Stereoselective Nondirected α-C(sp3)-H Functionalization of Oxygen Heterocycles.

ConspectusOxygen-containing heterocycles are increasingly recognized for their biological significance, especially in the field of drug discovery. Therefore, the enantioselective synthesis of oxygen-containing heterocycles has attracted great attention in the past few decades, and many ingenious synthetic strategies have been developed. Despite remarkable progress, they are often limited in terms of the diversity of target scaffolds, accessibility of starting materials, substrate scope, and stereoselectivity. Simple saturated heterocycles are easily accessible, making them ideal starting points for further transformations. Therefore, approaches to functionalize the existing C(sp3)-H bonds in these readily available saturated heterocycles appear to be of great potential, opening up new avenues for the design and development of chiral heterocyclic drug candidates. However, saturated oxygen-containing heterocycles have similar steric hindrance and no additional sites for the installation of directing groups, making the catalytic enantiofacial differentiation of oxygen-containing heterocycles extremely challenging. To date, stereoselective C(sp3)-H functionalization of saturated oxygen heterocycles remains an unsolved problem in contemporary organic synthesis.In this Account, we summarize the recent progress made in our laboratory in stereoselective functionalization of nondirected oxygen-containing heterocycles via hydrogen atom transfer (HAT)/nickel dual catalysis. First, we discuss the construction of high-value chiral oxygen heterocycles from simple and readily available oxacycles via enantioselective C(sp3)-H arylation and alkenylation reactions, focusing on the effects of the ring, ligands, and photocatalysts on C(sp3)-C(sp2) bond formation and their respective roles. Experimental and density functional theory calculation studies further elucidate the mechanism of the asymmetric C(sp3)-H functionalization reactions and the origin of the enantioselectivity. Second, we describe a novel catalytic system that we designed for the enantioselective C(sp3)-H alkylation of saturated heterocycles, providing an efficient strategy for the stereoselective construction of C(sp3)-C(sp3) bonds. Finally, we disclose a facile and versatile method to synthesize a wide range of C-glycosides from readily accessible and bench-stable 1-deoxyglycosides. We further develop a catalyst-controlled, site-divergent carbohydrate functionalization approach that can be used to synthesize various unexplored carbohydrates containing arylated quaternary stereocenters. The synthetic applicability of our developed method has been demonstrated in the stereoselective synthesis of natural products, blockbuster drugs, and versatile synthetic building blocks.