Synthesis of the thiazolone analogue of the acetylcholinesterase inhibitor, huperzine A

Article abstract of DOI:10.1002/hlca.19940770508

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) and then constructing the bicyclo[3.3.1]nonane substructure using our previously described Michael addition/aldol condensation methodology. 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 μM.