Over the past 30 years, a wealth of asymmetric catalytic methods from closed-shell substrates and intermediates have revolutionized drug discovery and materials synthesis. Yet, chiral catalysis of open-shell radical intermediates has proven to be challenging. Mild catalytic methods for radical generation have been limited until photoredox catalysis, which has allowed for catalytic and redox tunable radical formation. However, extending this to asymmetric catalysis has largely remained elusive due to the high reactivity and inability to engage radical intermediates in common selectivity manifolds. This proposal applies knowledge gleaned from the field of closed-shell enantioselective catalysis and from the emergent field of photoredox catalysis to advance the nascent field of asymmetric catalysis with radical species, and to subsequently study the mechanisms of these transformations to develop general principles for achieving enantioinduction in catalytic, open-shell chemistry. The goal of the proposed research is to leverage the ability of proton-coupled electron transfer (PCET) to break strong bonds with polar character to drive enantioselective catalytic transformations of cyclic substrates. This proposal overcomes two central pitfalls in enantioselective catalysis of radical intermediates: 1) racemic background arising from rapid reactions of highly reactive radical species generated in the absence of the chiral catalyst and 2) orchestrating stereoselective high order elementary reaction steps. PCET functions by Brnsted acid coordination, lowering the reduction potential of basic functional groups or Brnsted base lowering the oxidation potential of acidic functional groups. With redox tunable photocatalysts, and chiral acid/base catalysts, radicals will be exclusively generated in the presence of a chiral catalyst, shutting down racemic background. Furthermore, coupling this step to selectivity determining rapid unimolecular ring opening ensures catalyst and radical not diffuse from each other when being held together by a weak hydrogen-bonding interaction.
In aim 1) meso cyclic alcohols will be oxidatively desymmetrized via O-H PCET to generate alkoxy radicals, which will rapidly ring open via ?-scission, to provide aldehydes with a distal stereocenters. Dual chiral base and photoredox catalysis will enable PCET and chirality transfer through hydrogen bonding.
In aim 2) chiral acid and photoredox mediated PCET will reductively open racemic styrene oxides, which will be subsequently functionalized or deracemized in divergent interception of the benzylic radical intermediate. Kinetic and computational mechanistic investigations into the origin of enantioselectivity in these mechanistically distinct transformations will shed light onto requirements for asymmetric induction in oxidative and reductive radical catalysis. This work will make conceptual and practical advances in the application of asymmetric catalysis to the synthesis of stereochemically defined molecules of medicinal interest from radical intermediates and in doing so elucidate selectivity manifolds in radical chemistry, impacting efforts to improve human health.
The objective of this proposed research is to engage substrates in stereoselective ring opening reactions from a high-energy radical intermediate generated via substrate coordination to a chiral Brnsted acid or base in a proton-coupled electron transfer manifold, which has emerged as a powerful methodology to selectively homolyze strong polar bonds in the presence of substantially weaker bonds. Specific transformations of interest include the oxidative desymetrization of meso alcohols for the synthesis of aldehydes with distal stereocenters and reductive ring-opening functionalizations or redox-neutral deracemizations of styrene oxides. Both projects have the possibility for practical advances, as products are versatile chiral building blocks valuable in drug discovery, and conceptual advances, as unimolecular reactions are tractable for computational and kinetic studies to elucidate the origin of enantioinduction and understand general catalytic principles in oxidative, reductive, and redox-neutral catalytic enantioselective radical chemistry.
