Organocatalytic asymmetric azidation of sulfoxonium ylides: mild synthesis of enantioenriched α-azido ketones bearing a labile tertiary stereocenter

Disclosed here is a catalytic asymmetric azidation reaction for the efficient synthesis of alpha-azido ketones bearing a labile tertiary stereocenter. With a superb chiral squaramide catalyst, a mild asymmetric formal H-N-3 insertion of alpha-carbonyl sulfoxonium ylides proceeded with excellent efficiency and enantioselectivity. This organocatalytic process not only complements the previous alpha-azidation approaches for the formation of quaternary stereocenters and mostly for 1,3-dicarbonyl compounds, but also has advantages over the well-known metal-catalyzed asymmetric carbene insertion chemistry using alpha-diazocarbonyl compounds. Detailed mechanistic studies via control reactions and NMR studies provided important insights into the reaction pathway, which features reversible protonation and dynamic kinetic resolution. The curiosity in mechanism also led to the development of a simplified alternative protocol with a cheaper HN3 source.

Automated summary

A catalytic asymmetric azidation reaction for the efficient synthesis of alpha-azido ketones bearing a labile tertiary stereocenter is disclosed. Detailed mechanistic studies provided important insights into the reaction pathway, and a simplified alternative protocol using a cheaper HN3 source was developed.