Total Synthesis of Welwitindolinone Natural Products

Chapter one provides a summary of efforts towards the syntheses of the welwitindolinones with bicyclo[4.3.1]decane cores. Emphasis is given to more recent approaches that have successfully assembled the bicyclic core of the natural products. Chapters two and three are a discussion of our studies relating to a model system of the welwitindolinone natural products. Chapter two focuses on the use of an aryne cyclization to assemble the bicyclo[4.3.1]decane framework of the welwitindolinones. Chapter three covers initial attempts to install the bridgehead nitrogen substituent present in the natural products in addition to the synthesis of a functionalized aryne cyclization substrate. Chapters four and five present our total syntheses of the welwitindolinone natural products. The enantiospecific total syntheses of N-methylwelwitindolinone C isothiocyanate, N-methylwelwitindolinone C isonitrile, 3-hydroxy-N-methylwelwitindolinone C isothiocyanate and 3-hydroxy-N-methylwelwitindolinone C isonitrile are detailed. The approach to these natural products features an aryne cyclization to construct the bicyclo[4.3.1]decane core of the molecules as well as a late-stage nitrene insertion reaction to install the bridgehead nitrogen substituent. The use of a deuterium kinetic isotope effect to improve the yield of the nitrene insertion is also presented. In addition, a computational method to predict the stereochemistry of a previously unconfirmed stereocenter in the hydroxylated natural products as well as experimental validation of the computational findings is discussed