Synthesis of the Antimalarial Flindersial Alkaloids

The concept of mimicking nature to synthesize natural compounds has been successfully demonstrated in the synthesis of all the anti-malarial Flindersia alkaloids. Previous work on the biosynthesis of the related natural products borreverine and isoborreverine inspired us to synthesize racemic flinderoles A, B, and C in as few as three synthetic steps from simple and readily available materials. The development of reaction conditions for the dimerization of borrerine in the presence of acid is discussed in detail. The progress toward the enantioselective total synthesis of flinderoles A, B, and C is also presented. The retrosynthetic plan was inspired by the biomimetic synthesis of the flinderoles, in which an acid mediated amino cyclization would form the flinderole framework. Tryptamine and 3-butyn-2-one undergo a vinylogous Pictet-Spengler reaction to give a β-carboline, which opens to a 2-enone tryptamine in the presence of base. A BINOL catalyzed enantioselective conjugate addition of a vinyl boronic acid to the 2-enone tryptamine has been achieved. A pyrrolo[a]indole unit could be connected to another indole unit by a Sonagashira coupling reaction in a convergent manner.