New Palladium- and Gold-Catalyzed Alkene and Alkyne Difunctionalization Reactions for the Efficient, Stereoselective Synthesis of Azabicycles and B-Alkoxy Ketones.

Abstract

The research and development of new drug therapies is reliant upon synthetic methods that are able to deliver diverse drug-like molecules in a straightforward manner. Some of the most common structural motifs found in numerous pharmaceuticals and biologically active natural products are fused and bridging azabicyclic frameworks and 1,3-dioxygen units. However, methods for accessing these structures are limited in the types of scaffolds that can be prepared in an efficient manner from simple starting materials. To address this problem, the research described in this dissertation is focused on the development of novel palladium- and gold-catalyzed reactions for the direct synthesis of diverse azabicycles and 1,3-dioxygen units. Common to these new transformations is the metal-mediated difunctionalization of alkene and alkyne starting materials, allowing for the construction of azabicyclic and 1,3-dioxygen motifs with unique substitution patterns that cannot be easily accessed with existing methods. Specifically, the first half of this dissertation details the work put forth on extending the scope of Pd-catalyzed alkene aminoarylation reactions towards the synthesis of biologically significant pyrrolizidine, indolizidine, and tropane scaffolds. The construction of pyrrolizidines and indolizidines was achieved by developing a novel Pd-catalyzed aminopalladation/carbopalladation cascade reaction of readily accessible N-allyl-2-allylaniline derivatives. This tandem reaction rapidly develops molecular complexity, as 3 bonds and 2 stereocenters are formed in a single step, providing diverse indolizidine or pyrrolizidine products in good yield and diastereoselectivity. Likewise, we devised an intramolecular Pd-catalyzed alkene aminoarylation methodology for arriving at pharmaceutically relevant benzo-fused tropanes. These transformations are highly efficient, generating 2 bonds, 1-2 stereocenters, and the azabicyclic scaffold in a single step, ultimately providing various tropane derivatives in excellent yield and diastereoselectivity. The second half of this dissertation describes the multicomponent synthesis of beta-alkoxy ketones through the development of novel Au-catalyzed carboalkoxylation reactions of alkynes with hemiacetals. The described Au-catalyzed transformation provides a non-traditional and atom-economical approach for beta-alkoxy ketone synthesis via the intermolecular capture of gold(I) enol derivatives with in situ generated oxocarbenium ions. The intermolecular capture of gold(I) enol derivatives with carbon electrophiles is unprecedented and will likely facilitate the design of other useful Au-catalyzed transformations.