Access to Strained Rings and Heterocycles: Applications in the Synthesis of Bacterial Metabolites and Chemical Building Blocks - Project Summary/Abstract The studies described in this proposal seek to develop strategies for the synthesis of strained rings and heterocycles for two purposes: 1) the first total syntheses of novel azetidine-containing metabolites, and 2) rapid access to bifunctional strained ring and heterocycle building blocks. Regarding the first purpose, total syntheses of azetidomonamide A, azetidopyridone, and diazetidomonapyridone do not exist and are sorely needed so their biological functions in quorum-sensing behavior can be evaluated. These metabolites affect biofilm formation and production of redox-active metabolites in P. aeruginosa, which is partially implicated in adverse outcomes for cystic fibrosis patients. Thus, total syntheses of these metabolites are highly needed and will have a broader impact on human health through expanding understanding of biofilm formation by P. aeruginosa, and potentially allowing for development of anti-virulence treatments for it in the long term. For the second purpose, strained rings and heterocycles are increasingly prevalent in pharmacological motifs; strategies to access modular components are needed to enable expedient diversification and access to new bioactive molecules. For the syntheses of azetidomonamide A and diazetidomonapyridone (K99), we envision the development of intramolecular cyclization reactions to establish key challenging frameworks in the molecules, such as Z-exocyclic azetine moieties, 4/6 bicyclic pyridones, and 4/7 bicyclic carbamates. These efforts will not only allow us to establish the total syntheses of these metabolites, but contribute more broadly to chemical synthetic efforts in the development of new reactions to access these strained heterocyclic motifs. In the R00 component, we propose the development of organometallic methods to achieve the syntheses of bifunctional strained ring and heterocycle chemical building blocks. In the first phase, we anticipate diverting organometallic intermediates to Favorskii-type reactivity to generate N-heterocycles that contain multiple handles for further functionalization; in the second, we propose tuning organometallic intermediates to Ramberg- Bäcklund reactivity to access substituted strained-ring derivatives. In doing so, we will broaden knowledge of current chemical reactivity as well as provide strategies to make molecular scaffolds relevant to multiple industries, including those pertaining to pharmaceuticals. Overall, the proposed research is significant because it provides creative strategies to 1) establish the first total syntheses of azetidomonamide A and diazetidomonapyridone, which will enable their biological study, and 2) develop new reactivity paradigms for accessing modular molecular scaffolds with pharmacological relevance. Performing the K99 research in Prof. Reisman’s group at Caltech aligns well with their current success in the efficient total synthesis of complex natural products; this experience in the synthesis of strained heterocycles will augment my prior training in organometallic chemistry to prepare me for a future R1 academic career in which I develop methods to access these types of motifs in broader contexts.
