe,’ If Cassythia racemosa,5 ‘0 and Lysichiton camtarha- tiense.”” In the development of a modified type of aporphine synthesis an unexpected cleavage to o-nitro-toluene and N-methyl tetrahydroisoquinoline occurred on attempted reduction of the intermediate (29) with borohydride.” The use of catalytic reduction overcame the problem and the synthesis was completed normally using a Pschorr reaction.(31) 32) 48 T. Nakasato and S. Asada J. Pharm. SOC.Japan 1966,86 1205. 49 (a)T. Kametani and H. Yagi J. Chem. SOC.(C),1967,2182;(b)A. H. Jackson and J. A. Martine J. Chem. SOC.jC) 1967 2222. ” J. Slavik Coll. Czech. Chem. Comm. 1966,31,4184. (a)A. K. Kiang and K. Y. Sim J. Chem. SOC.(C),1967,282; (b)S. R. Johns and J. A. Lamberton Austral. J. Chem. 1967 20 1277; (c)K. L. Stuart and C. Chambers Tetrahedron Letters 1967,4135; (d) M.Shamma and W.A. Slusarchyk Tetrahedron 1967 23 2563; (e) V. Preininger J. Appelt L. SlavikovB and J. Slavik Coll. Czech. Chem. Comm. 1967 32,2682; (f)K. Bernauer Helu. Chim. Acta 1967 50 1583; (8)S. R. Johns J. A. Lamberton and A. A. Sioumis Austral. J. Chem. 1967 20 1457; (h) N. Katsui and K. Sato Tetrahedron Letters 1966 6257. ” J. L. Neumeyer B. R Neustadt and J. W. Weintraub Tetrahedron Letters 1967 3107; J. L. Neumeyer M. McCarthy and K. K. Weinhardt ibid. p. 1095. Alkaloids 433 Acularine-type system has been synthesised by a phenolic coupling reaction.' Homo-aporphines have been isolated for the first time. Floramultine from Kreysigia rnultiflora has the structure (30)and has been synthesi~ed.~~ A homo-protoaporphine kreysiginone (31) has been isolated from the same plant,5 s after a careful search.It has proved possible to extend the oxidative coupling route developed for the synthesis of protoaporphine alkaloids and aporphine alkaloids to their homol~gues.~~~ 55* 56 Ipecoside (32) provides a fascinating compound intermediate in the bio- genetic sequence from loganin (or similar terpenoid compound) (see also under Indole Alkaloids). A careful study showed that the base has the same absolute stereochemistry as the Ipecacuanha alkaloid^.^' The mass spectral fragmentation of morphine-type alkaloids has been ex- amined.58 Acutumine (33 ; R = Me) and acutumidine (33 ; R = H) are novel chlorine-containing bases isolated from Sinorneniurn ac~turn.~~ The absolute configuration of nudaurine has been determined by oxidation to D-( -)-glyceric 0- OMe OMe acid.60 Full details have appeared of Bentley's extensive investigations of morphine and thebaine derivatives.61 Codeinone has been transformed into thebaine and northebaine.62 Morphine has been synthesised by a new Amaryllidaceae Alkaloids.-A study of the 0.r.d.and c.d. curves of lycorine and related bases has led to the development of an empirical rule which allows prediction after examination of a model of the compound of the sign and magnitude of the 290 mp Cotton effect associated with the aromatic ring 53 T. Kametani T. Kikuchi and K. Fukumoto Chem Comm. 1967 546. s4 A. R. Battersby R. B. Bradbury R. B. Herbert M. H. G. Munro and R. Ramage Chem. Comm. 1967 450.s5 A. R. Battersby E. McDonald M. H. G. Munro and R. Ramage Chem. Comm. 1967 934. 56 T. Kametani K. Fukumoto H. Yagi and F. Satch Chem. Comm. 1967 878; T. Kametani F. Saton H. Yagi and K. Fukumoto ibid. p. 1103. " A. R. Battersby B. Gregory H. Spencer J. C. Turner M.-M. Janot P. Potier P. Francois and J. Levisalles Chem. Comm. 1967 219. s8 D. M. S. Wheeler T. H. Kinstle and K. L. Rinehart J. Amer. Chem. SOC.,1967,89,4494. 