Synthetic organic chemistry makes new compounds available for all fields of science, and synthetic chemists develop the tools to assemble chemical compounds more effectively. This proposal focuses on syntheses in four different classes of natural products. Synthesis of candidin and rimocidin, both polyene macrolides with potent antifungal properties, will be completed. The principle remaining challenge is attachment of the B-mycosamine sugar to the aglycones, and several new strategies have been developed to address this problem. The second compound of interest is SCH 351448, a complex macrolide that is the first small molecule activator of the LDL receptor promoter. This activity suggests a new therapeutic approach to controlling serum cholesterol levels. It will be synthesized using the 4-acetoxy-1,3-dioxane synthons developed in the previous grant period. Apicularen A is the third target. It is a very potent inhibitor of human cancer cell lines. Its preparation features a cyanohydrin acetonide coupling and a formal benzylic anion addition to an oxocarbenium ion. The final natural product is amphidinol 3. It has potent antifungal activity, and its structural assignment is provocative and worth investigating. Our proposed synthesis features a number of unusual convergent coupling strategies. The synthetic targets are challenging and interesting, and the new methods developed in these projects will be applicable to many other structures of contemporary interest.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043854-15
Application #
6749056
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Schwab, John M
Project Start
1990-04-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
15
Fiscal Year
2004
Total Cost
$283,393
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Perry, Matthew A; Hill, Richard R; Leong, Justin J et al. (2015) Stereochemical Outcomes in Reductive Cyclizations To Form Spirocyclic Heterocycles. Org Lett 17:3268-71
Tay, Gidget C; Huang, Chloe Y; Rychnovsky, Scott D (2014) Silyl enol ether Prins cyclization: diastereoselective formation of substituted tetrahydropyran-4-ones. J Org Chem 79:8733-49
Wagner, Alexander J; Rychnovsky, Scott D (2013) Determination of absolute configuration of secondary alcohols using thin-layer chromatography. J Org Chem 78:4594-8
Perry, Matthew A; Hill, Richard R; Rychnovsky, Scott D (2013) Trianion synthon approach to spirocyclic heterocycles. Org Lett 15:2226-9
Cleary, Leah; Mak, Victor W; Rychnovsky, Scott D et al. (2013) Origins of regio- and stereochemistry in type 2 intramolecular N-acylnitroso Diels-Alder reactions: a computational study of tether length and substituent effects. J Org Chem 78:4090-8
Tay, Gidget C; Gesinski, Michael R; Rychnovsky, Scott D (2013) Formation of highly substituted tetrahydropyranones: application to the total synthesis of cyanolide A. Org Lett 15:4536-9
Gesinski, Michael R; Rychnovsky, Scott D (2011) Total synthesis of the cyanolide A aglycon. J Am Chem Soc 133:9727-9
Reilly, Maureen K; Rychnovsky, Scott D (2011) DABO Boronates: Stable Heterocyclic Boronic Acid Complexes for Use in Suzuki-Miyaura Cross-Coupling Reactions. Synlett 2011:
Wagner, Alexander J; David, Jonathan G; Rychnovsky, Scott D (2011) Determination of absolute configuration using kinetic resolution catalysts. Org Lett 13:4470-3
Reilly, Maureen K; Rychnovsky, Scott D (2010) Allyl transfer to aldehydes and ketones by Bronsted acid activation of allyl and crotyl 1,3,2-dioxazaborolidines. Org Lett 12:4892-5

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