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 these alkaloids are described which
features oxidative C−C bond formation. Specifically, the first heterocoupling of two different types of carbonyl
species (ester and amide) is accomplished in good yield, on a preparative scale, and with complete
stereocontrol. The information gained in these model studies enabled an enantioselective total synthesis
of stephacidin A. The absolute configuration of these alkaloids was firmly established in collaboration with
Professor William Fenical. A full account of our successful efforts to convert stephacidin A into stephacidin
B via avrainvillamide is presented. Finally, the first analogues of these natural products have been prepared
and evaluated for anticancer activity.