Constructing a Biosynthetic Pathway of α-Arylglycines via C1 Extension of Aldehydes

The use of C1 molecules as feedstocks for producing high-value chemicals is an attractive yet technically inefficient process. Optically pure α-arylglycines are valuable pharmaceutical intermediates, but their efficient asymmetric biosynthesis from C1 molecules has not been reported. Herein, a multienzyme biosynthetic pathway was successfully designed and implemented for the asymmetric synthesis of α-arylglycines from the C1 molecule formaldehyde (HCHO) and aromatic aldehydes, which involved thiamine diphosphate (ThDP)-dependent enzyme-catalyzed hydroxymethylation, galactose oxidase (GOase)-catalyzed oxidation, and d or l -amino acid dehydrogenase-catalyzed reductive amination. The engineered GOase M 3-5 mutant (Y329I/M330F/S331R) demonstrated enhanced catalytic efficiency, achieving 2-oxo-2-phenylacetic acid ( 1c ) in an 80% isolated yield with a space-time yield of 6.0 g·L −1 ·h −1 . A one-pot, two-step cascade reaction combining oxidation and reductive amination was then developed to afford α-arylglycines and leucine with 56−99% ee and 63−98% isolated yields. Furthermore, this strategy was extended to a one-pot, three-step cascade, enabling the synthesis of enantio-complementary α-arylglycines from HCHO, aromatic aldehydes, and ammonium chloride in high isolated yields (62−90%). This study provides a practical and efficient strategy for producing high-value chiral amino acids from simple aldehydes.