lndolizidine Alkaloids J. A. Lamberton Division of Applied Organic Chemistry CSIRO GPO Box 4331 Melbourne Victoria Australia 3001 Reviewing the literature published between July 1982 and June 1983 (Continuing the coverage of literature in The Alkaloids Vol. 13 p. 82) 1 Slaframine Swainsonine and Castanospermine 2 Cyclizidine 3 Phenanthroindolizidines 4 Dendrobates Alkaloids 5 Miscellaneous Alkaloids 6 References 1 Slaframine Swainsonine and Castanospermine Slaframine (1) is the neurotoxic agent of Rhizoctonia legumini- cola and a second alkaloid from the same source was considered to be a 3,4,5-trihydroxypyrindine(2). The latter alkaloid has now been shown to be (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine(3),* identical with the alkaloid swainsonine for which the absolute configuration had not been established previously.Swainsonine a potent inhibitor of the enzyme a-mannosidase is the toxic constituent of Swainsona canescens and locoweeds (Astragalus spp.) (cf ref. 3b). The absolute configuration that has now been established* supports speculation that the enzyme-inhibitory action of this alkaloid results from the similarity of the protonated form of swainson- ine to the mannosyl cati~n.~?~ Slaframine and swainsonine have opposite absolute configurations at C-1 and C-8a.* Castanospermine (4) a related alkaloid from Castanospermum (3) OSiBuIMe '.-("" (7) R' = OSiButMe2,R2 = H (8) R' = H R2 = OSiButMe2 (9) australe (c. ref. 3a) is an inhibitor of almond emulsin p-glucosidase and P-glucocere brosidase.Slaframine has been synthesized from the diene-aldehyde (9, which was converted in several steps into the t-butyl- dimethylsilyl ether (6).An intramolecular imino-Diels-Alder reaction brought about by thermolysis of (6) in refluxing 1,2- dichlorobenzene gave a mixture of the bicyclic lactams (7) and (8) which were then converted into (+)-slaframine and (+)-1-epi-slaframine respectively.6 2 Cyclizidine Cyclizidine (9) an unusual indolizidine has been isolated from a previously undescribed species of the genus Streptomyces and the complete structure and relative stereochemistry have been established by X-ray crystallography and by spectroscopic studies. 3 Phenanthroindolizidines Two previously known alkaloids i.e.3,6,7-trimethoxyphen- anthroindolizidine (lo) [identical with (-)-deoxypergularin-ine] and 3,6,7-trimethoxy-l4-hydroxyphenanthroindolizidine (1 1) [identical with 0-methyltylophorinidine]have been isolat- ed from Ficus hispida. A third alkaloid hispidine is new and has been shown to be (12) i.e. the seco-analogue of A very thorough study has been reported of the synthesis of (+)-tylophorine by two synthetic routes one of which is a biogenetically patterned synthesis. This work includes synthe- ses of the related alkaloids (&)-septicine and (+)-deoxytylo-ph~rinine.~ New syntheses of (+)-tylophorine and the corre- sponding seco-alkaloid (& )-septiche have been achieved by means of a regioselective [3 + 21 cycloaddition between 1 -pyrroline 1-oxide and 3,4-dimethoxystyrene.O Syntheses of (&)-antofine and (&)-alkaloid C have also been described. 4 Dendrobates Alkaloids Neotropical poisonous frogs of the genus Dendrobates are a rich souce of alkaloids many of which are indolizidines. The extensive structural synthetic and biological studies of these compounds have been discussed in a detailed and authoritative review.]