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Synthesis of the Thiazolone Analogue of the Acetylcholinesterase Inhibitor, Huperzine A
Author(s) -
Kozikowski Alan P.,
Tückmantel Werner,
Saxena Ashima,
Doctor Bhupendra P.
Publication year - 1994
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19940770508
Subject(s) - chemistry , moiety , huperzine a , thiazole , nonane , stereochemistry , acetylcholinesterase , ring (chemistry) , bicyclic molecule , aldol condensation , cyclohexane , organic chemistry , catalysis , enzyme
The preparation of an analogue 3a of the acetylcholinesterase inhibitor, huperzine A ( 1 ), is described in which the pyridinone moiety of the natural product is replaced with a thiazolone moiety. The synthesis started from cyclohexane‐1,4‐dione monoethylene ketal ( 7 ) by first annulating the thiazole ring using the Gewald protocol (→ 8 ; Scheme 1 ) and then constructing the bicyclo[3.3.1]nonane substructure using our previously described Michael addition/aldol condensation methodology ( Scheme 3 ). The central problem was the protection of the thiazolone carbonyl group; only the 2‐unsubstituted thiazole survived the reaction conditions of the first half of the synthesis. Refunctionalization was later effected by lithiation and subsequent chlorination with hexachloroethane ( 30→31 ). Compound 3a was ineffective in the acetylcholinesterase inhibition assay in concentrations up to 14 μ M .