The primary objectives of this proposal are: (1) to demonstrate the concept of Lewis base activation of Lewis acids (Gutmann electron density polarization) as it applies to electrophilic species in Groups 16 and 17 in the Main Group, (2) to develop catalytic variants of classical main group reactions for which catalysis has yet to be realized, (3) to learn the structure/reactivity correlations and the rules for achieving high catalytic activity (turnover frequencies and turnover numbers) for the target reactions, (4) to design chiral Lewis bases that will impart high stereoselectivity and high chemical conversion for the introduction of new carbon and heteroatom substituted stereocenters, and (5) carry out detailed mechanistic (kinetics, spectroscopic, crystallographic, computational) investigations of the newly-invented catalytic reactions described below. The first major effort will be the development of catalytic, enantioselective variants of the most common reactions of electrophilic Group 16 and 17 reagents. Direct functionalization and cyclofunctionalization of alkenes bearing a tethered nucleophile (oxygen, nitrogen, carbon) is a powerful method for creating stereodefined chains, heterocycles and carbocycles. These reactions are efficiently initiated by electrophilic sulfur(II), chlorine(I), bromine(I), and iodine(I) reagents The design of Lewis bases to catalyze and control the constitutional and enantiofacial selectivity will constitute a major component of this program. The synthetic manipulation of the enantiomerically enriched, sulfur-containing products constitutes the second major activity. In addition to well-known functional manipulations, new, stereocontrolled, constructive replacements of the C-S bond that employ transition metal catalyzed coupling and direct ligand coupling reactions will be developed. A third major effort will be the invention, development, and exploration of a new subclass of Lewis base catalyzed reactions that employs higher oxidation state iodine(III) reagents for carbon-carbon bond formation. Catalysis of the ligand coupling reaction of iodonium salts is unprecedented and will be investigated for the construction of enantiomerically enriched ?-aryl, ?-alkenyl, ?-alkynyl, and also potentially ?-aryl substituted ketones and esters.

Public Health Relevance

This research proposal aims to develop a fundamentally new class of catalytic reactions of the main group elements, sulfur, chlorine, bromine, and iodine in various oxidation states. The conceptual foundation for the ability of Lewis bases to activate the electrophilic character of these elements has almost unlimited potential. Already, catalysis is involved in the processing of nearly a trillion dollars worth of goods produced annually in the US, and our contribution is for chemical reactions for which there is currently no catalytic process.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085235-03
Application #
8213452
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-03-22
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$289,490
Indirect Cost
$99,840
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Denmark, Scott E; Ryabchuk, Pavel; Burk, Matthew T et al. (2016) Toward Catalytic, Enantioselective Chlorolactonization of 1,2-Disubstituted Styrenyl Carboxylic Acids. J Org Chem 81:10411-10423
Cresswell, Alexander J; Eey, Stanley T-C; Denmark, Scott E (2015) Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities. Angew Chem Int Ed Engl 54:15642-82
Denmark, Scott E; Carson, Nessa (2015) Reinvestigation of a Catalytic, Enantioselective Alkene Dibromination and Chlorohydroxylation. Org Lett 17:5728-31
Denmark, Scott E; Rossi, Sergio; Webster, Matthew P et al. (2014) Catalytic, enantioselective sulfenylation of ketone-derived enoxysilanes. J Am Chem Soc 136:13016-28
Denmark, Scott E; Jaunet, Alex (2014) Catalytic, enantioselective, intramolecular carbosulfenylation of olefins. Preparative and stereochemical aspects. J Org Chem 79:140-71
Denmark, Scott E; Burk, Matthew T (2014) Development and mechanism of an enantioselective bromocycloetherification reaction via Lewis base/chiral Brønsted acid cooperative catalysis. Chirality 26:344-55
Denmark, Scott E; Chi, Hyung Min (2014) Lewis base catalyzed, enantioselective, intramolecular sulfenoamination of olefins. J Am Chem Soc 136:8915-8
Denmark, Scott E; Hartmann, Eduard; Kornfilt, David J P et al. (2014) Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes. Nat Chem 6:1056-64
Cresswell, Alexander J; Eey, Stanley T-C; Denmark, Scott E (2014) Catalytic, stereospecific syn-dichlorination of alkenes. Nat Chem 7:146-52
Denmark, Scott E; Chi, Hyung Min (2014) Catalytic, enantioselective, intramolecular carbosulfenylation of olefins. Mechanistic aspects: a remarkable case of negative catalysis. J Am Chem Soc 136:3655-63

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