The Development of Novel Methods for the α-Functionalization of Carbonyl Compounds to Generate High-Value Intermediates

Abstract

Photoredox organocatalysis has led to the development of several new catalytic asymmetric reactions within the MacMillan group. The reactive intermediates used in this process have proven to be generally applicable to a variety of systems that enable the synthesis of useful chiral organic molecules. This first section of this thesis details the development of photoredox organocatalysis and its application to a new reaction, namely the alpha-benzylation of aldehydes using electron-deficient benzyl and heterobenzyl bromides as substrates. The utility of this process towards forming key bonds in pharmaceutically relevant structures was demonstrated via the three-step synthesis of a clinical drug candidate.

The second half of this dissertation discusses oxy-allyl cations and their use as generic electrophilic intermediates for nucleophilic substitution reactions. A new generic process for the generation of oxy-allyl cation intermediates from simple alpha-tosyloxy substituted ketone starting materials and their subsequent trapping with a variety of simple nucleophiles is described. Finally, initial efforts into the development of an enantioselective variant of the nucleophilic substitution of alpha-tosyloxy ketones is detailed using simple chiral amines as catalytic bases.