Plans describe the continuation of an ambitious and highly successful program investigating the fundamental chemical behavior of recently discovered, biologically-active marine metabolites. The research plan details innovative solutions to the most challenging aspects presented by these unique natural products. Studies will advance basic synthesis methodology for stereocontrolled strategies toward highly functionalized target molecules. The program is organized in two categories. I. Macrolide Anti-tumor Antibiotics Part A: Plans for synthesis of amphidinolide P are presented. The amphidinolides are among the most potent anti-tumor agents discovered, with remarkable activity in nearly all NCI tumor cell lines. Extremely limited quantities have hampered biological research. The proposed chemistry will develop functionalized amphidinolide P. Part B. Efforts for synthesis of leucascandrolide A are presented. The recently discovered macrolide displays powerful anti- tumor and anti-fungal properties, and inhibits Candida albicans, an opportunistic yeast infection of many immunocompromised patients. Allylstannane methodology will offer innovative solutions for rapid construction of the alternating 1, 3, 5...oxygenation pattern. Efficient stereoselective syntheses of substituted tetrahydropyran rings, as bridging elements of this antibiotic will be addressed. II. Marine Diterpenes. Part A. Studies of the novel, nine-membered xenicanes are focused on the synthesis of 4-hydroxydictyolactone, a representative structure with anti-tumor and anti-bacterial activity. Investigations of intramolecules alpha-sulfonyl carbanion condensations with omega-aldehydes will provide for assembly of the rigid ring system. Studies of the three contiguous stereocenters (stereotriad) as presented in the xenicanes. Part B. Synthesis of the eleven-membered dolabellane diterpene 4,5-deoxyneodolabelline, will document two strategies for stereocontrolled formation of [9.3.0] cyclotetradecanes. Investigations will highlight previous discoveries for alpha-sulfonyl carbanion chemistry, used to trigger a transannular oxidative ring closure of the bridging pyran. Palladium-catalyzed macrocyclization offers an innovative strategy for stereocontrolled ring formation. A particularly rich spectrum of biological activity, including important anti-tumor activity, is exhibited throughout this class of novel medium-ring metabolites.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BNP (02))
Program Officer
Schwab, John M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University Bloomington
Schools of Arts and Sciences
United States
Zip Code
Williams, David R; Robinson, Leslie A; Bawel, Seth A (2015) Conformational effects and stereocontrol in synthesis studies of medium-ring dolabellane carbocycles. Tetrahedron Lett 56:3200-3203
Williams, David R; Plummer, Scott V; Patnaik, Samarjit (2011) Studies for the enantiocontrolled preparation of substituted tetrahydropyrans: Applications for the synthesis of leucascandrolide A macrolactone. Tetrahedron 67:5083-5097
Williams, David R; Fu, Liangfeng (2010) Efficient Suzuki and Stille Reactions for Regioselective Strategies of Incorporation of the 1,3-Oxazole Heterocycle. Mild Desulfonylation for the Synthesis of C-4 and C-5 Monosubstituted Oxazoles. Synlett 2010:1641-1646
Williams, David R; Shah, Akshay A (2010) Regioselective formation of 1,1-disubstituted allenylsilanes via cross-coupling reactions of 3-tri-n-butylstannyl-1-trimethylsilyl-1-propyne. Chem Commun (Camb) 46:4297-9
Williams, David R; Fultz, Micheal; Christos, Thomas E et al. (2010) A general preparation of (Z)-1-fluorostilbene derivatives for the design of conformationally restricted peptidomimetics. Tetrahedron Lett 51:121-124
Williams, David R; Fu, Liangfeng (2009) Methodology for the Synthesis of Substituted 1,3-Oxazoles. Synlett 2010:591-594
Williams, David R; Walsh, Martin J; Miller, Nathan A (2009) Studies for the synthesis of xenicane diterpenes. A stereocontrolled total synthesis of 4-hydroxydictyolactone. J Am Chem Soc 131:9038-45
Williams, David R; Robinson, Leslie A; Nevill, C Richard et al. (2007) Strategies for the synthesis of fusicoccanes by Nazarov reactions of dolabelladienones: total synthesis of (+)-fusicoauritone. Angew Chem Int Ed Engl 46:915-8