59 M. Tomita Y. Okamoto T. Kikuchi K. Osaki M. Nishikawa K. Kamiya Y. Sasaki K. Matoba and K. Goto Tetrahedron Letters 1967 2421 2425. 6o D. H. R. Barton R. James G. Kirby W. Dopke and H. Flentje Chem. Ber. 1967,100,2457. 61 K. W. Bentley and D. G. Hardy J. Amer. Chem. SOC.,1967,89,3267,et seq. 62 H. Rapoport C. H. Lovell H. R. Reist and M.E. Warren J. Amer. Chem. Soc. 1967,89 1942. 63 G. C. Morrison R. 0.Waite and J. Shave] Tetrahedron Letters 1967 4055. 64 K. Kuriyama T. Iwata M. Moriyama K. Kotera Y. Hameda R. Mitsui and K. Takeda J. Chem. Soc.(B) 1967 46. 434 J. A. Joule chr~mophore.~~ Co-ordinates are set on the aromatic ring as shown (34). The rule states that when looking along the axis -z to + z there are four back octants which can contribute as indicated (39 to the Cotton effect. The stereorepresentation (35)of a-lycorane shows how the rule correctly predicts a weak negative Cotton effect for this compound. The third stereoisomer of lycorane y-lycorane has been synthesised6’ and a new synthetic route to lycoramine has been developed.66 Indole Alkaloids.-Simpler alkaloids.The carbazole heptaphylline (36) has been isolated from Clausena hept~phylla~~ and 1,5-dimethoxygramine from Gymnacranthera paniculata.68 The base (37)from Dracontomelum rnangifer~m,~~ the biogenesis of which may be related to that of the canthinone group provides an example of a natural compound previously known as a synthetic laboratory product. The natural material may be partially racemic since an optically active synthetic sample is reported’’ as having a much larger specific rotation. The methoxyolivacine (38; R1 = Me RZ = H) and the methoxy- ellipticine (38; R’ = H R2= Me) have been obtained from Aspidosperma ~argasii’~and Ochrosia elliptica respectively and the latter compound synthesi~ed.~~ 65 N. Ueda T. Tokuyama and T.Sakan Bull. Chem. SOC.,Japan 1966,39,2012. 66 Y. Misaka T. Mizutani M. Sekido and S. Uyeo Chem. Comm. 1967 1258. 15’ B. S. Josh V.N. Kamat A. K. Saksena and T. K.Govindachari Tetrahedron Letters 1967 4019. 68 S.R. Johns J. A. Lamberton and J. L. Occolowitz Austral. J. Chem. 1967,u). 1737. 69 S. R.Johns J. A. Lamberton and J. L. Occolowitz Austral. J. Chem. 1966 19 1951. 70 S. Yamada and T. Kunieda Chem. and Pharm. Bull. (Japan) 1967 15 499. ’I1 R. H. Burnell and D. D. Casa Canad. J. Chern. 1967,45,8? 72 J. W. Loder Austral. J. Chem. 1966 19 1947. A lkaloids 435 R2 R' I1 R' Me Me (40) Two independent groups have demonstrated the relative stereochemistry of uleine (39; R' = CH, R2 = Et R3 =. H).73Bases (39 R' = CH, R2 = H R3 = Et) and (39; R' = 0 R2 = H R3 = Et) epimeric at C-3 with uleine and dasycarpidone (39; R' = 0,R2 = Et R3 = H) have been isolated from Aspidosperma subincan~rn.~~' The ring system of this group of alkaloids has been synthesised for the first time.74 An X-ray analysis of the bromobenzene adduct of hodgkinsine from Hodgkinsonia fmtescens shows it to be a novel trimer (40)'5 comprised of three N(b)-methyl tryptamine units.Details have appeared of the oxidative dimerisation of the Grignard derivative of N(b)-methyl tryptamine which yields mainly a mixture of racemic-and rneso-~himonanthine.~~ Physovenine (41) has been ~ynthesised.