Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers, and other N(8)-substituted analogues.
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.
Yu
Q S
QS
Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Pei
X F
XF
Holloway
H W
HW
Greig
N H
NH
Brossi
A
A
D000110:Acetylcholinesterase / Q000097:blood* / Q000302:isolation & purification; D002091:Butyrylcholinesterase / Q000097:blood* / Q000302:isolation & purification; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007202:Indicators and Reagents; C108183:N(8)-norphenserine; C108182:N(8)-norphysostigmine; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase