Asymmetric Radical Cyclopropanation of α,β-Unsaturated Amides with α-Boryl and α-Silyl Dibromomethanes via Cr(II)-Based Metalloradical Catalysis

Abstract

Transition-metal-catalyzed asymmetric carbene-transfer reactions represent a powerful strategy for synthesizing chiral cyclopropanes. However, current methods predominantly rely on stabilized carbene-bearing <i>α</i>-π-conjugated groups, restricting access to less stabilized carbenes, such as <i>α</i>-silyl and <i>α</i>-boryl carbenes. Herein, we present an unprecedented Cr(II)-based metalloradical system for the asymmetric cyclopropanation of <i>α</i>,<i>β</i>-unsaturated amides with <i>α</i>-boryl and <i>α</i>-silyl dibromomethanes in the presence of Mn as the reducing agent. Employing a chiral chromium complex, the reaction proceeds under mild conditions, yielding cyclopropanes with three contiguous stereocenters in high diastereo- and enantioselectivities. This method features a Cr-catalyzed radical-based stepwise cyclopropanation mechanism. The broad substrate scope, encompassing various <i>α</i>,<i>β</i>-unsaturated amides, demonstrates the protocol's versatility and robustness. Mechanistic insights, supported by experimental and computational studies, suggest the formation of <i>α</i>-Cr(III)-alkyl radical intermediates, delineating a pathway distinct from that of classical concerted cyclopropanations. This approach provides a powerful tool for synthesizing highly functionalized cyclopropanes, offering high potential for applications in drug discovery and development.