The research program outlined herein is directed toward the design and development of general strategies for the syntheses of natural and unnatural products that exhibit significant biological activity. During the course of these investigations, the scope and limitations of selected reactions and processes will be explored in the context of the total synthesis of complex molecules, and new methods for carbon-carbon bond formation and functional group manipulation will be discovered and developed. The specific objectives include completing the total syntheses of several biologically important natural products including the macrolide antibiotic erythromycin B, the antifungal antibiotic ambruticin, the anticancer agent FR-900482, and the squalene synthase inhibitor and antifungal agent zaragozic acid A. The basic strategies for the syntheses of these compounds are unique and involve the stereoselective elaboration of furans and hydropyrans derived therefrom, asymmetric cyclopropanations, ring closing metatheses, and vinylogous aldol reactions. The approach to erythromycin B features a non-biogenetic macrolactonization of a fully glycosylated seco-acid derivative. New biologically active targets have been selected that will serve as the forum for the invention of novel chemistry. For example, a general strategy for the synthesis of C-aryl glycoside antibiotics will be developed that features (4+2) cycloadditions of substituted furans with benzynes followed by the opening of the oxabicycloheptene adducts thus produced with glycosyl anions. The utility of the approach will then be demonstrated by its application to the synthesis of the anticancer agent rubiflavin A as well as other representative C-aryl glycosides such as galtamycinone. Quantities of the natural products and selected congeners will be prepared for submission to C. P. Starks, Inc., Eli Lilly Company, Merck, Abbott Laboratories, Pfizer, and GlaxoWellcome for biological evaluation as potential antibiotics and as antifungal, hypocholesterolemic and anticancer agents.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Texas Austin
Schools of Arts and Sciences
United States
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Klosowski, Daniel W; Martin, Stephen F (2018) Synthesis of (+)-Disparlure via Enantioselective Iodolactonization. Org Lett 20:1269-1271
Klosowski, Daniel W; Hethcox, J Caleb; Paull, Daniel H et al. (2018) Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications. J Org Chem 83:5954-5968
Martin, Stephen F (2017) Natural Products and Their Mimics as Targets of Opportunity for Discovery. J Org Chem 82:10757-10794
Hethcox, J Caleb; Shanahan, Charles S; Martin, Stephen F (2015) Diastereoselective addition of monoorganocuprates to a chiral fumarate: reaction development and synthesis of (-)-dihydroprotolichesterinic acid. Tetrahedron 71:6361-6368
Yang, Jingyue; Knueppel, Daniel; Cheng, Bo et al. (2015) Approaches to polycyclic 1,4-dioxygenated xanthones. Application to total synthesis of the aglycone of IB-00208. Org Lett 17:114-7
Knueppel, Daniel; Yang, Jingyue; Cheng, Bo et al. (2015) Total Synthesis of the Aglycone of IB-00208. Tetrahedron 71:5741-5757
Shanahan, Charles S; Fang, Chao; Paull, Daniel H et al. (2013) Asymmetric Formal Total Synthesis of the Stemofoline Alkaloids: The Evolution, Development and Application of a Catalytic Dipolar Cycloaddition Cascade. Tetrahedron 69:7592-7607
Fang, Chao; Paull, Daniel H; Hethcox, J Caleb et al. (2013) Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst. Org Lett 15:972
Fang, Chao; Shanahan, Charles S; Paull, Daniel H et al. (2012) Enantioselective formal total syntheses of didehydrostemofoline and isodidehydrostemofoline through a catalytic dipolar cycloaddition cascade. Angew Chem Int Ed Engl 51:10596-9
Fang, Chao; Paull, Daniel H; Hethcox, J Caleb et al. (2012) Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst. Org Lett 14:6290-3

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