Manipulating activity and chemoselectivity of a benzaldehyde lyase to synthesize α-hydroxyketones.

The α-hydroxyketone motif is a key structural element in many pharmaceuticals and serves as a versatile intermediate in the synthesis of fine chemicals and natural products. Benzaldehyde lyase (BAL), a thiamine diphosphate (ThDP)-dependent enzyme, has emerged as a prominent biocatalyst for the synthesis of α-hydroxyketones. In recent years, significant research efforts have focused on the engineering and discovery of BAL mutants with unique or enhanced properties. In this chapter, we first review the engineering and applications of BALs in α-hydroxyketone synthesis. Next, we outline strategies to engineer BALs for improved activity and chemoselectivity. Subsequently, molecular dynamics studies have elucidated the structural basis for improved catalytic performance. Finally, we detail general procedures for synthesizing α-hydroxymethyl ketones and for developing a one-pot concurrent reaction coupling BALs with carbonyl reductases. These biocatalytic processes offer efficient routes for the synthesis of α-hydroxymethyl ketones and chiral 1,2-diols.