DEVELOPMENT OF NON-NATURAL BIOCATALYTIC METHODS FOR ASYMMETRIC RADICAL REACTIONS

Abstract

Biocatalysis has become an increasingly important tool for the efficient construction of complex organic molecules. Enzymes offer several advantages over traditional small-molecule catalysts including exquisite selectivities, high turnover numbers, and a powerful catalyst optimization strategy via protein engineering and directed-evolution. Consequently, numerous examples exist of engineered enzymes substituting traditional synthetic methods, thereby increasing the efficiency of chemical synthesis. Despite these exciting developments, it is also clear that there is still room for improvement, particularly in the realm of chemical reactivity, where biocatalysis is dwarfed by the sheer number of chemical reactions available using traditional synthetic approaches. For these reasons, there is a great interest and an enduring challenge of finding new reactions which can be performed using enzymes.

The research described herein focuses on addressing long-standing challenges in asymmetric catalysis by using enzymes as a platform for the development of new reactivity. By developing new asymmetric reactions that are difficult to affect using traditional or biocatalytic methods, it is our lab’s hope that the scope of synthetic organic chemistry will be expanded in a useful fashion. We were keenly interested in solving selectivity challenges in free radical mediated transformations, including terminating radical reactions via enantioselective hydrogen atom transfer (HAT). We hypothesized that flavin-dependent ‘ene’-reductases (EREDs), an industrially relevant enzyme class, could serve as effective catalysts in this regard. While the role of flavoproteins in mediating single electron transfer (SET) has been explored in a biological context, direct single electron transfers from flavoenzymes to organic substrates are rare in nature, and had up until this point, never been studied within the framework of synthetic organic chemistry. In this dissertation I describe four distinct mechanisms by which radical chemistry can be initiated in an enzyme class which typically functions only through ionic mechanisms. This includes ground state SET, charge transfer complex photoexcitation-initiated SET, photoredox catalyst assisted SET, and direct photoinitiated SET. Each of these reaction manifolds allows for progressively more challenging reductions to occur, greatly broadening the scope of reactivity available this enzyme family.