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.
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.
|Böse, Dietrich; Denmark, Scott E (2018) Investigating the Enantiodetermining Step of a Chiral Lewis Base Catalyzed Bromocycloetherification of Privileged Alkenes. Synlett 29:433-439|
|Tao, Zhonglin; Robb, Kevin A; Zhao, Kuo et al. (2018) Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes. J Am Chem Soc 140:3569-3573|
|Denmark, Scott E; Kornfilt, David J P (2017) Catalytic, Enantioselective, Intramolecular Sulfenofunctionalization of Alkenes with Phenols. J Org Chem 82:3192-3222|
|Denmark, Scott E; Chi, Hyung Min (2017) Synthesis of 2-Alkenyl-Tethered Anilines. Synthesis (Stuttg) 49:2873-2888|
|Denmark, Scott E; Chi, Hyung Min (2017) Catalytic, Enantioselective, Intramolecular Sulfenoamination of Alkenes with Anilines. J Org Chem 82:3826-3843|
|Hartmann, Eduard; Denmark, Scott E (2017) Structural, Mechanistic, Spectroscopic, and Preparative Studies on the Lewis Base Catalyzed, Enantioselective Sulfenofunctionalization of Alkenes. Helv Chim Acta 100:|
|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; Chi, Hyung Min (2014) Lewis base catalyzed, enantioselective, intramolecular sulfenoamination of olefins. J Am Chem Soc 136:8915-8|
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