Asymmetric synthesis of structurally diverse (S)-β-amino alcohols from simple aldehydes and formaldehyde

Chiral β-amino alcohols represent a significant structural motif in many biologically active molecules. Developing an efficient biocatalytic method for synthesizing chiral β-amino alcohols with structural diversity is highly desirable. In this study, enzymatic hydroxymethylation of aryl-aliphatic aldehydes by benzaldehyde lyases (BALs) enabled the synthesis of α-hydroxymethyl ketones at high substrate loadings (200 ​mmol/L - 300 ​mmol/L). And the reductive amination of diverse α-hydroxymethyl ketones by amine dehydrogenases (AmDHs) was conducted for synthesizing chiral β-amino alcohols in high isolated yields (60 %–79 %). Furthermore, a one-pot, two-step enzymatic process involving BAL-catalyzed hydroxymethylation of aldehydes and subsequent AmDH-catalyzed reductive amination was developed, enabling the synthesis of aromatic, aliphatic and aryl-aliphatic ( S )-β-amino alcohols from corresponding aldehydes in good to excellent isolated yields (56 %–96 %) and excellent enantioselectivity (>99 % ee ). The practical utility of this methodology was further demonstrated through the synthesis of key intermediates for antiviral drug Telaprevir or ATP competitive ERK inhibitor BVD-523. A one-pot, two-step cascade reaction was designed and performed for the synthesis of chiral β-amino alcohols from aldehydes, formaldehyde and ammonia via hydroxymethylation-catalyzed by benzaldehyde lyases and reductive amination-catalyzed by amine dehydrogenases with high substrate loadings, good isolated yields and excellent stereoselectivity.