This proposal describes the development of novel chemical reactions for heterocycle synthesis and the application of these reactions to bioactive natural products. Specifically, a one-pot imine acylation/enol cyclization cascade has been developed that can selectively provide 4-oxazolidinones or pyrrolidones in a stereoselective fashion and these reactions have been applied to the total synthesis of the synoxazolidinones and pretazettine. The synoxazolidinones are recently discovered antimicrobial natural products with novel structures and promising activity against several clinically relevant bacterial strains. Pretazettine is an alkaloid bearing a densely functionalized pyrrolidine core and cytotoxic activit against several types of tumors. The objective of the proposed research is to develop a scalable and expedient approach to these two families of bioactive natural products and leverage the synthetic work to develop new chemical probes and lead compounds for antimicrobial and anticancer development. We have already developed a diastereoselective approach to the synoxazolidinones and prepared analogs with activity superior to that of the natural products.
We aim to further refine our synthetic approach and apply it to other members of the synoxazolidinone family while continuing to optimize the 4-oxazolidinone scaffolds for potency and selectivity towards bacteria. In parallel to these efforts we have expanded the scope of our reaction to provide pyrrolidone derivatives, which are broadly useful building blocks in medicinal chemistry and natural product synthesis. Utilizing this approach we propose an extremely rapid preparation of pretazettine, an alkaloid that has received significant attention from the synthetic community. We expect that our synthetic work will provide new reactions to construct heterocycles of broad utility and lead to approaches to natural products that enable their use as chemical probes. These synthetic studies are complimented by chemical biology studies to explore the activity of both natural products and analogs against clinically relevant bacteria and tumor cell lines. Taken together, these efforts will provide a framework for the development of new synthetic chemistry and potential lead compounds for the treatment of bacterial infections and cancer.

Public Health Relevance

The development of new treatments for resistant bacterial infections and aggressive cancers is a pressing need for public health. Natural products or their analogs have served as a major source of new classes of drugs over the last century and this proposal targets the study of a new class of natural products that have potential to be employed as novel treatments for human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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North Carolina State University Raleigh
Schools of Arts and Sciences
United States
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Mills, Jonathan J; Robinson, Kaylib R; Zehnder, Troy E et al. (2018) Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone?A. Angew Chem Int Ed Engl 57:8682-8686
Cusumano, Alexander Q; Pierce, Joshua G (2018) 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus. Bioorg Med Chem Lett 28:2732-2735
Shymanska, Nataliia V; Pierce, Joshua G (2017) Stereoselective Synthesis of Quaternary Pyrrolidine-2,3-diones and ?-Amino Acids. Org Lett 19:2961-2964
Cusumano, Alexander Q; Boudreau, Matthew W; Pierce, Joshua G (2017) Direct Access to Highly Functionalized Heterocycles through the Condensation of Cyclic Imines and ?-Oxoesters. J Org Chem 82:13714-13721
Edwards, Grant A; Shymanska, Nataliia V; Pierce, Joshua G (2017) 5-Benzylidene-4-oxazolidinones potently inhibit biofilm formation in Methicillin-resistant Staphylococcus aureus. Chem Commun (Camb) 53:7353-7356