The purpose of this proposal is to continue the development of the electron transfer initiated cyclization reaction and to use this methodology for the synthesis of biologically important structures. In this reaction the photoinitiated single electron oxidation of alkylarenes substituted at the homobenzylic position with an electron donating substituent produces radical cations containing substantially weakened and polarized benzylic carbon-carbon bonds. Appended nucleophiles, such as hydroxyl, ether, and amide groups can displace benzylic radicals, resulting in a cyclization reaction. The mild reaction conditions and unique chemoselectivity exhibited by single electron transfer make this reaction a potentially very powerful new method for constructing organic molecules. Specific goals for the project include: A thorough study of the types of cation stabilizing substituents, aromatic leaving groups, and nucleophiles tolerated by this reaction. This study includes the development of new heterogenerative cascade reactions. The development of a chemically initiated variant of the reaction. The development of an electron transfer initiated cyclorelease reaction from a polymer support. Employment of the reaction as the key step in brief total syntheses of potent antitumor and immunosuppressant agents from the pederin and mycalamide family, and the use of these sequences in the synthesis of analogs. The proposed program provides both new methodology for organic synthesis and efficient routes to challenging and medicinally important structures.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062924-04
Application #
6923595
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$211,093
Indirect Cost
Name
University of Pittsburgh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cui, Yubo; Villafane, Louis A; Clausen, Dane J et al. (2013) Bimolecular Coupling Reactions through Oxidatively Generated Aromatic Cations: Scope and Stereocontrol. Tetrahedron 69:7618-7626
Han, Xun; Floreancig, Paul E (2012) Synthesis of bridged inside-outside bicyclic ethers through oxidative transannular cyclization reactions. Org Lett 14:3808-11
Cui, Yubo; Balachandran, Raghavan; Day, Billy W et al. (2012) Synthesis and biological evaluation of neopeltolide and analogs. J Org Chem 77:2225-35
Peh, GuangRong; Floreancig, Paul E (2012) Cyclopropane compatibility with oxidative carbocation formation: total synthesis of clavosolide A. Org Lett 14:5614-7
Clausen, Dane J; Floreancig, Paul E (2012) Aromatic cations from oxidative carbon-hydrogen bond cleavage in bimolecular carbon-carbon bond forming reactions. J Org Chem 77:6574-82
Cui, Yubo; Floreancig, Paul E (2012) Synthesis of sulfur-containing heterocycles through oxidative carbon-hydrogen bond functionalization. Org Lett 14:1720-3
Clausen, Dane J; Wan, Shuangyi; Floreancig, Paul E (2011) Total synthesis of the protein phosphatase 2A inhibitor lactodehydrothyrsiferol. Angew Chem Int Ed Engl 50:5178-81
Liu, Lei; Floreancig, Paul E (2010) Stereoselective synthesis of tertiary ethers through geometric control of highly substituted oxocarbenium ions. Angew Chem Int Ed Engl 49:5894-7
Liu, Lei; Floreancig, Paul E (2010) Stereoselective heterocycle synthesis through oxidative carbon-hydrogen bond activation. Curr Opin Drug Discov Devel 13:733-47
Liu, Lei; Floreancig, Paul E (2010) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-catalyzed reactions employing MnO2 as a stoichiometric oxidant. Org Lett 12:4686-9

Showing the most recent 10 out of 30 publications