Stereochemical Editing of Quaternary Stereocenters Enabled by Enantioselective Recombination of C–C Bonds - PROJECT SUMMARY/ABSTRACT The stereochemistry of a pharmaceutical drug is of paramount importance as alternative stereoisomers can lead to vastly completely different outcomes in its efficacy, pharmacokinetic properties, and side-effects. Therefore, site-selective control to access the desired stereochemistry of a molecule (stereochemical editing), especially at a late-stage, has a direct impact on drug discovery and is at the forefront of innovation in synthetic organic chemistry. The objective of this proposed research is to develop a mild and efficient stereochemical editing strategy for quaternary stereocenters guided by enantioselective recombination of C–C bonds. Traditionally, stereochemical editing relies on the homolytic cleavage of a C–H bond via photoredox catalysis in the presence of a hydrogen bond donor and a hydrogen bond abstractor. Nevertheless, this system is simply unapplicable to quaternary stereocenters because they lack the required hydrogen bond. To overcome this challenge, the proposed research engages an innovative application of photoredox catalysis and asymmetric recombination of a C–C bond. The first approach will establish a dual asymmetric photoredox/nickel catalysis strategy. This system will be applied to effect a mesolytic cleavage of a target C–C bond, followed by asymmetric induction of a chiral nickel catalyst to promote an recombination of the C–C bond via intramolecular sp3–sp3 cross-coupling. If successful, this dual catalytic system will provide a fully stereocontrolled means to access to the quaternary stereocenters under mild conditions. The second approach will deploy a chiral counteranion of the photocatalyst to induce asymmetric ion-pairing with carbocationic intermediates. This method will utilize exceptionally simple, yet underexplored conditions to recombine C–C bonds to manipulate the quaternary stereocenters orthogonally to the previous approach. These studies are expected to enable a novel mode of action toward stereochemical editing of quaternary stereocenters and have applications, such as epimerization, racemization, and deracemization, in the discovery of pharmaceuticals, natural product synthesis, as well as derivatization of the existing drugs. The proposed research aligns well with my future development plan to broaden my expertise in modern methodology by ensuring exposure to the development of new techniques in photoredox and transition metal catalysis with mechanistic and kinetic studies. The Wendlandt lab’s extensive experience and expertise in photoredox catalysis, coupled with the state-of-the-art resources and facilities at MIT, provides the optimal environment to pursue and successfully execute the proposed research.
