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Enantioselective Total Syntheses of Akuammiline Alkaloids and Arynes as Building Blocks for Enantioenriched Products


This dissertation features two projects concerning natural product synthesis and reaction development. The importance of natural product synthesis in chemistry and medicine cannot be overstated. In addition to providing a complex setting to test and apply new synthetic methodologies, natural products play a vital role in public health. Their influence in the pharmaceutical industry is profound, as approximately half of all chemical entities to treat disease come from natural product mimics, derivatives, or natural products themselves. With new natural products being discovered daily, there exists an ongoing need to develop efficient syntheses of these compounds and their derivatives.

Chapters One, Two, Three, and Four focus on an unusual variant of the Fischer indolization reaction and its application in the total synthesis of a particularly interesting class of indole alkaloids named the akuammilines. Specifically, Chapter One provides an overview of the so-called ‘interrupted Fischer indolization reaction’. This reaction is described from a methodological standpoint and is then evaluated in the context of akuammiline alkaloid total synthesis.

Chapters Two, Three, and Four describe enantioselective syntheses of various akuammiline alkaloids, in addition to several akuammiline alkaloid derivatives. Central to our approach was the development of modern variants of the classic Fischer indolization reaction to generate high levels of complexity. These efforts culminated in the first enantioselective total syntheses of (–)-aspidophylline A, (+)-strictamine, (–)-2(S)-cathafoline, (–)-pseudoakuammigine, (+)-akuammiline, (–)-10-demethoxyvincorine, and derivatives therein.

Chapters Five describes an application of the distortion/interaction model to a variety of mono and disubstituted benzynes and substituted indolynes. Chapter Six is focused on the development of a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates with b-ketoester-derived substrates. Our approach provides a general solution to the challenging problem of stereoselective b-ketoester arylation/alkenylation, with formation of a quaternary center with enantiomeric excess up to 96%.

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