UC Berkeley

Abstract

The Total Synthesis of ()-Curvulamine and Related Poly-Pyrrolic Natural Products Through a Non-Obvious Convergent Approach

by

Karl Thomas Haelsig

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Thomas J. Maimone, Chair

First introduced to the scientific community in 2014, the curvulamine alkaloids are a family of natural products produced by fungi from the Curvularia and Bipolaris genus. Fungi from both genera are known facultative pathogens associated with agricultural crop diseases and human and animal pathologies. In Chapter I, the background and history of the curvulamine alkaloids is discussed, which proceeds a discussion on the distinct skeletal architectures of these family members. The three skeletal subtypes of the curvulamine alkaloids are introduced and their hypothetical biogenesis from the union of C10N indolizine fragments is presented. A more detailed discussion of congeners bearing the 5-7-6-5 tetracyclic core and belonging to the “secondary level” of structural complexity is then addressed. Next, the biological properties of members exhibiting antibiotic activity and anti-inflammatory properties is presented along with a proposed mechanism of action for family members containing a C3–C13 bridging ether. Prior total syntheses of natural products containing indolizine moieties are briefly mentioned, and the challenges with chemical synthesis in a pyrrole landscape are highlighted. Lastly, the motivations for pursing a chemical synthesis of these natural products are given, accompanied by the introduction of an overarching synthetic philosophy we adopted while in pursuit of these natural products.

In Chapter II the tetracyclic core of ()-curvulamine is presented through a retrosynthetic lens. Our commitment to leverage the innate reactivity of both pyrrole moieties to access the 5-7-6-5 tetracyclic core through convergent bond formations to afford the B- and C-ring of ()-curvulamine is discussed, and congruent revisions in our retrosynthetic disconnections are iteratively addressed. Inspired by biogenesis proposals for these alkaloids, our first synthetic attempts focused on the union of C10N synthetic fragments to prepare the tetracyclic core after a late-stage B-ring closure are discussed. With the lessons learned from our initial foray, an alternative approach toward C-ring formation and B-ring closure was investigated through the coupling of synthetic C9, C3, and C8 fragments. However, the inability to realize late-stage seven-membered ring formation led us to revise our applied synthetic units and overarching disconnection for preparing the tetracyclic core. Our revised investigations into tetracycle assembly focused on bond formations onto a pre-existing pyrroloazepinone nucleus to construct the C-ring and append a C2 side chain are presented, and the development of a robust and modular dearomative strategy for the five-step synthesis of a 5-7-6-5 tetracyclic homolog is documented. Subsequent attempts of performing a late-stage carbon extrusion at C3 of tetracyclic core homologs were fraught with challenges and hurdles, that ultimately proved to be an impassible synthetic barrier. Although, the failure to realize a carbon extrusion at C3 halted progress, we had developed a modular synthetic platform enabling alternative synthetic avenues to be explored in our pursuit of ()-curvulamine. Finally, a revision in our synthetic units toward ()-curvulamine and consideration of alternative nucleophiles is addressed.

Moving forward, with a convergent strategy for preparing tetracyclic intermediates realized, we highlight observations in our investigations into alternative Michael addition nucleophiles in our tetracycle construction sequence. From these investigations the eventual total synthesis of ()-curvulamine was realized. A synthesis featuring (i) a dearomative functionalization of a 10π heteroaromatic pyrrolo[1,2-a]azepinone synthetic unit, (ii) the discovery and development of a novel photocyclization reaction, and (iii) a final stereodivergent reduction to arrive at enantioenriched ()-curvulamine in ten steps. Lastly, we hope to harness our synthetic route for ()-curvulamine to approach fellow “second level” congeners and the higher order metabolite (+)-curindolizine, and have proposed synthetic routes currently being explored and will be reported in due course.

In conclusion, we have laid initial groundwork for chemical syntheses in a chemical space with limited prior exploration, and ultimately have achieved the first total synthesis of ()-curvulamine; to the best of our knowledge this work represents the first chemical synthesis of a natural product bearing two, embedded, electron-rich pyrrole moieties. Synthetic work in this bis-pyrrole landscape taught us many understated lessons and laid bare the challenges in choreographing synthetic strategies involving pyrrole-containing intermediates. We hope this work is instructive for chemical synthesis in this field and aids in elucidating the biological mechanism of action of curvulamine alkaloid family members.