The modulation of the biological activity in small-molecule drugs by introducing carbon-bound fluorine at specific sites has developed into a successful tool in medicinal and agro-chemistry. When the synthesis of this type of compounds requires the introduction of the difluoroacetate moiety, the versatile, reliable, and functional-group tolerant Reformatsky reaction, that is based upon organo-zinc reagents, is  a good choice – provided that asymmetric variants are available that create, due to an appropriate chiral information, the stereogenic carbon centers (C*) in an enantioselective manner. 

The review published by Prof. i. R Manfred Braun presents the efficient methods that were developed in order to obtain those targets. Among them are Gemcitabine, that serves for the treatment of metastatic pancreas cancer as well as HIV-protease inhibitors, and a series of other biologically active compounds.

Back in the 1990s, the Braun group at HHU had studied the asymmetric difluoro-Reformatsky reaction and developed the first enantioselective variant by simply adding to the reaction mixture commercially available N-methyl ephedrine, a chiral amino alcohol that functions as chiral ligand at the metal.

M. Braun, The Asymmetric Difluoro-Reformatsky Reaction, Eur. J. Org. Chem. 2021, 1825 – 1836. doi.org/10.1002/ejoc.202100004