Rhodium-Catalyzed Allylic Alkylation of Enolates and Homoenolates: Enantioselective Construction of α- and β-Stereogenic Carbonyl Compounds

Abstract

The asymmetric alkylation of enolates is a particularly versatile method for the construction of -stereogenic carbonyl motifs, which are ubiquitous in synthetic chemistry. Over the past several decades, the focus has shifted to the development of new catalytic methods that depart from classical stoichiometric stereoinduction strategies (eg. chiral auxiliary). In this way, the enantioselective alkylation of prochiral enolates greatly improves the step- and redox-economy of this process, in addition to enhancing the scope and selectivity of these reactions. The following thesis outlines some of our efforts in this area, in which we have recently developed an enantioselective rhodium-catalyzed allylic alkylation reaction with unstabilized enolates and related nucleophiles. The thesis is divided into three chapters, including a comprehensive literature review that highlights the current state-of-the-art methods, followed by two research chapters that detail the development, scope and mechanistic aspects of two novel “enolate” alkylation processes. Chapter 1 commences with a brief introduction to enolate alkylation, which is followed by a detailed analysis of the historical development and modern approaches for catalytic enantioselective enolate alkylation. The review is divided into two major subsections; namely, the reactions of cyclic and acyclic enolates will be treated separately, thus delineating the significant achievements in each area. Chapter 2 highlights our development of the enantioselective rhodium-catalyzed allylic alkylation of prochiral aldehyde enolates. This chapter opens with a summary of the related organocatalytic methods that employ enamine nucleophiles to construct α-stereogenic aldehydes. In this regard, the limitations with these methods set the stage for the development an alternative approach involving unstabilized aldehyde enolates. Hence, we have utilized an enantioselective rhodium-catalyzed allylic alkylation reaction to enable the construction of acyclic quaternary stereogenic centers from α-aryl aldehyde pronucleophiles. Chapter 3 illustrates the enantioselective rhodium-catalyzed allylic alkylation of a homoenolate nucleophile. After a brief introduction on homoenolate alkylation; namely, the use of heteroatom-stabilized allylic anions as synthetic homoenolate equivalents, our development of a catalytic enantioselective variant of this process is discussed. To this end, we have shown that lithiated unsaturated α-amino nitriles deliver β-stereogenic carbonyls via regioselective allylic alkylation followed by in situ hydrolysis of the cyanoenamine intermediates.