This is a broadly directed program to investigate fundamental advances in chemical synthesis of novel biologically active natural products. The major areas have been categorized by distinct structural motifs and bioactivity. I. Novel Marine Oxazoles. Research will execute a synthesis of Hennoxazole A, a promising lead in the search for new antiviral agents. While this unique bis-oxazole also displays peripheral analgesic activity comparable to indomethacin, its unusual structure and antiviral significance (IC50 0.6 m/mL), make this a compelling case for chemical synthesis. Phorboxazole A exhibits remarkable antitumor activity in all 60 NCI cell lines, and is one of the most potent cytostatic macrocycles yet discovered. Chemical studies will explore enantioselective allylstannane condensations with aldehydes as a convergent construction of carbohydrates which are C-linked to a heterocyclic core. Overall a general approach to novel nucleosides is detailed. II. Novel Anti-Infective Cyclitols. Studies for synthesis of funiculosin and related 4-hydroxy-2-pyridinones will provide novel C-linked heterocyclic cyclitols as potent antifungal agents. Funiculosin shows in vivo antifungal potency comparable to griseofulvin with low toxicity. The Saegusa oxidation will be explored as a ring closure event, and internal conjugate additions in funiculosin, as well as apiosporamide, will be examined as a relevant chemical feature of bioactivity. III. Polycyclic Marine Alkaloids. Zoanthamine is an alkaloid with anti-inflamatory and analgesic effects. Proposed studies will investigate Pd(O)-catalyzed cross-coupling reactions for ring closure. Studies of the Michael reaction will be exploited for stereocontrolled formation of quaternary carbons in ring annelation processes. IV. Large-Ring Carbocycles. Efforts to complete synthesis studies of the lankacidins are described. These macrocyclic antitumor agents exhibit important antibiotic effects against resistant organisms. New strategies for macrocyclization are introduced. Acyl nitrene insertions for preparation of lankacyclinol are described.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM041560-15
Application #
2397621
Study Section
Special Emphasis Panel (ZRG3-SSS-Z (12))
Project Start
1982-04-01
Project End
2001-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
15
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Indiana University Bloomington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Williams, David R; Claeboe, Christopher D; Liang, Bo et al. (2012) A bidirectional S(E)' strategy for 1,5-syn and 1,5-anti stereocontrol toward the synthesis of complex polyols. Org Lett 14:3866-9
Williams, David R; Klein, J Cullen; Chow, Nicholas S C (2011) Studies of intramolecular Diels-Alder reactions of nitroalkenes for the stereocontrolled synthesis of trans-decalin ring systems. Tetrahedron Lett 52:2120-2123
Williams, David R; Walsh, Martin J; Claeboe, Christopher D et al. (2009) Studies for the synthesis of marine natural products. Pure Appl Chem 81:181
Williams, David R; Nag, Partha P; Zorn, Nicolas (2008) Strategies for the synthesis of the novel antitumor agent peloruside A. Curr Opin Drug Discov Devel 11:251-71
Williams, David R; Reeves, Jonathan T; Nag, Partha P et al. (2006) Studies of the generation and pericyclic behavior of cyclic pentadienyl carbanions. Alkylation reactions as an efficient route to functionalized cis-bicyclo[3.3.0]octenes. J Am Chem Soc 128:12339-48
Williams, David R; Morales-Ramos, Angel I; Williams, Catherine M (2006) Reactivity studies of 3,3-bis(trimethylsilyl)-2-methyl-1-propene in Lewis acid-catalyzed allylation reactions. Org Lett 8:4393-6
Williams, David R; Berliner, Martin A; Stroup, Bryan W et al. (2005) Samarium Barbier reactions of alpha-iodomethyloxazoles and thiazoles with aliphatic aldehydes. Org Lett 7:4099-102
Williams, David R; Kammler, David C; Donnell, Andrew F et al. (2005) Total synthesis of (+)-apiosporamide: assignment of relative and absolute configuration. Angew Chem Int Ed Engl 44:6715-8
Williams, David R; Reeves, Jonathan T (2004) Carbolithiation for the generation of cyclooctadienyl anions and tandem electrocyclization/alkylation to functionalized cis-bicyclo[3.3.0]octenes. J Am Chem Soc 126:3434-5
Williams, David R; Kiryanov, Andre A; Emde, Ulrich et al. (2004) Studies of stereocontrolled allylation reactions for the total synthesis of phorboxazole A. Proc Natl Acad Sci U S A 101:12058-63

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