Asymmetric Radical Reactions in Flavin-Dependent 'Ene'-Reductases

Abstract

The field of asymmetric radical catalysis has witnessed tremendous growth over the past 30 years, spurred predominantly by the emergence of single electron transfer as a mild method for radical generation. Most methods rely on transiently formed diastereomeric complexes to induce asymmetry. Relatively few methods exist for stereochemical control of prochiral radicals. This thesis describes the application of commonly used biocatalysts, ‘ene’-reductases, for enantioselective synthesis via radical intermediates.

The first half of this thesis describes an enantioselective synthesis of 3,3-disubstituted oxindoles through redox-neutral radical cyclizations using ‘ene’-reductases (ERED’s). Importantly, this is the first reported example of ERED’s performing a redox-neutral reaction,. The reaction is tolerant across a wide variety of alkyl substitutions on the aromatic ring and on the malonyl position. Mechanistic studies suggest the reaction proceeds via the flavin semiquinone serving as the reductant, and flavin quinone serving as the oxidant. Constant light irradiation of the reaction generates flavin semiquinone, and also serves as a rescue mechanism for species that have fallen out of the active redox state. These studies provide the groundwork for future redox-neutral cyclizations in ERED’s.

The second half of this thesis describes the asymmetric hydrogenation of vinyl pyridines through photoenzymatic catalysis using ERED’s and exogenous photocatalyst. Thorough mechanistic studies suggest photocatalyst reduces the olefin to produce a radical anion that is quenched by enzymatic flavin. These studies provide the groundwork for reactions initiated by photocatalyst that can be enantioselectively selectively quenched by active site flavin.