Strategies towards the Synthesis of Azetidine-Containing Metabolites Produced by Pseudomonas aeruginosa - Project Summary/Abstract Total syntheses of novel azetidine-containing metabolites (azetidomonamide A, azetidopyridone, and diazetidomonapyridone) from Pseudomonas aeruginosa do not exist, and are sorely needed so their biological functions in quorum-sensing behavior can be evaluated. In particular, the exact mode of their production from the non-ribosomal peptide synthetase (NRPS) enzymatic cluster is unknown; furthermore, elucidating the exact role of these metabolites in modulating quorum-sensing behavior in P. aeruginosa is not currently possible due to the minute quantities of metabolites produced in the natural bacterial system. Additionally, these metabolites affect overall bacterial biofilm formation and the production of redox-active metabolites, which are partially implicated in adverse outcomes for cystic fibrosis patients infected with P. aeruginosa. Thus, total syntheses of these metabolites are highly needed and will have a broader impact on human health through expanding our understanding of biofilm formation by P. aeruginosa, and potentially allowing for development of anti-virulence treatments for it in the long term. The studies described in this proposal seek to develop strategies for synthesis of these novel azetidine- containing metabolites. Importantly, we propose orthogonal approaches that mitigate the risk of the overall goal while still pushing chemical boundaries by leveraging modern chemistry in complex contexts. For the synthesis of azetidomonamide A (Aim1), our design involves accessing and employing a unique ynamide cascade to cyclize the system; a second approach utilizes enzymatic biocatalysis to install the alcohol stereocenter. For the synthesis of diazetidomonapyridone (Aim 2), we first propose strategies for accessing the azetidopyridone precursor. The initial approach would build on existing chemistry by utilizing a Pd-catalyzed cascade cyclization with CO in a complex setting; an alternative approach alleviates the risk of the former approach by employing condensation reactivity to install the requisite cyclic system. To access diazetidomonapyridone from the azetidopyridone, we envision two approaches. The first employs a biomimetic reflection of literature precedent by directly subjecting azetidopyridone to azetidomonamide A, which undergo spontaneous reaction under basic conditions to access the target metabolite. Additionally, we propose accessing diazetidomonapyridone via a bio-inspired approach that leverages ring formation to control alkene geometry. Overall, the proposed research is significant because it provides creative strategies to establish the first total syntheses of azetidomonamide A, azetidopyridone, which will enable their biological study. More broadly, these strategies can be used to access similar scaffolds in other bacterial metabolites that have yet to be synthesized. Performing this research in Prof. Reisman’s group at Caltech aligns well with their current success in the efficient total synthesis of complex natural products and will augment my prior training in organometallic chemistry to prepare me for a future academic career as a professor.
