The objective of this proposal is to develop the first practical, efficient, and enantioselective laboratory synthetic route(s) to the tetracycline antibiotics. The goal is to devise a route of twelve or fewer synthetic steps, perhaps as few as eight steps, beginning with benzoic acid as a starting material. A constraint that the synthetic route be versatile is also imposed, allowing for the introduction of substantive structural variability at a late stage, particularly within the C and D rings of the tetracycline structure, where prior research has shown that there is great opportunity for antibiotic development. Synthesis of a wide range of new tetracyclines for evaluation as improved antibiotics and, potentially antitumor agents is proposed. A particular focus is the development of effective antibiotics against tetracycline-resistant microorganisms. Adaptation and/or modification of these synthetic routes to target new tetracycline structures with antitumor activity, such as SF-2575 (TAN-1518 X) will also be attempted.
| Wright, Peter M; Myers, Andrew G (2011) Methodological Advances Permit the Stereocontrolled Construction of Diverse Fully Synthetic Tetracyclines Containing an All-Carbon Quaternary Center at Position C5a. Tetrahedron 67:9853-9869 |
| Kummer, David A; Li, Derun; Dion, Amelie et al. (2011) A practical, convergent route to the key precursor to the tetracycline antibiotics. Chem Sci 2:1710-1718 |
| Sun, Cuixiang; Wang, Qiu; Brubaker, Jason D et al. (2008) A robust platform for the synthesis of new tetracycline antibiotics. J Am Chem Soc 130:17913-27 |
| Brubaker, Jason D; Myers, Andrew G (2007) A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics. Org Lett 9:3523-5 |
| Charest, Mark G; Lerner, Christian D; Brubaker, Jason D et al. (2005) A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 308:395-8 |