~~ YohimbP and related alkaloids. The sign of the double Cotton effect between 295-280 and 255-250 mp can be used in the absence of strongly absorbing chromophores elsewhere in the molecule to ascertain the absolute stereo- chemistry at C-3 of yohimbane and corynantheane alkaloids7* When the C-3 hydrogen is 01 a positive Cotton effect is observed (see also Ref.70) and vice versa. A similar effect has been found for 7-substituted indolenines (42) derived 73 (a)A. J. Gaskell and J. A. Joule Chn. and Ind. 1967 1089; (b) M. Shamma J. A. Weiss and R. J. Shine Tetrahedron Letters 1967 2489. '* A. Jackson and J. A. Joule Chem. Comm. 1967,459. 75 J. Fridrichsons M. F. Mackay and A. McL. Mathieson Tetrahedron Letters 1967 3521. 76 E. S. Hall F. McCapra and A. I. Scott Tetrahedron 1967,23,4131. 77 B. Longmore and B. Robinson Coll. Czech. Chem. Comm. 1967. 32 2184. 78 W.Klyne R. J. Swan,N. J. Dastoor A. A. Gorman and H. Schmid Helv. Chim. Acta 1967 50,115. 436 J. A. Joule from yohimbane." The a-substituted compounds displayed positive Cotton effects and vice versa. A study of corynantheidine alkaloids has shown that although the c.d. and 0.r.d. curves of these compounds are more complex they can also be used in a determination of absolute stereochemistry.80 Several papers8' deal with the elucidation of the relative and absolute stereochemistry of oxindole alkaloids. It has been suggested81b that the use of the Cahn- Ingold-Prelog convention would avoid ambiguities in defining the stereo- chemistry at the spiro-C-7 in such bases. Formulation (43)represents the 7R-configurat ion. R H R =CH,Ph or OAc (42) Me0K-y R2 (44) Aspidosperrna excelsurn has yielded' excelsinine which is 1 0-methoxy corynanthine and Rauwdjk~discolor tetraphylline (44;R' = H R = OH).83 Herbaceine (44;R1 = OMe RZ = H.P-CO,Me) and herbaline (45),dihydro-bases of the heteroyohimbine and hetero-oxindole types respectively have been obtained from Vinca herb~cea.~~ The alkaloids of commercial Gambir prove to be of a ring E aromatic yohimbe type,85 gambirtannine is (46;R = H,) and oxogambirtannine (46;R = 0).Gambirine from Uncaria garnbier is 79 M. von Strandtmann R. Eilertsen and J. Shavel J. Org. Chem. 1966 31 4202. "W. F. Trager C. M. Lee and A. H. Beckett Tetrahedron 1967 23,375. 81 (a) N. K. Hart S. R. Johns and 3. A. Lamberton Chem. Comm. 1967 87; A. F.Beecham N. K. Hart S. R. Johns and J. A. Lamberton ibid. p. 535 ;(b)J. Poisson and J. L. Pousset Tetrahedron Letters 1967 1919. 82 P. R. Benoin R. H. Burnell and 3. D. Medina Canad. J. Chem. 1967,45,725. G. Combes L. Fonzes and F. Winternit& Phytochem. 1966,5 1065. I. Ognyanov B. Pyuskyulev M. Shamma J. A. Weiss and R. J. Shine Chm. Comm. 1967,579. L. Merlini R Mondelli G. Nasini and M. Hesse Tetrahedron 1967 23,3129. A lkaloids 437 formulated as (47; R' = OH R2= H R3 = Me)86 and hervin from Vinca herbacea as (47; R' = H R2 = OMe R3 = H 19,20-dehydr0).~~ Antirhine (48) isolated from Antirhea putaminosa is an alkaloid of the hunterburnine group.88 Cordifoline (49) from Adina cordifolia has an intriguing and bio- genetically significant stru~ture.~' Not only is this base unusual in retaining the tryptophan carboxyl carbon atom but it also incorporates the terpenoid precursor of the C, unit at an intermediate stage of elaboration (see also Isoquinoline Alkaloids).(45) MeO,C)\/O R' (48) (49) Me0,C \ HOCH-The isolation of another" strychnos type alkaloid (+)-lochneridine in a form enantiomeric'l with that obtained previously is also of biogenetic significance. Details have a~peared'~ of structural work on caracurine-I1 and its formation from toxiferine-I. 1 1-Methoxylimatine and 11-methoxylimatinine have been isolslted from Aspidosperma limae.' Alstonia rnacrophylla has provided a quaternary alkaloid macrosalhine for 86 L. Merlini R. Mondelli and G. Nasini Tetrahedron Letters 1967 1571.'' I. Ognyanov B. Pyuskyulev B. Bozjanov and M. Hesse Helv. Chim. Acta 1967,50 754. S. R. Johns J. A. Lamberton and J. L. Occolowitq Austral. J. Chem. 196'1 #) 1463. 