Enantioselective a-Functionalization of Carbonyl Compounds via Copper Catalysis

Abstract

Over the last several decades, the rapid growth of asymmetric catalysis has resulted in many new strategies for constructing carbon-carbon and carbon-heteroatom bonds enantioselectively. The versatility of catalyst construction and the economical/environmental advantages to this synthetic approach have undoubtedly contributed to its popularity. Within the field, the most commonly utilized strategies for imparting stereochemical bias on synthetic processes are transition metal catalysis and organocatalysis.

The enantioselective α-functionalization of carbonyl compounds is of particular importance in synthesis. The techniques for achieving these reactions involve (1) activating electrophiles with catalysts in the presence of electron-rich π-systems or (2) forming catalytic enamines or enolates in the presence of electrophiles. The products of these transformations are also quite useful, in that they possess versatile functional handles for subsequent structural elaboration. This thesis describes the development of three new enantioselective α-functionalization methods using both copper and amine catalysis. Chapter 2 discusses the use of mechanistic insights to discover a broadly applicable organocatalytic α-oxidation of aldehydes. For productive coupling, both the nucleophile and electrophile require activation by an amine and metal catalyst, respectively. Chapter 3 details a new enantioselective α-arylation of bidentate enol silanes using ligated copper catalysis in combination with diaryliodonium salts. Consideration of transition state structure was critical for enantioselectivity in these studies. Finally, Chapter 4 outlines a related α-arylation of monodentate enol silanes using a tridentate bisoxazoline framework on copper. By hypothesizing how the addition of a tethering group on the ligand would alter the rates of oxidative addition and reductive elimination at the metal center, we overcame the requirement of substrate chelation.