Copper-Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp3 )-H/C(sp)-H Cross-Coupling with Rationally Designed Oxazoline-Derived N,N,P(O)-Ligands

Abstract

The intermolecular asymmetric radical oxidative C(sp³ )-C(sp) cross-coupling of C(sp³ )-H bonds with readily available terminal alkynes is a promising method to forge chiral C(sp³ )-C(sp) bonds because of the high atom and step economy, but remains underexplored. Here, we report a copper-catalyzed asymmetric C(sp³ )-C(sp) cross-coupling of (hetero)benzylic and (cyclic)allylic C-H bonds with terminal alkynes that occurs with high to excellent enantioselectivity. Critical to the success is the rational design of chiral oxazoline-derived N,N,P(O)-ligands that not only tolerate the strong oxidative conditions which are requisite for intermolecular hydrogen atom abstraction (HAA) processes but also induce the challenging enantiocontrol. Direct access to a range of synthetically useful chiral benzylic alkynes and 1,4-enynes, high site-selectivity among similar C(sp³ )-H bonds, and facile synthesis of enantioenriched medicinally relevant compounds make this approach very attractive.

Keywords: alkynylation; anionic N,N,P(O)-ligands; copper catalysis; oxidative cross-coupling; radical asymmetric chemistry.