Enantioselective Total Synthesis of Avrainvillamide and the Stephacidins

In this article, full details regarding our total synthesis of avrainvillamide and the stephacidins are presented. After an introduction and summary of prior synthetic studies in this family of structurally complex anticancer natural products, the evolution of a final synthetic approach is described. Thus, a thorough description of three separate model studies is provided for construction of the characteristic bicyclo[2.2.2]diazaoctane ring system common to these alkaloids. The first and second approaches sought to build the core using formal Diels−Alder and vinyl radical pathways, respectively. Although these strategies failed in their primary objective, they fostered the development of a new and mechanistically intriguing method for the synthesis of indolic enamides such as those found in numerous bioactive natural products. The scope and generality of this simple method for the direct dehydrogenation of tryptophan derivatives is described. Finally, details of a third and successful route to the core of...