Divergent and Scalable Synthesis of α-Hydroxy/Keto-β-amino Acid Analogues by the Catalytic Enantioselective Addition of Glyoxylate Cyanohydrin to Imines

Abstract

The catalytic enantioselective addition of glyoxylate cyanohydrin to imines to afford α-keto-β-amino acid equivalents is reported. Sterically tuned aminobenzothiadiazine catalysts provided high yields and stereoselectivities (up to 100% yield, 99% ee, >99:1 dr) for both aromatic and aliphatic imines, and the stereodivergent synthesis of both diastereomers was achieved. The optimal catalytic system was scalable, even with a low catalyst loading. The resulting adducts were converted into various chiral building blocks, including β-amino acid analogues, which are important motifs in medicinal chemistry, while maintaining a high enantiomeric excess.