AN ASYMMETRIC RADICAL ALLYLATION OF AMIDES VIA A PHOTOENZYMATIC MEDIATED ?-SCISSION

Abstract

This thesis describes a photoenzymatic allylation of ?-chloroamides with allyl silanes using flavin-dependent ‘ene’-reductases (EREDs). An engineered ERED can catalyze annulative allylic alkylation to prepare 5, 6, and 7-membered lactams with high levels of enantioselectivity. Ultrafast transient absorption spectroscopy indicates that radical termination occurs via β-scission of the silyl group to afford a silyl radical, a distinct mechanism by comparison to traditional radical allylations involving allyl silanes. Moreover, this represents a new strategy for radical termination using EREDs. This method enables intermolecular couplings with allyl sulfones, allyl silanes, and silyl enol ethers. Overall, this method highlights the opportunity for EREDs to catalyze new enantioselective radical termination strategies beyond hydrogen atom transfer. Chapter 1 discusses the prevalence of asymmetry in the world and the importance of developing enantioselective synthetic methods. Biocatalysis is an essential tool for enabling the rapid synthesis of enantioenriched chiral molecules. Photoenzymatic processes serve as a new tool for enabling enantioselective radical C–C bond-forming reactions. Chapter 2 describes the optimization of the photoenzymatic desilylative allylation catalyzed by flavin-dependent ‘ene’-reductases to provide lactams. I also describe the synthetic challenges associated with the synthesis and design of the allyl silane substrates. Finally, chapter 3 discusses the mechanistic nuances governing this net-reductive radical allylation transformation through transient absorption spectroscopy. These studies support a desilylative β-scission mechanism for radical termination. This mechanism was previously unknown in the photoenzymatic literature.