The Asymmetric Difluoro‐Reformatsky Reaction

Abstract

The structural motif of α,α-difluoro-substituted carboxyl and carbonyl groups with hydroxy-or amino-substituents at the stereogenic carbon in β-position is found frequently in drugs and biologically active compounds. A straightforward method for obtaining those targets in high enantiomeric purity is given by asymmetric difluoro-Reformatsky and imino-difluoro-Reformatsky reactions that lead to α,α-difluorinated β-hydroxyand β-amino-carboxylates or β-lactams. Three concepts that open a route to this type of compounds are discussed here. Firstly, chiral substrates are able to induce stereoselectivity in the formation of the newly created stereogenic center. Secondly, covalently bound and removable chiral auxiliaries are used in asymmetric syntheses and, thirdly, chiral additives and ligands at the metal direct the addition of the zinc enolate, the Reformatsky reagent, to aldehydes or imines in an enantioselective manner. The review closes with a short discussion of more recently developed difluoro-aldol reactions that may be considered as alternatives to the Reformatsky procedure.