Enantioselective formal carbene insertion into C–N bond of aminal as a concise track to chiral α-amino-β2,2-amino acids and synthetic applications

Abstract

Chiral α-amino-β2,2-amino acid is an ubiquitous fragment that presents in natural products, pharmaceuticals, and bioactive molecules. However, the catalytic enantioselective synthesis of α-amino-β2,2-amino acids with structural complexity and diversity remains a significant challenge. Herein, a highly enantioselective formal C–N bond insertion of aminals with metal carbene species that was generated in situ from diazo compound has been developed by employing a cooperative catalysis of achiral dirhodium complex with chiral phosphonic acid, providing a practical and efficient protocol for expeditious access to optically pure α-amino-β2,2-amino acid derivatives bearing an α-tetra-substituted stereo center with broad substrate scope. The reaction was proposed to proceed through an enantioselective reassembly of enolate intermediate generated in situ from rhodium carbene with methylene iminium ion via chiral ionic pair interaction. Further synthetic applications of these generated poly-functionalized products furnish different types of key intermediates for the formal synthesis of many bioactive molecules. In addition, these amino acid derivatives could also serve as novel potential tail chains of resorcinol dibenzyl ether type PD-1/PD-L1 small molecule inhibitors.

Keywords

• Asymmetric catalysis
• Metal carbene
• Cooperative catalysis
• Chiral α,β-diamino acids
• Ammonium ylide