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UBC Theses and Dissertations

Approaches to synthesis of D-series thiopeptide antibiotics Ferguson, Mai Lam


This thesis describes a diversity-oriented route to the pyridine-thiazole core cluster of D-series thiopeptide antibiotics. This approach is essential to medicinal chemistry investigations in aiming to develop new antibacterial agents based on the thiopeptide substances. Such new therapeutic resources would address an urgent need for new anti-infective agents to treat antibiotic-resistant Gram-positive pathogens such as methycilline-resistant S. aureus (MRSA), C. difficile, and other organisms of current concern. The research described herein unveiled a practical solution to a long-standing difficulty in thiopeptide chemistry: the so-called “thiazole problem.” Briefly, the foregoing objectives are best attained through transition metal mediated coupling reactions of appropriate 2-thiazolyl organometallic agents with 2-pyridyl triflates. However, 2-thiazolyl organometallics can be difficult to make and/or chemically unstable. This is especially true of highly desirable, but unknown, 2-borylthiazoles, which would be valuable for Suzuki-type coupling reactions. Readily available 2-thiazole carboxylic acids are shown to be excellent components of such processes, removing any need for the preparation of thiazolyl (or pyridyl) organometallics. The new technology nicely complements earlier methods developed in our group to assemble the complex core structure of D-series thiopeptide antibiotics.

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