Deracemization of Beta2- and Gamma2-amino acids

About This Grant

PROJECT SUMMARY/ABSTRACT The pharmaceutical and agrochemical industries rely heavily on the stereoselective preparation of chiral molecules because opposite enantiomers often demonstrate disparate activities. Though numerous approaches exist to obtain enantiomerically enriched material, these methods typically require the synthesis of specialized starting materials/reagents. The catalytic deracemization of racemic material is an attractive alternative, as racemic synthesis is often straightforward and enantioinduction can be achieved by a catalytic rather than stoichiometric process. In recent years, photocatalysis has emerged as a strategy for driving systems out of equilibrium and accomplishing deracemization reactions. However, despite the prevalence of the α-carbonyl stereocenter in peptidomimetics, natural products, and pharmaceuticals, the catalytic deracemization of this scaffold has not been achieved in a general sense; this may be in part due to the challenges associated with generating a reactive intermediate at the acidic α-position under mild conditions, coupled with the lack of nucleophilic HAA reagents. This proposal seeks to unlock a new reactivity platform within the field of stereochemical editing and utilize it to enable deracemization of α-carbonyl stereocenters. Leveraging the Wendlandt group’s expertise in asymmetric catalysis, we will investigate stereoselective hydrogen atom abstraction (HAA) using chiral amine-borane catalysts and develop a deracemization protocol for the conversion of racemic starting materials into high-value enantioenriched products. Prior literature has established proof of concept for kinetic resolution of α-carbonyl stereocenters with these reagents, albeit with modest selectivity outcomes; however, their extension to deracemization has not yet been investigated or accomplished. We seek to leverage these chiral amine-boryl radicals and photoredox catalysis for the development of a novel method for the deracemization of α-carbonyl stereocenters, with a particular focus on biologically active motifs such as β2- and γ2- amino acids. Ultimately, we seek to establish amine-boranes as a modern reagent class for selective HAA of acidic C–H bonds and gain a deeper understanding of the factors affecting enantioselectivity of HAA with amine-boryl radical species. We will accomplish these goals through synthesis of novel catalysts and evaluation of their reactivity via spectroscopic studies. Research will be carried out at MIT, an institution that excels in synthetic chemistry. I will receive training in asymmetric catalysis from Prof. Alison Wendlandt, a trailblazer in the stereochemical editing field, training in photophysics from Prof. Schlau-Cohen, an expert in ultrafast spectroscopy, as well as training in organoboron chemistry through informal interactions with Prof. Robert Gilliard and his research group at MIT. The proposed research is highly complementary to my doctoral training in the data science-driven study of pharmaceutically relevant reactions, enabling me to expand my skillset to include asymmetric catalysis, photophysics, and main group catalysis.