Efficient and Stereoselective Enzymatic Synthesis of Multisubstituted α , β -Diamino Acid

Abstract α,β-Diamino acids are privileged motifs present in numerous bioactive natural products and synthetic molecules, yet their asymmetric synthesis remains challenging and limited in scope. Herein, we repurpose l-threonine aldolases to catalyze a stereoselective intermolecular Mannich-type reaction, enabling the direct and scalable synthesis of densely functionalized α,β-diamino acids. By exploiting enzyme sequence diversity, we accessed more than 50 derivatives from simple precursors with high efficiency (up to 97% yield) and selectivity (up to >99% d.r. and >99% e.r.). The reaction achieves total turnover numbers of up to 18,000 and titers reaching 77.4 g L–1, representing the highest reported productivity for this class of biocatalytic transformation and meeting key benchmarks for industrial application. Mechanistic investigations suggest that the deprotonation of glycine contributes to the rate-determining step of the highly efficient catalytic cycle. Selected derivatives were shown to effectively suppress osteoclastogenesis, identifying a chemotype with potential for osteoporosis intervention.