Tethered aza-Wacker Technology for Complex Antibiotic Assembly

Project Summary The number of bacterial strains resistant to clinically used antibiotics continues to increase at a frightening pace, and the lack of viable first-line treatments of these bacterial infections has forced clinicians to consider second- line antibiotic options such as polymyxins and aminoglycosides. Such reserve antibiotics often carry the risk of

significant toxicity and subsequent patient harm. Thus, the timely development of new antibacterial agents, preferably with modes of action distinct from ones currently employed, is essential for the global decrease of human morbidity and mortality. The chemical synthesis of known antibacterial natural products is a strategy that

has yielded great dividends in the past and continues to furnish important clinical therapeutics in the present. Often, while entrenched in the construction of such complex molecules, the synthetic practitioner is confronted by the limitations of available technology. Thus, the development of new organic methodology is often intimately

joined with the pursuit of biologically-active natural products. The overarching themes guiding this R35 proposal are the development of new tethered aza-Wacker cyclization reactions and their use in the synthesis of nitrogenous antibiotics. The importance of a tethered reaction is that it frees the synthetic practitioner from the

constraint of needing a pre-existing C–N bond in order to forge a new one, and our laboratory has published several studies in this area. We plan to apply this technology for the synthesis of the unusual dichlorinated polyketide antibiotics Bactobolins A-B and Acybolin A. Bactobolins A and B were first isolated from the culture

broth of Pseudomonas yoshidomiensis and have been demonstrated to have broad antibacterial activity against a variety of pathogenic gram-positive and gram-negative organisms. Recent work has pinpointed the antibacterial activity of Bactobolin A to inhibition of bacterial protein translation via binding to an unprecedented

site on the 50s prokaryotic subunit (L2); a crystal structure exists showing this interaction. Despite their rich biological activity, there exists only one racemic synthesis (Weinreb) and one enantiospecific synthesis (Švenda) of Bactobolin A. Acybolin A is a recently isolated antibiotic with activity against Bactobolin-resistant strains of B.

subtilis, suggesting a disparate mode of action from Bactobolins despite structural homology. There currently exists no synthesis of the Acybolin family of natural products, no exploration of analogues, and limited analysis of biological activity. A key step in our proposed synthesis of these compounds is a reaction recently developed

in our laboratory, the sulfamate aza-Wacker cyclization. The expected outcomes of this line of research include the development of powerful new methods for the site-selective amination of alkene moieties and access to a variety of new antibacterial compounds through precise stereocontrolled synthesis. Collectively, this work will

establish a broad and robust program of synthetic chemical innovation and antibiotic design in my laboratory.