Catalytic generation of vanadium and zinc enolates for the formation of C-C, C-N, and C-X bonds

Enolates are one of the most fundamental and widely used reactive intermediates for the formation of carbon bonds. However, their formation is often times plagued by the need for cryogenic reaction temperatures, the generation of stoichiometric waste by-products, and poor selectivities. New catalytic methods for the generation and subsequent reaction of enolates that proceed under mild reaction conditions and with high levels of selectivity are needed. This thesis describes the development of seven such methods for the catalytic generation and subsequent reactivity of vanadium and zinc enolates. The first chapter is a review chapter that sets the stage for the first half of the thesis. This chapter chronicles the development within our group of a vanadium-catalyzed interrupted Meyer-Schuster reaction to selectively form and trap vanadium enolates created from propargylic and allenylic alcohols. The next four chapters of this thesis describe new methods involving these vanadium enolates that result in the formation of carbon-carbon, carbon-nitrogen, and carbon-halide bonds. Chapters two through four utilize allenylic alcohols as enolate precursors that result in the formation of α-functionalized α', β'-unsaturated ketones, while chapter five utilizes propargylic alcohols as enolate precursors to yield complementary α-functionalized α, β-unsaturated ketones. More specifically, chapter two describes a method of generating aldol products from starting materials that lack carbonyl functionality. In this work, a vanadium/lanthanum dual catalytic cycle merges the interrupted Meyer-Schuster reaction with the Meinwald rearrangement of epoxides to in situ form vanadium enolates and aldehydes that undergo coupling. In the third and fourth chapters, the scope of reactions involving vanadium enolates formed from allenylic alcohols is expanded to include carbon-heteroatom bond forming processes through the use of dialkyl azodicarboxylate nitrogen electrophiles and electrophilic halide sources. Chapter five pivots to the use of propargylic alcohols as enolate precursors that also undergo subsequent trapping with electrophilic halide sources. This process results in geometrically defined tri- and tetrasubstituted acyclic olefins bearing a vinyl halide functional group handle for further elaboration into geometrically defined all-carbon tetrasubstituted olefins. The final three chapters describe the development of zinc-ProPhenol-catalyzed asymmetric enolate transformations. Chapters six and seven describe the use of heteroatom electrophiles for the synthesis of chiral hydrazines and amines. Chapter six deals with the use of cyclic ketone nucleophiles and describes the first catalytic system that can utilize both unbranched and α-branched ketones for the formation of α-secondary and α-tertiary amino products. In the seventh chapter, this methodology is expanded to include acyclic α-branched ketones, a class of nucleophiles that have previously evaded use in electrophilic amination processes due to the added challenge of needing to control both enolate geometry and facial selectivity in approach of the electrophile. The final chapter describes the use of acyclic α-fluoroketones, generated from the methodology disclosed in chapter four, as nucleophiles in the catalytic, asymmetric Mannich reaction. This process proceeds with a wide range of aryl, heteroaryl, and cyclopropyl aliphatic imine acceptors and results in the formation of densely substituted chiral β-fluoroamines.

Keywords: Chemistry.
Advisor: Trost Barry M. 
Burns Noah
Du Bois Justin