Abstract

In this program we propose to investigate the synthesis and chemistry of a series of natural products of biological interest. It is expected that from this work will emerge new reactions of value to chemical synthesis, new modes of strategic analysis of synthetic problems, and new access to compounds worthy of evaluation in several biological settings. The natural products which form the goal structures around which the program is organized are: (i) compactin-mevinolin and a Fusarium derived metabolite, (ii) heptelidic acid, (iii) rishirilide. (iv) aflavinine, (v) erythrina alkaloids, (vi) zincophorin, (vii) A-58365A, (viii) castanospermine, (ix) apramycin, and (x) amauromine. The general chemical issues which will be of significant concern with respect to these targets are: (a) the lactonic enolate version of the Claisen rearrangement, (b) free radical cyclization reactions of nitrogen containing compounds, (c) the 2+2+2 cyclization reaction, (d) the aldimine- diene cyclocondensation reaction, and (e) radical substitution reactions of aryl and allylic silanes and stannanes. Among the sorts of biological activities manifested by the goal systems are: inhibition of cholesterol biosynthesis, hypotensive responses, inhibition of glyceraldehyde-3-phosphate dehydrogenase, inhibition of plasmin inhibitors, trimming enzyme inactivators, ACE inhibitors, and inhibition of phytohemeagglutinin response.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025848-10
Application #
3338299
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1980-01-01
Project End
1992-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Type
Schools of Arts and Sciences
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Hartung, John; J D Wright, Benjamin; Danishefsky, Samuel J (2014) Studies toward the total synthesis of pluraflavin A. Chemistry 20:8731-6
Pham, Hung V; Paton, Robert S; Ross, Audrey G et al. (2014) Intramolecular Diels-Alder reactions of cycloalkenones: stereoselectivity, Lewis acid acceleration, and halogen substituent effects. J Am Chem Soc 136:2397-403
Zhang, Qiang; Johnston, Eric V; Shieh, Jae-Hung et al. (2014) Synthesis of granulocyte-macrophage colony-stimulating factor as homogeneous glycoforms and early comparisons with yeast cell-derived material. Proc Natl Acad Sci U S A 111:2885-90
Townsend, Steven D; Ross, Audrey G; Liu, Kai et al. (2014) Stereospecific cis- and trans-ring fusions arising from common intermediates. Proc Natl Acad Sci U S A 111:7931-5
Peng, Feng; Grote, Robin E; Wilson, Rebecca M et al. (2013) Pattern recognition analysis in complex molecule synthesis and the preparation of iso-Diels-Alder motifs. Proc Natl Acad Sci U S A 110:10904-9
Wang, Ting; Danishefsky, Samuel J (2013) Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles. Proc Natl Acad Sci U S A 110:11708-13
Wang, Ping; Dong, Suwei; Shieh, Jae-Hung et al. (2013) Erythropoietin derived by chemical synthesis. Science 342:1357-1360
Wilson, Rebecca M; Dong, Suwei; Wang, Ping et al. (2013) The winding pathway to erythropoietin along the chemistry-biology frontier: a success at last. Angew Chem Int Ed Engl 52:7646-65
Ross, Audrey G; Townsend, Steven D; Danishefsky, Samuel J (2013) Halocycloalkenones as Diels-Alder dienophiles. Applications to generating useful structural patterns. J Org Chem 78:204-10
Peng, Feng; Dai, Mingji; Angeles, Angie R et al. (2012) Permuting Diels-Alder and Robinson Annulation Stereopatterns. Chem Sci 3:3076-3080

Showing the most recent 10 out of 79 publications