[Studies on analogues of huperzine A for treatment of senile dementia. VI. Asymmetric total synthesis of 14-nor-huperzine A and its inhibitory activity of acetylcholinesterase].
OBJECTIVE
To study asymmetric total synthesis of 14-nor-huperzine A 2 and its inhibitory activity on acetylcholinesterase.


METHODS
Highly enantioselective synthesis of compound 5 from beta-keto-ester 3 and 2-methylene-1,3-propanediol diacetate 4 by palladium-catalyzed bicycloannulation was carried out using new chiral ferrocenylphosphine ligands, such as 10, 11, followed by regioselective double-bond migration to produce compound 6. Optically pure 6 was obtained after enantio-enrichment recrystallization. Then, according to similar procedures of huperzine A synthesis, the target compound 14-nor-huperzine A 2 was prepared. The inhibitory activity was tested with rat erythrocyte membrame acetylcholinesterase.


RESULTS
The inhibitory activity of synthetic (-)-14-nor-huperzine A was 8 fold less potent than that of (-)-huperzine A.


CONCLUSIONS
A hydrogen-bond between 14-methyl group of (-) huperzine A and the main-chain oxygen of His 440 is necessary for the highly acetylcholinesterase inhibitory activity of huperzine A.
He
Xu-chang
XC
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Yu
Geng-li
GL
Bai
Dong-lu
DL
D000110:Acetylcholinesterase / Q000378:metabolism*; D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000201:enzymology; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
C484874:14-norhuperzine A; D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D012717:Sesquiterpenes; C050426:huperzine A; D000110:Acetylcholinesterase