The long-term objective of this proposal is to develop short, mild, general, and versatile synthetic routes to polyfunctionalized indole alkaloids. The key step in this methodology is a recently developed, palladium catalyzed, N-heteroannulation reaction of 2-nitrostyrenes employing carbon monoxide as the reducing agent. An in depth study of a variety of functionalized 2-nitrostyrenes will be undertaken to demonstrate the synthetic versatility and generality of the cyclization. General routes to compounds having an indole nucleus such as 2-fluoro-, 3-fluoro-, and 2,3-difluoroindoles, indole-2-acetic acids, indole-3- acetic acids, indole-3-acetonitriles, tryptamines, beta-carbolines, 1,2,3,4-tetrahydro-beta-carbolines, pyrrolo[4,3,2-de]quinolines, and pyrrolo[3,2d]indoles will be pursued. As a venue to demonstrate the N- heteroannulation reaction's versatility, syntheses of a number of biologically active indoles of pharmacological interest will be pursued. For example, total syntheses (or formal total syntheses) of methoxycamalexin (phytoalexin and fungitoxin), nosiheptide (antibiotic), LY-311727 (s-PLA2 inhibitor), BE 10988 (topoisomerase II inhibitor), 7- bromo-eudistomin D (antiviral), bufotenine (hallucinogens), spider venoms (neurotoxins), damirone C and CC-1065 (cytotoxins) are proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057416-02
Application #
6151212
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1999-02-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$147,505
Indirect Cost
Name
West Virginia University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506