Oxidation reactions are essential for both functional group manipulation and heteroatom introduction in the synthesis of biologically relevant compounds. Newly discovered and significantly improved oxidative processes can have a direct impact on the efficiency of and approaches to the execution of targeted synthesis. Therefore, the development of selective, practical oxidation reactions is a continuing challenge facing chemists in both academia and industry. A key consideration is selection of the stoichiometric oxidant where versatility, expense, and environmental impact need to be addressed. An attractive approach to this issue is the use of metal-catalyzed oxidations coupled to a practical terminal oxidant such as molecular oxygen or hydrogen peroxide. Therefore, a central goal of oxidation catalysis, and of this program, is the discovery and development of highly active, robust catalysts compatible with practical oxidants. Palladium(II) salts with oxidatively stable ligands have been selected as catalysts primarily due to their ability to effectively use molecular oxygen as a terminal oxidant. The use of ligands allows for high reaction selectivity, including enantioselectivity, and for the design of well-defined Pd-complexes capable of high turnover numbers. Importantly, Pd-catalyzed reactions have revolutionized synthesis through the development of cross-coupling reactions, forming a vast array of C-C, C-N, C-S, and C-O bonds. Therefore, a fundamental goal of the proposed research is to integrate Pd-catalyzed oxidation reactions with cross-coupling processes. The current proposal is directed toward the development of new Pd-catalyzed olefin functionalization reactions via oxidation chemistry. Specifically, we will (1) study and develop our recently discovered Pd-catalyzed aerobic dialkoxylation reactions of styrenes containing a phenol, including expansion to tandem intramolecular addition of nucleophiles/Diels-Alder processes, (2) investigate the scope and mechanism of a recently discovered ligand-modulated direct oxygen coupled Wacker oxidation and develop kinetic resolution and dynamic kinetic resolution of olefins yielding enantiomerically enriched substrates and products, and (3) develop olefin functionalization reactions wherein Pd-catalyzed cross-coupling reactions utilizing organometallic reagents are paired with aerobic alcohol oxidation. The proposed research described herein will be approached using method discovery and development, facilitated by elucidation of mechanistic details using physical organic chemistry techniques. The goal of the proposed research is to develop new metal catalyzed olefin oxidation chemistry employing simple substrates and practical terminal oxidants (O2 and simple peroxides) to create diverse bond constructions in a stereocontrolled manner. Advances in the proposed methodology will directly impact the biomedical mission by providing efficient access to novel derivatives of biologically active core structures.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063540-08
Application #
7821334
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
2001-09-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
8
Fiscal Year
2010
Total Cost
$283,091
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
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Zhang, Chun; Tutkowski, Brandon; DeLuca, Ryan J et al. (2017) Palladium-Catalyzed Enantioselective Heck Alkenylation of Trisubstituted Allylic Alkenols: A Redox-Relay Strategy to Construct Vicinal Stereocenters. Chem Sci 8:2277-2282
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Xu, Liping; Zhang, Xin; McCammant, Matthew S et al. (2016) Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene. J Org Chem :
Patel, Harshkumar H; Sigman, Matthew S (2016) Enantioselective Palladium-Catalyzed Alkenylation of Trisubstituted Alkenols To Form Allylic Quaternary Centers. J Am Chem Soc 138:14226-14229
Chen, Zhi-Min; Hilton, Margaret J; Sigman, Matthew S (2016) Palladium-Catalyzed Enantioselective Redox-Relay Heck Arylation of 1,1-Disubstituted Homoallylic Alcohols. J Am Chem Soc 138:11461-4
Race, Nicholas J; Schwalm, Cristiane S; Nakamuro, Takayuki et al. (2016) Palladium-Catalyzed Enantioselective Intermolecular Coupling of Phenols and Allylic Alcohols. J Am Chem Soc 138:15881-15884
Yamamoto, Eiji; Hilton, Margaret J; Orlandi, Manuel et al. (2016) Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer. J Am Chem Soc 138:15877-15880
McCammant, Matthew S; Shigeta, Takashi; Sigman, Matthew S (2016) Palladium-Catalyzed 1,3-Difunctionalization Using Terminal Alkenes with Alkenyl Nonaflates and Aryl Boronic Acids. Org Lett 18:1792-5
Patel, Harshkumar H; Sigman, Matthew S (2015) Palladium-catalyzed enantioselective Heck alkenylation of acyclic alkenols using a redox-relay strategy. J Am Chem Soc 137:3462-5

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