Progress toward the total synthesis of (+)-peloruside A

The dissertation contained herein describes the synthetic efforts toward the total synthesis of (+)-peloruside A, which comprises four generations of synthetic strategies and the total synthesis of (−)-2- epi-peloruside A. (+)-Peloruside A is a highly potent 16-membered, microtubule-stabilizing macrolide that was first isolated from the sponge Mycale (Carmia) off the coast of New Zealand.* Chapter 1 highlights the significance of (+)-peloruside A to the scientific community. First, the biological properties of (+)-peloruside A, consisting of the mode of action and potency of the macrolide toward a wide range of cancer cell lines, are discussed. Next, three previous total syntheses, one by De Brabander of the unnatural antipode and one each by Taylor and Ghosh, of the natural enantiomer are highlighted. Finally, seven synthetic efforts from the organic chemistry community toward peloruside A are summarized. Chapter 2 focuses on the seven years and four generations of research conducted by the Smith group toward peloruside A. Initially, a brief overview of the first-generation approach toward the unnatural antipode, (−)-peloruside A, is highlighted. The following four sections focus on the second-generation strategy toward (+)-peloruside A, which culminates in the total synthesis of (−)-2-epi-peloruside A. This work led to a modified third-generation approach toward (+)-peloruside A, which after extensive investigation was ultimately met with failure. Finally, a fourth-generation proposal is presented - one with the potential of culminating in the total synthesis of (+)-peloruside A. *Please refer to dissertation for diagram