89 R. T. Brown and L. R. Row Chem. Comm. 1967,453. 90 Ann. Reports 1960 56 288. 91 P. Lathuilliere L. Olivier J. Levy and J. Le Men Ann. pharmfrane. 1966 24 547. 92 A. R. Battersby H. F. Hodson G. V. Rao and D. A. Yeowell J. Chem. SOC.(C) 1967. 2335. 93 M. Pinar and H. Schmid Helu. Chim. Acta 1967 50 89. 438 J. A. Joule which the structure (50) which is a new structural type has been proposed.94 Pyrolysis of the chloride form produces a Hofmann product which has the same skeleton as alstophylline. From the same Alstonia species macralstoni- dine has been obtained." Macralstonidine is a dimer of N(a)-methylsatpagine (51) and a macroline type unit (52) utilising one mole of formaldehyde in the 9 H H i52) Me & linkage.The acidic fission of the alkaloid (53) which yields these three com- ponents is envisaged as proceeding by hydrolysis of the ketal followed by a retro Michael reaction and finally reverse aldol loss of formaldehyde. The point and mode of attachment was demonstrated by isotopic labelling. Partial 10 H H-\N/-18 94 Z. M. Khan M. Hew and H. Schmid Helv. Chim.Acta 1967 50 1002. 95 E. E. Waldner M. Hesse W. I. Taylor and H. Schmid Helv. Chirn. Acta 1967,50 1926. Alkaloids 439 hydrolysis using deuteriated hydrochloric acid allowed the isolation (with the placing of deuterium atom labels by mass spectrometry) of 10 D (53) (9,10,11 12,18,18,18,20,11',12') 9 D (52) (9,10,11,12,18,18,18,20,20),and 3 D (51) (9',11' 12').These patterns of labelling taken in conjunction with the presence of an AB quartet for two ortho aromatic hydrogen atoms in the n.m.r.spectrum of the alkaloid define the mode of linkage as shown in (53). The structure of isocorymine has been revi~ed.'~ Picraline undergoes a remarkable fission with zinc-hydrochloric acid to give an indole (54).97 Details have appeared of two methods for converting dihydrocorynantheine types into burnamicine types.98 The ring system of vobasine has been obtained by ~ynthesis.~' The important step involved formation of the medium-sized ring by intramolecular acylation of an indole a-position (55)+ (56).The ring system of mavacurine has been preparedio0 synthetically for the first time. 1 'N H \/N Et (54) CH,Ph 0-mPPA w Me Me HO,C J (55) (56) Cl The amide acid (57) underwent a double cyclisation on treatment with phosphorus pentachloride. The partial synthesis of ajmaline from deoxyajmalol-A has been completed by the development of a method for the conversion of deoxyajmaline into ajmaline."' Ajmaline has been obtained by an alternative totally synthetic 96 C. W. L. Bevan M.B. Patel A. H. Rees and A. G. Loudon Tetrahedron 1967 23 3809. 97 A. Z. Britten J. A. Joule and G. F. Smith Tetrahedron 1967,23 1971. 98 L. J. Dolby and S. Sakai Tetrahedron 1967 23 1. 99 S. Yamada and T. Shioiri Tetrahedron Letters 1967 351.loo 0.N. Tolkachev V. G. Korobko T. A. Shapiro and N. A. Preobrazhenskii Khim. getorotsikl. Soedinenii 1967 313. lo' J. D. Hobson and J. G. McCluskey .I.Chern. SOC.(C) 1967,2015. 