A five-year plan is proposed for the continued exploration of new synthetic strategies employing vinyl sulfones as the focal point of multiply-convergent total syntheses of biologically important natural and unnatural products. This proposal has three major project areas: (1) The investigation of alpha-heteroatom-substituted sulfones as progenitors for alpha-sulfonyl anions and alpha-sulfonyl radicals. These intermediates will be utilized in the development of new medium-ring annulation reactions as applied to the total synthesis of homochiral cytochalasin C 103; (2) The total synthesis of homochiral homoharringtonine 104, an antileukemia agent currently in Phase II clinical trials. Intramolecular transacylation of a cephalotaxine derivative will be exploited to synthesize a highly hindered ester; (3) The total synthesis of three homochiral, pyrrole-fused prostacyclin analogs 151-153, predicted by computer modeling to be exceptionally potent inhibitors of platelet aggregation. This study should provide important new agents for the prevention of neutrophil-mediated oxidative injury of the myocardia during reperfusion, as well as affording new materials which have potential as antimetastatic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032693-11
Application #
2176695
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1990-12-01
Project End
1995-11-30
Budget Start
1993-12-01
Budget End
1995-11-30
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Purdue University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907