Catalytic Enantioselective Synthesis of Protecting-Group-Free 1,5-Benzothiazepines

A one-pot enantioselective route to N-unprotected 2,3-dihydro-1,5-benzothiazepinones, by an organocatalyzed sulfa-Michael reaction of readily available a,b-unsaturated N-acyl pyrazoles with 2-aminothiophenols followed by silica-gel-catalyzed lactamization, has been developed. The method proceeds under mild conditions at room temperature and it requires only 1 mol% catalyst loading, to give 2-aryl/alkyl-substituted 1,5-benzothiazepines in generally good to excellent yields and enantioselectivities. The process, used for a short synthesis of antidepressant drug (R)-thiazesim, represents the first method to access enantioenriched unprotected 1,5-benzothiazepines, which are useful for rapid derivatization in drug discovery