Total Syntheses of Indole Alkaloids and Determination of the Electrophilicity of Benzyne and Related Intermediates

This dissertation encompasses several projects pertaining to natural product total synthesis, reaction methodology development, and kinetic studies. The total synthesis of natural products continues to be a fruitful area of research in organic chemistry. The successful completion of a total synthesis endeavor not only affirms ambitious route designs, but can also allow access to significant amounts of biologically-active compounds. Given that natural product structures inspire the development of new agrochemicals and pharmaceuticals, their syntheses are a worthwhile endeavor. Also, the development of new reaction methodologies and the understanding of fundamental reactivities of many intermediates remain important areas of research.Chapter One offers a current perspective on the field of natural product total synthesis. Alhough historically viewed as a highly competitive field, several recent examples show the growing spirit of collaboration in total synthesis. By forming alliances with chemists in other fields, industries, or laboratories, total synthesis chemists have made many breakthroughs that would arguably not be possible if working independently.Chapters Two and Three describe our laboratory’s total syntheses of several bioactive akuammiline alkaloids, including strictamine, 2(S)-cathafoline, akuammiline, -akuammigine, and 10-demethoxynorvincorine. Our strategic approach to the natural products focused on the use of a modern variant of a classic reaction, the Fischer indolization reaction, to install several rings and the common quaternary center found in each target. This strategy allowed for the first total syntheses of akuammilines bearing the methanoquinolizidine core and those that also bear vicinal quaternary centers. In addition, rearrangements of the methanoquinolizidine core were developed that allowed us to access pyrrolidinoindoline-containing akuammilines.Chapter Four describes a series of kinetic studies used to determine the electrophilicity parameter of benzyne and related aryne intermediates. Arynes are a family of strained intermediates whose existence has been postulated for over 100 years. Recent advances have confirmed their existence and proven their synthetic utility. An advanced knowledge of their reactivity thus far has remained elusive. Our laboratory employed the diffusion clock method to measure the rates of reaction between several arynes and a variety of different nucleophilic reaction partners. The result allowed for the first quantification of the electrophilicity of these strained intermediates and should influence synthetic planning in the future.Chapter Five includes a study in the development of reaction methodology. Utilizing a variant of the Fischer Indolization reaction, our laboratory discovered a general method for making aza-indoline structures. This methodology was applied in the synthesis of derivatives of akuammiline alkaloids and Alzheimer’s therapeutic molecules. In addition, a predictive computational model of reactivity was derived