Development of Synthetic Methods to Enable the Synthesis of Pyrroloiminoquinone Alkaloids

Citation

Rezgui, Samir Peter (2026) Development of Synthetic Methods to Enable the Synthesis of Pyrroloiminoquinone Alkaloids. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/xmbz-by61. https://resolver.caltech.edu/CaltechTHESIS:07162025-124644565

Abstract

Natural product total synthesis continues to serve as a driving force for inventions in organic chemistry, and is an essential paradigm in the Stoltz group. The content of this thesis reflects this central objective. Chapter 1 focuses on the total synthesis of aleutianamine— a new pyrroloiminoquinone alkaloid natural product that possesses an unprecedented structure and potent anti-tumor activity. Herein is described a non-biomimetic synthesis that hinges upon the development of a dearomative thiophene arylation to construct the unique [3.3.1] ring system of the natural product. An unconventional ketone installation was then developed to install the alkenyl bromide, and finally, an oxidative amination/thioaminal formation protocol was developed to complete the synthesis. Additionally, a novel Larock/Buchwald–Hartwig annulation/cyclization was developed to access the core of the natural product.

Chapter 2 focuses on leveraging the Larock/Buchwald–Hartwig annulation/cyclization developed en route to aleutianamine to access several pyrroloiminoquinone alkaloids in a divergent manner. This strategy led to the shortest synthetic sequences at the time of four pyrroloiminoquinone alkaloids, and the first synthesis of another.

Chapter 3 describes the progress toward the total synthesis of atkamine, another pyrroloiminoquinone that has yet to be synthesized, by further leveraging of the Larock/Buchwald–Hartwig annulation/cyclization. The development of additional reaction methodologies were investigated to try and rapidly access the complex bicyclic ring system of this natural product.

Finally, Chapter 4 describes the synthesis of authentic standards to enable investigations of pinene secondary organic aerosols. Access to these standards allowed for the identification and formation mechanism of dimer esters in pinene organic aerosols, which has been a long-standing challenge in the field.