The objective of this research program is to develop new reaction methodology for synthesizing economically important and biologically relevant carbocyclic and heterocyclic molecules. Studies will focus on the elaboration and advancement of nickel-catalyzed annulations and cyclizations that function under user-friendly conditions and employ benign starting materials. These reactions will include regioselective cycloadditions of unsaturated hydrocarbons with heterocumulenes and new cyclization-based molecular rearrangements. These reactions will find utility in the synthesis of a variety of pharmaceuticals and biologically active substrates for which current synthetic approaches are either non-existent or inefficient. The initial phases will build upon previous accomplishments involving nickel-based catalysts for mediating carbon dioxide/diyne and isocyanate/diyne annulations to produce 2-pyrones and 2-pyridones, respectively. The substrate scope of this particular system will be expanded to include other heterocumulenes and other unsaturated hydrocarbons. Ultimately, this should afford a rich array of complex carbocyclic, heterocyclic, and fused-ring compounds. Key mechanistic steps will be explored through the use of model compounds permitting concomitant catalyst re-design (e.g., through use of new ligands and/or metals) to enhance reaction performance and scope. Parallel efforts will focus on nickel-catalyzed cyclization rearrangements of readily accessible unactivated cyclopropylen-ynes as atom-economical syntheses of heterocycles and carbocycles under mild conditions. Throughout the proposal, opportunities are described for preparing biologically or commercially important substrates or related analogues and will be pursued. This research program will reverberate across the scientific disciplines of organic and organometallic chemistry, chemical biology, and medicinal chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM076125-01
Application #
7016442
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2005-09-30
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$281,000
Indirect Cost
Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Spahn, Nathan A; Nguyen, Minh H; Renner, Jonas et al. (2017) Regioselective Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Forming 4,6-Disubstituted 2-Aminopyridines from Terminal Alkynes and Cyanamides. J Org Chem 82:234-242
Staudaher, Nicholas D; Arif, Atta M; Louie, Janis (2016) Synergy between Experimental and Computational Chemistry Reveals the Mechanism of Decomposition of Nickel-Ketene Complexes. J Am Chem Soc :
Thakur, Ashish; Louie, Janis (2015) Advances in nickel-catalyzed cycloaddition reactions to construct carbocycles and heterocycles. Acc Chem Res 48:2354-65
Thakur, Ashish; Evangelista, Judah L; Kumar, Puneet et al. (2015) An in Situ Approach to Nickel-Catalyzed Cycloaddition of Alkynes and 3-Azetidinones. J Org Chem 80:9951-8
Staudaher, Nicholas D; Stolley, Ryan M; Louie, Janis (2014) Synthesis, mechanism of formation, and catalytic activity of Xantphos nickel ?-complexes. Chem Commun (Camb) 50:15577-80
Kumar, Puneet; Thakur, Ashish; Hong, Xin et al. (2014) Ni(NHC)]-catalyzed cycloaddition of diynes and tropone: apparent enone cycloaddition involving an 8? insertion. J Am Chem Soc 136:17844-51
Stolley, Ryan M; Duong, Hung A; Louie, Janis (2013) Mechanistic Evaluation of the Ni(IPr)2-Catalyzed Cycloaddition of Alkynes and Nitriles to Afford Pyridines: Evidence for the Formation of a Key ? (1)-Ni(IPr)2(RCN) Intermediate. Organometallics 32:4952-4960
Lane, Timothy K; Nguyen, Minh H; D'Souza, Brendan R et al. (2013) The iron-catalyzed construction of 2-aminopyrimidines from alkynenitriles and cyanamides. Chem Commun (Camb) 49:7735-7
Thakur, Ashish; Facer, Megan E; Louie, Janis (2013) Nickel-catalyzed cycloaddition of 1,3-dienes with 3-azetidinones and 3-oxetanones. Angew Chem Int Ed Engl 52:12161-5
Lane, Timothy K; D'Souza, Brendan R; Louie, Janis (2012) Iron-catalyzed formation of 2-aminopyridines from diynes and cyanamides. J Org Chem 77:7555-63

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