Enantioselective desymmetrizing hydroamination to synthesize complex all-carbon quaternary stereocenter containing saturated heterocyclic structures

This Project Grant award of $548,701 from the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859) supports fundamental chemical research at Bryn Mawr College from September 1, 2025 through August 31, 2028. The research focuses on developing enantioselective desymmetrizing hydroamination methodology to synthesize complex saturated heterocyclic structures containing all-carbon quaternary stereocenters—a critical structural feature common in bioactive pharmaceutical compounds and natural products.

The project will deliver an efficient synthetic tool utilizing chiral copper catalysts to construct fused heterocyclic compounds with bridgehead quaternary carbons from inexpensive benzoic acid derivatives in four to five steps. The methodology builds upon Birch reduction-alkylation reactions to generate symmetrical cyclohexadiene structures, which are subsequently desymmetrized through enantioselective alkene hydroamination. This research addresses a significant gap in synthetic chemistry, as thousands of bioactive molecules containing fused heterocyclic rings with quaternary carbons at the bridgehead lack a general synthetic approach. The use of copper catalysts provides advantages in cost-effectiveness and environmental benignity while advancing the foundation for improved drug design and synthesis.

Abstract

Heterocyclic rings and tetrahedral carbons are common components of successful small molecule drugs. The polarity and hydrogen bonding capability of heterocyclic rings promotes solubility in aqueous solutions and provides opportunities for critical intermolecular force interactions with protein targets, thereby promoting drug-protein binding affinity. Tetrahedral carbons in drugs create selective interactions with protein targets thereby minimizing unwanted side effects due to interactions with non-target proteins or other biomolecules. Tetrahedral carbons are also believed to facilitate small molecule dissolution because more three-dimensional molecules pack less efficiently into the solid phase and therefore more readily separate. All-carbon quaternary carbons are one of the most difficult types of tetrahedral carbons and are common in bioactive molecules, especially those found in nature. In fact, structure searches of fused heterocyclic rings with quaternary carbons at the bridgehead are found by the thousands in bioactive molecules, yet there is no general synthetic tool to enantioselectively construct these molecules. The current proposal describes an efficient synthetic tool to enantioselectively construct fused heterocyclic compounds with bridgehead quaternary carbons from inexpensive benzoic acid derivatives in four or five steps. The method generates symmetrical cyclohexadiene structures from birch reduction-alkylation reactions of benzoic acid derivatives and then desymmetrizes them through enantioselective alkene hydroamination reactions. The proposal will explore the use of chiral copper catalysts to facilitate the enantioselective desymmetrizing hydroamination reaction. Copper has the advantage of both low cost and being environmentally benign. The research would build on the enantioselective desymmetrizing mizoroki- heck reactions that we have previously reported for both palladium and nickel chiral catalysts. IT also seeks to extend the impressive copper-catalyzed hydroamination work by other researchers to enantioselective desymmetrizing reactions. Critical to the reaction development will be the use of computational chemistry to model the key amino- cupration step, which is the likely rate and enantioselectivity determining step based on literature precedent. Leveraging our experience with understanding the basis of enantioselectivity in the analogous 1,2-insertion of the desymmetrizing NI-catalyzed mizoroki-heck reaction, we will accelerate the search for optimal chiral ligands by modeling the key amino-cupration step. Most importantly, the project will provide three undergraduate students and one graduate student with exposure to and training in contemporary synthetic chemistry reaction development to address an important deficiency in the armamentarium of synthetic tools for complex molecule synthesis in the 21ST century.