440 J. A. Joule route ;lo2 N-methyl-3-indolylacetylchloride was condensed with the mag- nesium chelate of ethyl hydrogen A3-cyclopentenyl malonate to give (58 ; R' = C02Et R2 = 0)which was transformed to the desired amino alcohol (58; R' = CH,OH R2 = H,NH,) and its epimer by successive treatment with acetamide and lithium aluminium hydride. After protection this com- pound was cleaved as shown to a di-aldehyde which existed as (59)and cyclised to (60)on acid treatment. The aldehyde group was transformed into nitrile. the CH,OBz Me (58) / (60) 10 (61) Et Ajmaline 13,'14 11 12 Reagents 1 BzCl ;2 OsO ;3 NaIO,; 4 HOAc ; 5 H,NOH ; 6 BzCl ; 7 Ph,CNa-Etl; 8 MeONa; 9 DMSO-Ac,O; 10 HCl-HOAc; 11 H,; 12 LiAl(OEt),H; 13 H,; 14 LiAlH ethyl group introduced by base catalysed alkylation and the ester group converted to aldehyde (61).Treatment of (61) with acid afforded a cyclised product (62) and this was transformed as outlined to ajmaline. Iboga alkaloids. The hydroxyindolenine derivative of coronaridine has been isolatedlo3 from Conopharyngia durissima and synthesised from coronaridine by peracid treatment. The mono-N-oxide of voacamine obtained from Voacanga ~fricana'~~ has been prepared by acid-catalysed condensation of lo2 S. Masamune S. K. Ang C. Egli N. Nakatsuka S.K. Sarkar and Y. Yasunari J. Amer. Chem. SOC.,1967,89,2506. lo' B.C. Das E. Fellion and M. Plat. Compt. rend. 1967 264 C 1765. F.Puisieux J.-P. Devissaguet C. Mict and J. Poisson Bull. SOC.chim. France 1967 251. Alkaloids 441 the N-oxide of vobasinol and voacangine. Details have been publishedLo5 of a synthesis of desethyl ibogamine which utilises methyl 3-cyclohexene-l- carboxylate as a basis for forming the isoquinuclidine system via a 4-amino- cyclohexane carboxylic acid. A preliminary report of another way of con- structing the isoquinuclidine nucleus and of its use to synthesise desethylibog- amine has been given."' The important step involves reaction of 3-indolyl-acetic anhydride with the ethylene imine derivative (63) which provides in one step (64)both the indolylethyl isoquinuclidine ring system and the functionality necessary for closing onto the indole a-position.(63) The amide (66; R' = 0,R2 = OAc) can be obtained from (65) by treatment with acetic anhydride. The reaction must involve initial intramolecular acylation of the tertiary nitrogen with subsequent ring opening."' Standard operations were used to convert the amide (66; R' = 0 R2 = OAc) to the base (66; R' = H, RZ = OH) which in the presence of acid condensed oia an electrophilic centre generated at C-16 with vindoline to give a synthetic dimer of the vinblastine type. *05 J. W. Huffman C. B. S. Rao and T. Kamiya. J. Orq. Chem.. 1967. 32. 697. lo6 W. Nagata. S. Hirai K. Kawata. and T. Okumura J. Arner.Clirw. Soc.. 1967.89. 5046. lo' J. Harley-Mason and Atta-ur-Rahman Chem. Comm. 1967 1048. 442 J. A. Joule Aspidosperma alkaloids. A detailed studylo8 has been made of the mass spectral fragmentation of the schizozygine type of base. The structure (67) has been assigned both to voaphylline'09" from Voacanga ufiicana and to cono- florinel Ogb from Conopharyngia Zongiflora. Both bases were chemically related to (+)-quebrachamine. Rhazidine proves to be' lo a salt derived by a cyclisation (N(b)-,C-2)of the hydroxyindolenine derivative of ( +)-quebrachamine. Also in the same optical series as ( +)-quebrachamine is 16-methoxytabersonine. I 10-Oxocylindrocarpidine from Tabernaemontana arnygdalifoliu can be synthe- sised by permanganate oxidation of cylindrocarpidine.' l2 Kopsingine (68 ; R = OMe) and kopsaporine (68; R = H) have been isolated from Kopsia singapurensis.'' -OH H (67) '"'M. Hesse and U. Renner Helu. Chim.Acta 1966,49 1875. '09 (a) N. Kunesch B. C. Das and J. Poisson Bull. SOC.chim.France 1967 2155;(b)J. J. Dugan M. Hesse U. Renner and H. Schmid Helu. Chim Acta 1967,50,60. 