An artificial biocatalytic cascade for the synthesis of aryl l-threo-β-hydroxy-α-aminobutyric acids via a carbon-chain extension strategy

Abstract

Chiral aryl β-hydroxy-α-aminobutyric acids (β-HABAs) and their derivatives are essential building blocks for numerous active ingredients in chemicals, pharmaceuticals and bioactive natural products. Developing efficient synthesis methods for stereoselectively constructing C–C bonds of aryl β-HABAs from readily available substrates is of great significance. Herein, we developed an artificial biocatalytic cascade to synthesize β-HABA analogues from achiral benzaldehyde derivatives, glycine, and L-threonine. This one-pot, two-stage biotransformation was achieved using a modular cascade approach that involved two whole-cell catalysis systems (WCCSs): (i) aldol addition and dehydration to yield the corresponding α-keto acids and (ii) decarboxylation, transaldolation, oxidation, and coenzyme regeneration to produce aryl β-HABAs. The cascade reaction was successfully applied to synthesize aryl L-threo-β-HABAs functionalized with p-F, p-Cl, p-Br, p-NO₂ and p-CF₃ in >99% de and >99% yield. Therefore, this biocatalytic process presents an attractive strategy for converting low-cost substrates into chiral aryl β-HABAs by effectively managing the unstable aryl acetaldehyde intermediates.