TOTAL SYNTHESES AND ANTICHOLINESTERASE ACTIVITIES OF (3AS)-N(8)-NORPHYSOSTIGMINE, (3AS)-N(8)-NORPHENSERINE, THEIR ANTIPODAL ISOMERS, AND OTHER N(8)-SUBSTITUTED ANALOGS

N(8)-Benzylesermethole (6) was prepared from 5-methoxytryptamine (1) i n five steps. Resolution of compound 6 by dibenzoyl- and ditoluyltarta ric acid provided enantiomers (-)- and (+)-7. After demethylation, rea ction with isocyanates and catalytic debenzylation over hydrogen, the total syntheses of(-)-and (+)-N(8)-norphysostigmine [(-)-and (+)-11] a nd (-)-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 configurat ions and optical purity of compounds (-)-11, (-)-12, (+)-11, and (+)-1 2 were confirmed by a comparison of their optical rotations with those of the compounds synthesized from physostigmine [(-)-13]. The anticho linesterase activities of N(8)-nor-and N(8)-substituted analogues, (-) -and (+)-9, -10, -11, -12, 15, and 16, were compared with those of phy sostigmine [(-)-and (+)-13] and phenserine [(-)- and (+)-14] and are r eported.