Enzyme-Mediated Cross-Benzoin Reaction of Highly Enolizable Aldehydes and Aryl Aldehydes for Acess to Chiral Phosphonates

Enzymatic catalysis has emerged as an attractive technology for organic synthesis but remains in its infancy for constructing biologically-relevant chiral phosphonates. Here, we disclose a highly chemo- and enantioselective reactions between highly enolizable 2-phosphonate aldehydes and aryl aldehydes for synthesis of chiral phosphonates. This reaction mediated by PfBAL or its mutant A28G features the first example of cross-benzoin reaction involving highly enolizable aldehydes, an elusive challenge previously. Unlike the small molecule NHC-mediated process that give complex mixture of multiple adducts, our enzymatic process selectively gives biologically active hydroxyl ketone-containing phosphonate products in excellent yields and enantioselectivities. The chiral phosphonate products can be obtained on gram scales and carry rich reactivities for further downstream transformation to afford diverse molecules, which will bring more opportunity to the development of novel C-P drugs. This work opened a new avenue in the development of novel cross-benzoin reaction and will stimulate the widespread application of cross-benzoin in organic synthesis.