2015 Theses Doctoral

Strategies for the Concise Synthesis of the Akuammiline Alkaloids

Smith, Myles Warwick

The akuammiline alkaloids are an intriguing class of natural products that display an array of biological activities and structural diversity. Despite being known for over 125 years, it is surprising that these complex monoterpene indole alkaloids have only recently elicited sustained interest from the synthetic community, especially given the storied history of this broad family in the development of the art of total synthesis, and, in particular, heterocyclic chemistry. This dissertation details our efforts to address these deficiencies through work directed at the unique akuammiline alkaloid (+)-scholarisine A, ultimately yielding a concise and enantiospecific preparation of this challenging target. Building on this initial success, we have initiated studies aiming to generalize these strategies to the akuammiline class as whole, efforts that have been empowered by the development of several novel synthetic transforms. These investigations have culminated in the efficient synthesis of a collection of advanced intermediates en route to the varied frameworks represented by strictamine and 10-demethoxynorvincorine. In addition, we have leveraged our expertise gained within these challenging contexts towards a method with utility beyond the akuammiline class, one that is likely to find broad application in both natural product synthesis and the assembly of medicinally-relevant building blocks.