Chirospecific synthesis of nitrogen and side chain modified analogs of (+)-anatoxin

Abstract

Received J a n u a r y 23, 1989 Improvements in the chirospecific synthesis of (+)-anatoxin from D-glutamic acid have resulted in a process that gives enantiomerically pure material in reproducible 25 % overall yield. The major synthetic modifications have been in the decarbonylative iminium ion cyclization and in the introduction of the enone moiety. With multigram quantities of (+)-anatoxin thus available, a series of nitrogen and side chain modified analogues has been prepared. These analogues were chosen to provide probes for the agonist-receptor interaction model of acetylcholine. They include secondary, tertiary, and quatemary nitrogen derivatives and those in which the carbonyl function has been converted to secondary and tertiary alcohol and ester functions. Cheng, M. T.; Mutter, L. C.; Abood, L.G. J . Am. Chem. SOC. 1986,108, 7864. (c) Compound (+)-3 is the precursor of (+)-l in Edwards' synthesis of (+)-anatoxin from cocaine;% 3 has also been synthesized in racemic form.

The Chemistry and Pharmacology of Anatoxin-a and Related Homotropanes with respect to Nicotinic Acetylcholine Receptors

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Aspectos toxicológicos e químicos da Anatoxina-a e seus análogos

“…O iodeto 4b foi obtido pelo tratamento do álcool 3 com iodo e trifenil fosfina. Os compostos 4a e 4b, assim obtidos, foram transformados na (±)-Anatoxina-a 1 através de metodologia já descrita por Rapoport et al 45 , destacando-se como vantagem desta rota a possibilidade de obtenção da toxina em escala de gramas.…”

“…Na seqüência, ocorreu uma ciclização eletrofílica, posteriormente usou-se reagentes de selênio para introduzir uma ligação dupla, em posição definida, através da eliminação de selenóxido 7. Os compostos 8 foram reduzidos por hidrogenação e os assim obtidos (9) foram transformados nos análo-gos 10, seguindo novamente a estratégia proposta por Rapoport 45 . Forro e colaboradores 47 propuseram como um possível material de partida para síntese da Anatoxina-a, enantiomericamente pura, as β-lactamas 16 e 17 (Esquema 3).…”