Taming highly enolizable aldehydes for catalytic asymmetric C-C coupling with nucleophiles remains an elusive challenge compared to widely explored simple alkyl or aryl aldehydes. Herein, we use ThDP-dependent enzymes to realize the direct C-C coupling of highly enolizable 2-phosphonate aldehydes with in situ-generated dynamically reversible nucleophiles (acyl anions). Unlike NHC-mediated reactions that yield complex mixtures of multiple adducts, our enzymatic process selectively produces biologically active β-hydroxy phosphonates with high yields (up to 95%) and excellent enantioselectivities (up to 99% ee). The products can be obtained on gram scales and exhibit rich reactivity for downstream transformations to afford diverse molecules. BAL (or its mutant A28G) and BAL enzymes serve as enantiocomplementary pairs, enabling the synthesis of both product configurations. Mechanistic studies proved that the entrance directions of the active cavities of these two enzyme pairs were distinct, leading to acyl anions formed from these two enzyme pairs attacking 2-phosphonate aldehydes from different orientations.
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