Total Syntheses and Anticholinesterase Activities of (3aS)-N(8)-Norphysostigmine, (3aS)-N(8)-Norphenserine, Their Antipodal Isomers, and OtherN(8)-Substituted Analogues

Journal of Medicinal Chemistry
1997.0

Abstract

N(8)-Benzylesermethole (6) was prepared from 5-methoxytryptamine (1) in five steps. Resolution of compound 6 by dibenzoyl- and ditoluyltartaric acid provided enantiomers (-)- and (+)-7. After demethylation, reaction with isocyanates and catalytic debenzylation over hydrogen, the total syntheses of (-)- and (+)-N(8)-norphysostigmine [(-)- and (+)-11] and (-)- and (+)-N(8)-norphenserine [(-)- and (+)-12] were accomplished, (-)-N(8)-Norphysostigmine [(-)-11] and (-)-N(8)-norphenserine [(-)-12] were also obtained by transformations of natural physostigmine [(-)-13] and phenserine [(-)-14] prepared from (-)-13. The absolute configurations and optical purity of compounds (-)-11, (-)-12, (+)-11, and (+)-12 were confirmed by a comparison of their optical rotations with those of the compounds synthesized from physostigmine [(-)-13]. The anticholinesterase activities of N(8)-nor- and N(8)-substituted analogues, (-)- and (+)-9, -10, -11, -12, 15, and 16, were compared with those of physostigmine [(-)- and (+)-13] and phenserine [(-)- and (+)-14] and are reported.

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