Enantiocomplementary Synthesis of Chiral 2,3-Dihydroxy Aryl Ketones via ThDP-Dependent Enzymatic Catalysis

Abstract

A green and enantiocomplementary biocatalytic platform for chiral 2,3-dihydroxy aryl ketones has been developed. This method employs ThDP-dependent enzymes to catalyze the direct coupling of aryl aldehydes with unprotected glycolaldehyde in aqueous media under mild conditions, achieving perfect atom economy (100%) without toxic reagents or protecting groups. Through protein engineering, two complementary biocatalysts were obtained: PfBAL_A28S delivers (R)-products (up to 93% yield, 99% ee), while PaBAL M3 provides (S)-enantiomers (up to 95% ee) with broad substrate tolerance. Practical utility is demonstrated by gram-scale syntheses (up to 9.7 g) of bioactive compounds, including the natural product C-veratrylglycol (5.4 g, 76% yield). This biocatalytic system dramatically outperforms conventional NHC organocatalysis, offering a sustainable alternative for accessing pharmaceutically relevant scaffolds. Mechanistic studies elucidate the structural basis for the observed enantiocomplementarity.