Stereoselective Electrophilic Additions to Alpha-Trialkylsilyl-Beta,Gamma-Unsaturated Esters

Abstract

This dissertation details stereoselective additions to alpha-trialkylsilyl beta, gamma-unsaturated esters synthesized from alpha-trialkylsilyl alpha, beta-unsaturated esters. This work is divided into five chapters. Chapter 1 utilizes organometallic methodology and begins by discussing background of the Suzuki-Miyaura cross-coupling reaction. It goes on to outline our efforts toward palladium-catalyzed cross coupling of alpha-bromoketones via their palladium enolates. The goal of this chapter was to develop a dependable method to prepare gamma-substituted alpha, beta-unsaturated esters through a Suzuki-Miyaura cross-coupling using substituted boronic acids as a precursor to gamma-halogenated alpha, beta-unsaturated esters discussed in Chapter 3. Chapter 2 details an approach to simultaneous installation of these three functional groups mediated by alpha-silyl alpha, beta-unsaturated esters, starting from ethyl prop-2-ynoate (ethyl propiolate). Initial synthetic steps include a catalytic carbocupration with copper iodide, various Grignard reagents, and trialkylsilyl triflate to yield alpha-silyl alpha,beta-unsaturated esters with (E)-selectivity (>20:1) of the newly formed olefin. Deprotonation of the alpha-trialkylsilyl alpha, beta-unsaturated ester at its gamma-position, followed by kinetic reprotonation of this species, yielded the deconjugated alpha-trialkylsilyl beta,gamma-unsaturated ester, retaining good selectivity for the (E)-alkenes (>20:1). Chapter 3 discusses the halogenation of the various previously obtained alpha-trialkylsilyl beta, gamma-unsaturated ester with halo-succinimides (NXS, X = Cl, Br, and I). These reactions retain excellent diastereoselectivity (>20:1) when carried out on the series of deconjugated alpha-trialkylsilyl beta, gamma-unsaturated esters prepared previously, providing a straightforward approach to preparing gamma-halo-(E)-alpha,beta-unsaturated esters.Chapter 4 further expands the usefulness of these ester intermediates by showing that they can be converted into beta, gamma -epoxy esters, with good selectivity for the formation of the epoxide ring anti to the previously installed α-trialkylsilyl substituent (dr ~6:1). We also demonstrate that these intermediates can be further converted into valuable γ-hydroxy compounds with excellent regioselectivity and good stereoselectivity. The alcohol products are obtained through epoxide ring opening and desilylation, to produce a gamma-hydroxy alpha, beta-unsaturated ester as the (E)-olefin (>20:1). Chapter 5 outlines future directions for the research outlined, as well as, natural products that could be synthesized utilizing the methods outlined in this dissertation.