Diastereoselective Synthesis of β-Branched α-Amino Acids from β, γ-Unsaturated Amides and Glycine-Derived Imines via Tandem Isomerization-Conjugate Addition

Abstract

A base-promoted diastereoselective synthesis of β-branched α-amino acid derivatives is reported, proceeding via tandem isomerization–conjugate addition of β,γ-unsaturated amides with glycine-derived imines under transition-metal-free conditions. The operationally simple protocol tolerates a range of ester- and amide-derived imines, affording products in high diastereoselectivity (up to 20:1 dr). The products are readily transformed into γ-lactam and β-methylated glutamic acid analogues. Control experiments reveal a pronounced dependence of stereoselectivity on the bidentate tether, solvent, and alkali metals, supporting a chelation-controlled stereochemical model. This work highlights alkali metal-bidentate coordination as an effective strategy for stereocontrol in base promoted C–C bond-forming reactions. In addition, certain products also inhibited the growth of MCF-7 cancer cell lines.