Research Projects

The direct functionalization of C–H bonds which allows the installation of a variety of atoms and groups in place of hydrogen, has emerged as a highly investigated method in organic chemistry. Among various approaches toward C–H functionalization, visible light-induced hydrogen atom transfer (HAT) has garnered growing interest. Nevertheless, given the ubiquity of C–H bonds in organic molecules, achieving precise control over site-selectivity remains a crucial issue. MacMillan group, in 2015, disclosed an effective strategy wherein by taking advantage of the polar hydroxyl group, the vicinal C–H bond was selectively activated via HAT under dual catalytic system involving an iridium-based photocatalyst and a HAT catalyst, quinuclidine. Although the pursuit of quinuclidine-mediated HAT catalysis has accelerated the growth of this field, their use in asymmetric HAT catalysis remained unexplored. In this context, chiral quinuclidines—possessing stereochemical information at the periphery of nitrogen center—have been successfully utilized by Phipps group for enantioselective hydrogen atom abstraction (HAA) in the epimerization and asymmetric oxidation of meso-diols. Based on these reports, we sought to exploit the chiral functional handle embedded in the quinuclidine moiety for achieving asymmetric photocatalyzed HAT processes. For this purpose, we propose to harness the bifunctional nature of (thio)urea- or squaramide-based quinuclidine catalysts in conjunction with suitable photocatalyst for developing the enantioselective photocatalytic α-C-H functionalization of feedstock alcohols with various sulfonyl oxime-ethers and Michael acceptors. The electrophilic nitrogen radical cation in the quinuclidinium unit, generated through reductive quenching of excited photocatalyst by quinuclidine, would undergo HAT from α-position of hydroxyl group in alcohols, forming α-hydroxy radical. Additionally, the appended (thio)urea- or squaramide-unit would engage in hydrogen bonding with alcohol and other reaction partner, thereby assisting in organizing the substrates within the chiral pocket and governing the face-selective attack of α-hydroxy radical to achieve high enantioselectivity. Capitalizing on this concept, we will further investigate bicyclo[1.1.0]butanes as radical acceptors. Owing to the high ring strain of BCBs, we expect to trap the α-hydroxy radical based on radical-mediated strain-release strategy, enabling the formation of synthetically important enantio-enriched cyclobutane derivatives. We hope that the proposed synergistic interplay between the photocatalyst and the bifunctional chiral quinuclidine catalyst will emerge into a new dual catalytic system for achieving stereoselective transformations of specific C-H bonds through HAT process. Successful realization of this concept will be particularly useful for late-stage functionalization in natural product synthesis and selective C-H bond modification in medicinally important molecules.