'lo S. Markey K. Biernann and B. Witkop Tetrahedron Letters 1967 157. B. Pyuskyulev I. KompiS I. Ognyanov and G. Spiteller Coll. Czech. Chem. Comm. 1967,32 1289. H. Achenbach Tetrahedron Letters 1967 1793. 'I3 D. W. Thomas,K.Biernann A. K. Kiang and R D. Arnarasingham J. Arner. Chem.SOC. 1967 89 3235. Alkaloids 443 Leurosidine (69; R1= H R2= OH) differs'I4 from vinblastine (69; R' = OH R2= H) only in the position of the hydroxyl group in the cleavamine half.An X-ray analysis of haplophytine dihydrobromide (70) from Huplophyton cimicidum shows it to be a novel dimeric type consisting of a cimicime half-linked to a canthinone moiety.' '' The base itself is considered to be (71). Pycnanthinine (72) can be split by acid treatment into (+)-pleio- carpamine ( -)-6,7-dehydroaspidospermidine and formaldehyde.'' The Me0 MeH (71) fission (as indicated) represents the reverse of the suggested biosynthetic mode of formation. Callichiline a dimeric alkaloid from the Callichilia species proves like vobtusine to be resistant to cleavage."7 From an extensive study of the mass spectrometric fragmentation of the base and of various simple derivatives formed by modification of the chromophore of the vincadifformine half the base was shown to be composed of a beninine moiety and a modified vincadifformine unit."7 The highly hindered N-1' hydrogen of the beninine unit proved totally resistant to detection by acylation in callichiline or any of its derivatives and was only detected by its exchange with deuterium oxide in the mass spectr~meter.~"~ The position of the aromatic methoxyl group was N.Neuss L. L. Huckstep and N. J. Cone Tetrahedron Letters 1967 811. I. D. Rae M. Rosenberger A. G. Szabo C. R. Willis P. Yates D. E. Zacharias G. A. Jeffrey B. Douglas J. L. Kirkpatrick and J. A. Weisbach J. Amer. Chem. Soc. 1967.89 3061. 'I6 A. A. Gorman and H. Schmid Monatsh. 1967,98 1554. (a)M.Plat N. Kunesch J. Poisson C. Djerassi and H. Budzikiewicz,Bull. SOC.chim. France 1967 2669; (b) V. Agwada. A. A. Gorman M. Hesse and H. Schmid Helu. Chim. Acta 1967 50 1939. P 444 J. A. Joule H etc. - I deduced from the n.m.r. spectrum of the 15'-mononitro derivative of calli- chiline. The formulation (73) for the dimer is consistent with all the known facts and is considered' 17' the best working hypothesis. Structures involving linkages 2'4 3'-22'-7 and 2'-21 3'-22'-20 have also to be considered.'17' QZ Me0 OMe Alkaloids 445 A remarkable disruption of the aromatic ring of 17-alkoxyaspidosperma alkaloids occurs on oxidation with iodine-sodium hydroxide' l8 when com- pounds with a part structure (74) are formed.The earlier synthetic approach' '' which yielded stereospecifically' 2o 3a-methyl aspidospermidine by rearrange- ment of a suitable eburnea skeleton has been modified to produce aspidos- permidine itself.',' Lycopodium Alkaloids.-The novel bases cernuine (75; R' = H R2 = 0) and lycocernuine (75; R' = OH R2 = 0) from Lycopodium cernuum have been shown to have the structures and relative stereochemistry shown by a combination of chemical and spectral studies. 