* and important studies in this field have continued. (f)-Gephyrotoxin (1 3) has been obtained by an entirely new total synthesis in which cyclohexenone buta- 1,3-diene succin- imide ethyl bromoacetate and propyne were the starting mater- ials. This route was adapted to the preparation of (+)-dihydro-gephyrotoxin (14) a structure which previously had been assigned tentatively to a minor Dendrobatid alkaloid.Confor- OMe OMe (10) R = H (11) R = OH NATURAL PRODUCT REPORTS 1984 (13) R = CeCH (14) R = CH=CHz Ph Ph PNhO PNAO l+..pH2 %? Me Me (17) AcO 'COMe "'"fMe H brn R2 1. (18) (19) R' = H R2 = Bu" (20) R' = Bun R2 = H mational preferences of (13) (14) and related compounds as indicated by H n.m.r. studies have been disc~ssed.~~ Another new approachlj to (&)-gephyrotoxin gave the tricyclic enamine ketones (1 5; R = a-H) and (1 5;R = P-H) which had been converted into ( -t)-gephyrotoxin in a previous successful synthesis. In studies directed at synthesis of the pumiliotoxin A class of alkaloids it has been shown that N-acyl-2-isopropenylpyrrol-idines such as the benzamide (16) react with N-bromosuccin- imide and water in a highly stereoselective way to give mainly the isomer (1 7).A mechanism involving carbonyl participation has been suggested.I5 The product resulting from ozonolysis of pumiliotoxin B diacetate has been shown to be identical with synthetic 3,4-diacetoxypentan-2-one (18) that was derived from L-( +)-tartaric acid and this shows that pumiliotoxin B (cJ ref. 3c) has the absolute configuration (R,R)for the C-15,C16-diol group.I6 The threo configuration for this diol group was assigned previously. The indolizidines (19) and (20),which are stereo- isomers of gephyrotoxin 223AB have been prepared by stereoselective syntheses. 5 Miscellaneous Alkaloids A detailed account has been published of the previously reported synthesis of (+)-elaeokanine C which was obtained by a 1,3-dipolar cycloaddition of I-pyrroline I-oxide.19 Julipro- sopine has been isolated from two more species of the genus Prosopis (P.glandulosa and P.farcta).20 A further synthesis of 6-coniceine has been described.2 An extensive review of indolizidine alkaloids has been published. 22 6 References 1 F. P. Guengerich S. J. DiMari and H. P. Broquist J. Am. Chem. SOC.,1973 95 2055. 2 M. J. Schneider F. S. Ungemach H. P. Broquist and T. M. Harris Tetrahedron 1983 39 29. 3 J. A. Lamberton in 'The Alkaloids' ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1982 Vol.12 p. 69; (b) 1983 Vol. 13 p. 82; (c)1983 Vol. 13 p. 84. 4 P. R. Dorling C. R. Huxtable and S. M. Colegate Biochem. J. 1980 191 649. 5 R. Saul J. P. Chambers R. J. Molyneux and A. D. Elbein Arch. Biochem. Biophys. 1983 221 593. 6 R. A. Gobao M. L. Bremmer andS. M. Weinreb J. Am. Chem. SOC.,1982 104 7065. 7 A. A. Freer D. Gardner D. Greatbanks J. P. Poyser and G. A. Sim. J. Chem. SOC. Chem. Commun. 1982 1160. 8 S. R. Venkatachalam and N. B. Mulchandani Naturwissenscha! ten 1982 69 287. 9 J. E. Cragg R. B. Herbert F. B. Jackson C. J. Moody and I. T. Nicolson J. Chem. SOC. Perkin Trans. 1 1982 2477. 10 H. Iida M. Tanaka and C. Kibayashi J. Chem. Soc. Chem. Commun. 1983 271. 11 D. S. Bhakuni and P. K. Gupta Indian J. Chem. Sect.B 1982 21 393. 12 J. W. Daly Progr. Chem. Org. Nat. Prod. 1982 41 207. 13 D. J. Hart and K. Kanai J. Am. Chem. Soc. 1983 105 1255. 14 Y. Ito E. Nakajo M. Nakatsuka and T. Saegusa Tetrahedron Lett. 1983 24 2881. 15 L. E. Overman and R. J. McCready Tetrahedron Lett. 1982 23 4887. 16 M. Uemura K. Shimada T. Tokuyama and J. W. Daly Tetrahedron Lett. 1982 23 4369. 17 L. E. Overman and R. J. McCready Tetrahedron Lett. 1982 23 2355. 18 D. J. Hart and Y.-M. Tsai J. Org. Chem. 1982 47 4403. 19 H. Otomasu N. Takatsu T. Honda and T. Kametani Tetrahedron 1982 38 2627. 20 K. Usmanghani Q. N. Saqib and V. U. Ahmad J. Chem. SOC. Pak. 1982 4 285. 21 S. Danishefsky E. Taniyama and R. R. Webb Tetrahedron Lett. 1983 24 11. 22 E. Gellert J. Nat. Prod. (Lloydia) 1982 45 50.