This proposal details the development of a family of catalytic protocols for the cyclization/addition of functionalized dienes and related substrates such as eneallenes, enones and imino olefins which display the activity, selectivity, generality, and functional group compatibility suitable for application to organic synthesis. The significance of this project stems from both the wealth of biologically active carbocyclic and heterocyclic molecules and the paucity of diastereo- and enantioselective annulation protocols. Electrophilic late transition metal complexes such as (phen)Pd(Me)(OEt2)(+)BAr4(-)(phen = 1,10-phenanthroline, Ar = 3.5 C6H3(CF3)2) (1) display a unique combination of high activity and low oxophilicity and will therefore be employed as cyclization/addition catalysts. Significantly, preliminary results point to the potential of this approach. Specifically, 1 has proven a highly active and highly tolerant catalyst for the cyclization /hydrosilylation of a range of functionalized 1,6-dienes to form silylated cyclopentane derivatives in good yield and with excellent regio- and diasteroselectivity. More importantly, continued effort in this area has the potential to achieve the goals of this proposal. Realization of these goals would produce a powerful tool for the synthesis of naturally occurring and pharmacologically active carbocycles and heterocycles.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059830-04
Application #
6526155
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$184,840
Indirect Cost
Name
Duke University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Perch, Nicholas S; Widenhoefer, Ross A (2004) Mechanism of palladium-catalyzed diene cyclization/hydrosilylation: direct observation of intramolecular carbometalation. J Am Chem Soc 126:6332-46
Chakrapani, Harinath; Liu, Cong; Widenhoefer, Ross A (2003) Enantioselective cyclization/hydrosilylation of 1,6-enynes catalyzed by a cationic rhodium bis(phosphine) complex. Org Lett 5:157-9
Wang, Xiang; Chakrapani, Harinath; Madine, James W et al. (2002) Cyclization/hydrosilylation of functionalized 1,6-diynes catalyzed by cationic platinum complexes containing bidentate nitrogen ligands. J Org Chem 67:2778-88
Madine, J W; Wang, X; Widenhoefer, R A (2001) Cyclization/hydrosilylation of functionalized diynes catalyzed by a cationic platinum phenanthroline complex. Org Lett 3:385-8
Goj, L A; Widenhoefer, R A (2001) Mechanistic studies of the cycloisomerization of dimethyl diallylmalonate catalyzed by a cationic palladium phenanthroline complex. J Am Chem Soc 123:11133-47
Kisanga, P; Goj, L A; Widenhoefer, R A (2001) Cycloisomerization of functionalized 1,5- and 1,6-dienes catalyzed by cationic palladium phenanthroline complexes. J Org Chem 66:635-7
Pei, T; Widenhoefer, R A (2001) Palladium-catalyzed asymmetric diene cyclization/hydrosilylation employing functionalized silanes and disiloxanes. J Org Chem 66:7639-45
Wang, X; Chakrapani, H; Stengone, C N et al. (2001) Synthesis of carbobicyclic compounds via palladium-catalyzed cyclization/hydrosilylation: evidence for reversible silylpalladation. J Org Chem 66:1755-60
Pei, T; Widenhoefer, R A (2000) Use of pentamethyldisiloxane in the palladium-catalyzed cyclization/hydrosilylation of functionalized dienes. Org Lett 2:1469-71
Perch, N S; Pei, T; Widenhoefer, R A (2000) Enantioselective diene Cyclization/Hydrosilylation catalyzed by optically active palladium bisoxazoline and pyridine-oxazoline complexes. J Org Chem 65:3836-45