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

• Published in: Journal of medicinal chemistry 1997-08, Vol.40 (18), p.2895-2901
• Main Authors: Yu, Qian-sheng, Pei, Xue-Feng, Holloway, Harold W, Greig, Nigel H, Brossi, Arnold
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - blood; Acetylcholinesterase - isolation & purification; Biological and medical sciences; Butyrylcholinesterase - blood; Butyrylcholinesterase - isolation & purification; Catecholaminergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Erythrocytes - enzymology; Humans; Indicators and Reagents; Isomerism; Kinetics; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Physostigmine - analogs & derivatives; Physostigmine - chemical synthesis; Physostigmine - chemistry; Physostigmine - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970210v

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.