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.