Activation of Weak Nucleophiles in Anion-Binding Catalysis

Abstract

Anion-binding catalysis has emerged as a powerful principle for the development of highly enantioselective transformations. This strategy relies on the ability of dual hydrogen-bond donors to promote anion abstraction from neutral substrates to generate cationic electrophiles such as iminium ions and oxocarbenium ions. Activation of nucleophiles in anion-binding reactions can further expand the scope of both electrophiles and nucleophiles in this mode of catalysis. The research described in this dissertation explores the use of thiourea catalysts to activate weak nucleophiles in two distinct reactions.

In Chapter 1, a diastereoselective glycosylation reaction of glycosyl halides is reported. The transformation is catalyzed by macrocyclic bis-thiourea catalysts to afford β-glycosides. Experimental and computational evidence indicate a stereospecific, invertive mechanism in which thiourea moieties facilitate leaving group departure and the amide carbonyl group of the catalyst activates alcohol nucleophiles via general base catalysis.

In Chapter 2, an enantioselective aza-Sakurai cyclization of chlorolactams is described. The reaction is effected by an electron-rich thiourea catalyst to provide an efficient entry into indolizidine and quinolizidine frameworks. Structure-enantioselectivity relationship studies and mechanistic analysis point to a dual role of the catalyst wherein the thiourea moiety of the catalyst is engaged in both generation of electrophile and Lewis base activation of allylsilane.