This proposal details the development of new, catalytic reaction methodology for the efficient asymmetric synthesis of polyacetate- and polypropionate-derived macrolide antibiotics, It has been documented that drug-resistant bacterial and fungal infections represent a problem of rapidly growing importance. More than simply achieving syntheses of such compounds, the focus of the proposal is on advancing the frontiers of efficiency, waste-minimization and economic viability of such synthetic efforts. The ultimate goal is thus the realization of practicable and practical chemistry that will affect both the discovery and process phases of research into new medicinal agents. ? ? This proposal addresses both the continuation and further development of the most promising discoveries made in the previous funding period, as well as exciting new directions only recently initiated. The reactions under study have as their unifying theme tandem reaction methodology. Tandem reactions are inherently more efficient as multiple chemical transformations may be accomplished, and multiple stereogenic centers may be established in a single operation. In this fashion, large segments of the target natural products may be synthesized with unprecedented efficiency employing only readily available and environmentally benign reagents.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
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Columbia University (N.Y.)
Other Domestic Higher Education
New York
United States
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Suen, Linda M; Tekle-Smith, Makeda A; Williamson, Kevin S et al. (2018) Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1. Nat Commun 9:4710
Foley, Corinne N; Chen, Liang-An; Sackett, Dan L et al. (2017) Synthesis and Evaluation of a Linkable Functional Group-Equipped Analogue of the Epothilones. ACS Med Chem Lett 8:701-704
Chen, Liang-An; Ashley, Melissa A; Leighton, James L (2017) Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester. J Am Chem Soc 139:4568-4573
Tekle-Smith, Makeda A; Williamson, Kevin S; Hughes, Isaac F et al. (2017) Direct, Mild, and General n-Bu4NBr-Catalyzed Aldehyde Allylsilylation with Allyl Chlorides. Org Lett 19:6024-6027
Foley, Corinne N; Leighton, James L (2015) A Highly Stereoselective, Efficient, and Scalable Synthesis of the C(1)-C(9) Fragment of the Epothilones. Org Lett 17:5858-61
Ho, Stephen; Sackett, Dan L; Leighton, James L (2015) A ""methyl extension"" strategy for polyketide natural product linker site validation and its application to dictyostatin. J Am Chem Soc 137:14047-50
Foley, Corinne N; Leighton, James L (2014) Beyond the Roche ester: a new approach to polypropionate stereotriad synthesis. Org Lett 16:1180-3
Suen, Linda M; Steigerwald, Michael L; Leighton, James L (2013) A new and more powerfully activating diamine for practical and scalable enantioselective aldehyde crotylsilylation reactions. Chem Sci 4:2413-2417
Ho, Stephen; Bucher, Cyril; Leighton, James L (2013) A highly step-economical synthesis of dictyostatin. Angew Chem Int Ed Engl 52:6757-61
Tanis, Paul S; Infantine, Joshua R; Leighton, James L (2013) Exploiting pseudo C2-symmetry for an efficient synthesis of the F-ring of the spongistatins. Org Lett 15:5464-7

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