Evolution of Strategies Toward the Total Synthesis of Aleutianamine

A full account of our total synthesis of aleutianamine (1) is disclosed. An initial α-thioketone derivatization approach was thwarted by a failed enolate functionalization. A second-generation approach employing palladium-catalyzed Barbier addition enabled the successful construction of the [3.3.1]bicyclononane moiety of the natural product, but unsuccessful downstream functionalization and poor material throughput led to the abandonment of this approach. Along the way, a one-pot Larock indolization/Buchwald-Hartwig amination cascade was developed for the synthesis of tricyclic diaminoindole derivatives. Eventually, the total synthesis was accomplished via a novel dearomative arylation of an aminothiophene, which allowed rapid access to the molecular skeleton of aleutianamine including the challenging bridgehead sulfide. Following construction of the core, cerium-mediated oxidative amination and palladium-catalyzed decarboxylative pinacol-type rearrangement enabled chemoselective introduction of the C10 aniline and alkenyl bromide, leading to the total synthesis of aleutianamine.