Thiol-free multicomponent synthesis of non-racemic β-acyloxy thioethers from biocatalytically obtained chiral halohydrins

A novel multicomponent chemoenzymatic strategy for the preparation of enantioenriched β-acyloxy thioethers has been developed. This robust methodology employs mild bases, air atmosphere, room temperature and avoids the use of foul-smelling thiols. Instead, potassium thioacetate is employed as a universal sulfur source. This chemoselective strategy tolerates aromatic and aliphatic components and diverse functional groups. The chirality is enzymatically defined by ADH-catalyzed bioreduction of α-haloketones delivering an enantioenriched halohydrin which is one of the three components, and the optical purity remains untouched in the final product. Semipreparative scale multicomponent reaction affords high yield of the products (up to 96%). A novel thiol-free MCR for the mild synthesis of enantioenriched β-acetoxy sulfides using enzymatically prepared chiral halohydrins, potassium thioacetate and electrophiles is described.