Enantioselective Decarboxylative Synthesis of Chiral α-Silylamines and α-Germylamines

Abstract

Metalloids bridge the properties of metals and nonmetals, creating unique opportunities in drug discovery. However, the potential of silicon- and germanium-containing scaffolds in organic synthesis and medicinal chemistry remain underexplored, largely owing to the lack of general stereocontrolled synthetic methods, particularly for value-added chiral α-silylamines and α-germylamines. Here, we report a robust nickel-catalyzed enantioselective decarboxylative cross-coupling of amino acid or peptide-derived redox-active esters with silylzinc and germylzinc reagents. The method exhibits a broad substrate scope and delivers excellent performance under mild conditions. Its efficacy is further demonstrated through the late-stage diversification of complex bioactive peptides, and both enantiomers can be accessed with high stereochemical fidelity. Mechanistic investigations delineate the origin of stereocontrol, while preliminary biological evaluations show promising activities, with Ge substitution in several cases surpassing Si and certain clinically marketed boron-containing drugs. Collectively, this work establishes an efficient and enantioselective route to chiral α-silylamines and α-germylamines, underscoring their potential to expand peptide chemical space and to enable the development of peptide-based therapeutics and diagnostics.