Light-Driven Deracemization of Atropisomers Enabled by Chiral Photocatalysts

Princeton University, Princeton NJ

Investigators

Abstract

PROJECT SUMMARY Small-molecule medicines have saved countless lives, but a plethora of proteins remain “undruggable” because of the molecular complexity needed to interrupt disease-causing processes. Generally, small-molecule drugs operate by intimate binding to a target protein; maximizing specific drug/protein interactions enables high potency and minimizes off-target effects. One promising strategy to improve drug binding is to incorporate structural rigidity by an atropisomeric axis, wherein restricted bond rotation leads to distinct chiral atropisomers. However, current methods to access atropisomers, including asymmetric couplings and chiral separations, lack generality and efficiency. In contrast, deracemization of racemates, which are readily formed by cross-couplings, represents an attractive approach to access atropisomers. Recent efforts have enabled deracemization of atropisomers by combining racemization catalysts with chiral separations, but these approaches require chiral reagents that limit applicability; deracemization without stoichiometric additives is challenging because the transformation is thermodynamically unfavorable. The proposed research focuses on the development of a broadly applicable strategy to deracemize atropisomers by light-driven processes that utilize excited-state energy surfaces to achieve this net-uphill reaction. The impact of this work is to enable facile access to atropisomers from readily available racemates, making possible the design and rapid synthesis of new drug candidates. In contrast to prior approaches for catalytic deracemization of engineered substrates that rely on pendant binding sites which mitigate generality, the innovation of the proposed approach is a set of readily accessible photocatalysts designed to bind the native functionality in atropisomers and to react by different activation pathways tailored to these different groups. Specifically, the proposed research will create new photocatalyst scaffolds that will enantioselectively bind two distinct classes of atropisomers, biaryls and anilides, and enable stereoselective photoinduced energy or electron transfer to facilitate deracemization. Modular synthetic routes are presented to access two libraries of catalysts that span a wide range of photophysical properties, chiral environments, and binding elements that will be iteratively combined to optimize for substrate binding. For each distinct class of atropisomers, subsequent excited-state quenching experiments will be conducted to evaluate catalysts for their ability to discriminate between substrate enantiomers and facilitate enantioselective energy or electron transfer. Catalysts that exhibit the most disparate ground-state binding affinities and excited-state quenching kinetics will be applied for deracemization of atropisomers, and studies of the deracemization of complex structures, particularly those found in pharmaceutically relevant molecules, will demonstrate the applicability and generality of the proposed method. Achieving the specific aims of the proposed research will enable practical, general access to enantiopure atropisomers, expand access to new chiral frameworks for drug discovery and ultimately leading to improvements of disease-treating therapeutics.