The Total Synthesis of Aleutianamine, (–)-Crotonolide D, and (–)-Crotonine G

Author: Yu, Hao

Year: 2026

Degree: Dissertation (Ph.D.)

Advisor: Stoltz, Brian M.

Committee Members: Fu, Gregory C.; Goddard, William A., III; Robb, Maxwell J.; Stoltz, Brian M.

Option: Chemistry

DOI: 10.7907/cn84-6g19

Abstract

The first chapter describes the total synthesis of aleutianamine, a pyrroloiminoquinone alkaloid that displays potent and selective cytotoxicity towards pancreatic cancer PANC-1 cell line (IC₅₀ = 25 nM). An initial a-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.

The second chapter details the total synthesis of crotonolide D and crotonine G. The synthetic approach employs a SmI₂ mediated ketyl radical cyclization to form the highly congested quaternary carbon at the center of these complex molecules. Following the furan introduction, the core structure of the natural product is constructed via oxidative olefin cleavage to install the unusual C19 and C20 oxidation. Finally, palladium-catalyzed carbonylation, furan oxidation and acid mediated condensation/epimerization completes the synthesis.