22 Dehydrogenation of dihydro- deoxyepiallocernuine (75; R1= H R2= H, 9 and 13a-H)gave 2-butyl-6- hexyl-4-methylpyridine derived from the c ring and containing all the carbon atoms. Central in the structure determination was the tricyclic degradation product (76) obtained from allocernuine (75; R' = H R2 = 0 13a-H) by successive reduction with sodium borohydride and lithium aluminium hydride.This tricyclic compound was obtained as an intermediate in a synthesis of dihydrodeoxyepiallocernuine,' 2b starting from 2,4,6-collidine. (75) Serrati~~e"~ have been chemically inter-related with and fa~cettimine''~ serratinine. The photochemical addition of allene to double bonds has been used in elegant syntheses of 12-epi-ly~opodine'~~ and annotinine. '26 Terpenoid and Steroidal Alkaloids.-More of the chemistry of the complex alkaloids of Duphniphyllum macropodurn has been re~0rted.l~~ It has been suggested that these bases may be derived from four isoprene and one acetate 118 B. W. Bycroft L. Goldman and H. Schmid Helo. Chim. Acta 1967,50 1193.'I9 Ann. Reports 1966,62 386. 0.Kennar K. A. Kerr Q G. Watson J. K. Fawcett and L. Riva di Sanseverino Chem. Comm. 1967 1286. J. Harley-Mason and M. Kaplan Chem. Comm. 1967,915. 122 (a)W. A. Ayer J. K. Jenkins S. Valverde-Lopez and R.H. Burnell Canad. J. Chem. 1967,45 433; W. A. Ayer J. K. Jenkins K. Piers and S. Valverde-Lopez ibid. p. 445; (b)W. A. Ayer and K. Piers Canad. J. Chem. 1967 45 451. Y. Inubushi H. Ishii and T. Harayama Chem. and Pharrn. Bull. (Japan) 1967 15 250. 124 Y. Inubushi H. Ishii T. Harayama R. H. Burnell W. A. Ayer and B. Altenkirk Tetrahedron Letters 1967 1069. 12' H. Dugas M. E. Hazenberg Z. Valenta and K. Wiesner Tetrahedron Letters 1967,4931. 126 K. Wiesner and I. Jirkovsky Tetrahedron Letters 1967 2077; K.Wiesner and L. Poon ibid. p. 4937. 12' S. Yamamura H. Irikawa and Y. Hirata Tetrahedron Letters 1967 3361; T. Nakano and Y. Saeki ibid. p. 4791. 446 J. A. Joule unit. Full details of Nagata's synthetic work on atisine veatchine and garryine have appeared.'28 Pachysandra alkaloid studies continue to produce interesting variations such as pachysandrine-B [77; R' = CO*CH:C(Me), R2 = P-OAc] and pachysandrine-D [77;R1= H R2 = ol-O*CO*CH:C(Me),J.129 The lactone alkaloids [part structure (78)] and the lactam alkaloids [part structure (79)] may arise from the pachysandrine D and B types respectively by condensations involving the N-methyl carbon atom. Veralkamine (80) from Veratrum album has the unusual 17~-methyl-18-nor-l7-isocholestane carbon ~keleton.'~' R' JeJ &?-J Me+DO Me H (79) HO Verazine (81)also from Veratrum album has been synthesised from tomatid-5- en-3P-01.' 31 The relative configuration of the 23-hydroxyl group of veratramine W.Nagata T. Sugasawa M. Narisada T. Wakabayashi and Y. Hayase J. Amer. Chem. Soc. 1967,89 1483; W. Nagata M. Narisada T. Wakabayashi and T. Sugasawa ihid. p. 1499. M. Tomita S. Uyeo and T. Kikuchi Chem. and Pharm. Bull. (Japan),1967,15 193; T. Kikuchi S. Uyeo and T. Nishinaga ibid. p. 577. 130 J. Tomko A. Vassovh G. Adam K. Schreiber and E. Hohne Tetrahedron Letters 1967 3907. 131 (a)G. Adam K. Schreiber,J. Tomko and A. VassovA Tetrahedron 1967.23,167;(b)G. Adam K. Schreiber and J. Tomko Annulen 1967,707.203. Alkaloids 447 and jervine has been revised on the basis of an n.m.r.17-Acetyl-5a-aetioJerva-12,14,16-trien-3~-ol and transformed into has been synthesi~ed'~~" veratramine and jer~ine.'~~~ Galbulimima Alkaloids.-More of the chemistry of this group has been described.'