Synthesis of Ergot Alkaloids from Tryptophan

The first total syntheses of lysergine and setoclavine are described, as well as a new and efficient synthesis of lysergic acid. The starting material for these syntheses is tryptophan, protected as its dihydro, dibenzoyl derivative. This material is dehydrated to the corresponding azlactone, which undergoes stereoselective intramolecular Friedel-Crafts acylation to give a tricyclic ketone intermediate. Reformatsky reaction with ethyl a-(bromomethy1)acrylate introduces the remaining four carbons and leads to a spiro methylene lactone that represents the branching point of the three syntheses. The high selectivity of the reactions described permits the synthesis of optically active ergot alkaloids from L-tryptophan. Ergot alkaloids possess a range of biological activity, and a number of ailments are currently treated with ergoline derivatives.' The parent structure of these agents, lysergic acid ( l ) , has been I Lrrargic a c i d Z R . H. Lyaarglna 3 R .OH, Saioclovlne seminal in the origin of psychopharmacology and its abuse as the diethylamide made LSD a household term in the 1960s. The significance of 1 as a synthetic target may be weighed by the fact that of the six total three have appeared during the last 2 years. The position of lysergic acid among the ergot alkaloids is more than symbolic. I t provides the starting material for the formal syntheses* of several other ergolines such as lysergine (2) and setoclavine (3), both of which were unknown in racemic form before our synthetic work. Synthetic approaches to the ergot alkaloids have been compiled in an extensive, recent reviewg which concludes that chemical synthesis is not yet able to compete with fermentation processes for access to these substances. The central intermediate in several successful syntheses has been Uhle's ketonelo 4, (Scheme I) either as the protected derivative 5 or its carbonyl transposition'la product 6. The former was involved in both Kornfeld's2 and Ramage's4 synthesis of lysergic acid as well as Kornfeld's12 synthesis of isosetoclavine (7). The latter is encountered in Ninomiya's6 synthesis of 1 and is a key intermediate in the synthesis of cis-fused dihydroisolysergyl derivatives. I b The alternative to Uhle's ketone has been the preparation of 4-substituted indoles'j as in Scheme 11. For example, 8 has been (!) For a review on the pharmacology of these compounds, see: Berde, B., Schild, H. O., Eds. "Ergot Alkaloids and Related Compounds"; SpringerVerlag: Berlin, 1978. (2) Kornfeld, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. SOC. 1956, 78, 3087-3114. (3) Julia, M.; LeGoffc, F.; Igolen, J.; Baillarge, M. Tetrahedron Lett. 1969, 1569-1571. (4) Ramage, R.; Armstrong, V. W.; Coulton, S. Tetrahedron Suppl. 1981, 37, 157-164. Preliminary Communication: Tetrahedron Lett. 1976, ( 5 ) Oppolzer, W.; Francotte, E.; Battig, K. Helv. Chim. Acta 1981, 64, (6) Kiguchi, T.; Hashimoto, C.; Naito, T.; Ninomiya, I. Heterocycles 1982, (7) Rebek, J.; Tai, D. F. Tetrahedron Lett. 1983, 24, 859-860. (8) Yamatodani, S.; Abe, M. Bull. Agr. Chem. SOC. Jpn. 1956,20,95-96 (9) Horwell, D. C. Tetrahedron 1980, 36, 3123-3149. (10) Uhle, F. C. J . Am. Chem. SOC. 1949, 71, 761-766. Uhle, F. C.; McEwen, C. M.; Schroter, H.; Yuan, C.; Baker, B. W. Ibid. 1959, 82, 1200-1 207. (1 1) (a) Nichols, D. E.; Robinson, J. M.; Li, G. S.; Cassady, J. M.; Floss, H. G. Org. Prep. Proced. Int. 1977, 9, 277-80. (b) Cassady, J. M.; Li, G. S.; Spitzner, E. B.; Floss, H. G. J . Med. Chem. 1974, 17, 300-307. (12) Kornfeld, E. C.; Bach, N. J. Chem. Ind. (London) 1971, 1233-34. (13) Kozikowski, A. P. Heterocycles 1981, 16, 267-291. 4311-4314.