Synthesis of the Thiazolone Analogue of the Acetylcholinesterase Inhibitor, Huperzine A

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 .