. '34 The bases so far recognised comprise variations (in the 0-acyl and 0-alkyl residues) on three skeleta the himba~ine,'~~ the hirnbosine (82; R' = Ac R2 = Ac R3= Bz R4 = OAc) and the himbadine (83; R' = Me R2 = R3= H) systems. The numbering given for himbosine is based on a postulated polyacetate biogenesis. An elegant analysis' 34a of the chemistry and spectral properties of himandridine (82; R' = H R2 = Bz R3 = Me R4 = OH) and its derivatives allowed the derivation of its structure independently of the X-ray analysis' 36 of himbosine with which it was subsequently chemically interrelated.' 34b Central in the structure deter-& '' M OR' &Me H~II 6 I! 11 Hg \\\\\ H 12 1 19 IS 18 'Me H - R4+\:3 l4 s R3H sfi:l6 17 CO,Me -R' OR3 ORz (82) (83) OMe (84) (85) 13' J.W. Scott L. J. Durham H. A. P. De Jongh U. Burckhardt and W. S. Johnson Tetrahedron Letters 196 7 2381. lJ3 (a) W. S. Johnson J. M. Cox D. W. Graham and H. W. Whitlock J. Amer. Chem. SOC.,1967 89,4524; (b)W. S. Jonnson H. A. P. de Jongh C. E. Coverdale J. W. Scott and U. Burckhardt ibid. p. 4523; T. Masamune M. Takasugie. A. Murai and K. Kobayashi ibid. p. 4521. IJ4 (a)L. bi.Mander E. Ritchie and W. C. Taylor. Austral. J. Chem. 1967,20,981; (b)L.N. Mander E. Ritchie and W. C. Taylor ibid. p. 1021 ;(c) G. B. Guise L. N. Mander R. H. Prager M. Rasmiissen E. Ritchie and W. C. Taylor ibid. p. 1029; L. M. Mander R. H. Prager M. Rasmiissen E. Ritchie and W. C. Taylor ibid. p. 1473; (d)L. N. Mander R H. Prager M. Rasmiissen E. Ritchie and W. C. Taylor ibid. p. 1705. Ann. Reports 1961,58,287. 136 F. M. Lovell Proc. Chem. SOC. 1964 58. 448 J. A. Joule mination was an aromatisation reaction to (84),brought about by the action of hot benzoyl chloride on the base. Further degradation of this product gave the naphthalene (85) which was synthesised. The N-acetyl derivative (83; R' = Ac R2 = R3 = H) of G.B.13 an alkaloid of the himbadine type has been obtained'34u from himandrine (82; R' = H R2 = Bz R3 = Me R4 = H).The crucial step in the interconversion involved the ingenious use of chromous chloride to cleave the nitrogen from a position y to an qJ.3-unsaturated ketone (86) +(83; R' = H R2 = CO,Me R3 = OMe). Miscellaneous Alkaloids.-From Cassipourea species gerrardine (87) and cassipourine (88) have been isolated and their structures determined by X-ray ~rystallography.'~' Solapalmatine [Me2N-(CH2),] N*CO*(CH,), *Me and solapalmitenine [Me2N *(CH2),I2 -N *CO .CH CH .(CH,) Me from Solanum tripartitum have tumour inhibitory properties. '38 The structure (89) 13' W. G. Wright and F. L. Waren J. Chem. SOC.(C) 1967 283 284; R. G. Cooks. F. L. Warren and D. H. Williams ibid. p. 286. 138 S. M. Kupchan A. P. Davies S. J. Barboutis H.K. Schnoes and A. L. Burlingame J. Amer. Chem. SOC.,1967,89 5718. Alkaloids 449 of stenine from Stemona tuberosa was demonstrated by interconversion with tuberstemonine. 39 Zapotidine has been synthesised. 140 Cocculolidine (90) from Cocculus trilobus has insecticidal properties. 14' Full -details have been given of the synthesis of securinine and virosecurinine. 142 139 S. Uyeo H. Irie and H. Harada Chem. and Pharm. Bull. (Japan) 1967 15 768; H. Harada H. Irie N. Masaki K. Osaki and S. Uyeo Chem. Comm. 1967,460. R. Mechoulam and A. Hirshfeld Tetrahedron 1967 23 239. 141 K. Wada S. Marumo and K. Munakata Agric. and Bid. Chem. (Japan) 1967,31,452. Z. Horii M. Hanaoka Y. Yamawaki Y. Tamura S. Saito N. Shigematsu N. Kotera H. Yoshi- kawa Y.Sato H.Nakai and N. Sugimoto Tetrahedron 1967 23 1165.