UC Berkeley

The synthesis and absolute stereochemical determination of cycloprodigiosin has been completed. Chapter 1 discusses the historical, synthetic, and biological background of prodiginine natural products, specifically of prodigiosin and cycloprodigiosin. Chapter 2 details our synthetic attempts for the synthesis of cycloprodigiosin and the strategy used to determine the absolute stereochemistry at the C4’ position of this prodiginine. The syntheses of both enantiomers of cycloprodigiosin were completed in an efficient five step sequence utilizing a Barton-Schöllkopf-Zard pyrrole synthesis. Cycloprodigiosin was isolated from its parent bacterial source, Pseudoalteromonas rubra, by Tristan de Rond in a collaboration with the Keasling group at UC Berkeley. The natural isolate was determined to exist as a scalemic mixture in a ratio of 83:17 (R):(S) at C4’. The enzyme responsible for the final oxidative cyclization event from prodigiosin to cycloprodigiosin was identified as the alkylglycerol monooxygenase-like enzyme PRUB680.

The second topic of this thesis details the first total synthesis of ambiguine P in 19 steps from (S)-carvone. The isolation, biosynthentic, and synthetic background of the ambiguine family of natural products is discussed in Chapter 3. The challenges associated with the synthesis of pentacyclic ambiguines are described in Chapter 4 and focus on the formation of the pentacyclic core in addition to the installation of the C12 quaternary center. The 1st generation synthetic approach to access the ambiguine pentacyclic core involves a key γ-enolate cross-coupling reaction to form the tetracyclic precursor. The intermediates in this approach were synthesized from indole and (S)-carvone using an intermolecular Nicholas alkylation. The 2nd generation synthetic route to access the key pentacyclic core involves an intramolecular Nicholas alkylation at C2 of indole, followed by Friedel-Crafts cyclization at C4 to successfully generate the pentacylic core.

Chapter 5 describes the completion of ambiguine P; many strategies were explored to install the C12 quaternary center, and eventually a directed C–C bond construction utilizing formates was found that successfully formed the C–C bond on the desired α-face. The requisite vinyl group at C12 and the amide functionality at C11 were installed using an interrupted Peterson olefination strategy. Attempts are described to access ambiguine L from these late-stage intermediates using benzylic oxidation and hydration methodologies.