The carbon-carbon double bond is arguably the most important functional group in all of organic chemistry. Aside from its central position in defining structure, the ability to create two vicinal stereogenic carbon atoms by the introduction of two new bonds at the termini of a double bond has elevated it to this rarefied status. Count- less reactions have been introduced to effect regio, diastereo and enantioselective functionalization of double bonds with good generality. However, only recently have organic chemists turned their attention to the enantio- controlled introduction of elements in the main group such as sulfur, chlorine, bromine and iodine, in combina- tion with the much more common elements carbon, nitrogen and oxygen. Although intriguing, these recent reports constitute an ad hoc application of known catalysts and concepts to the solution of creating new, cata- lytic enantioselective transformations. Our long-term goal is to construct the mechanistic/physical organic foundation for the development of generally applicable and highly selective alkene functionalization reactions. The primary objectives of this proposal are to: (1) apply the concept of Lewis base activation of Lewis acids developed in these laboratories, activate electrophilic species in Groups 16 and 17 in the Main Group, (2) learn the structure/reactivity correlations and the rules for achieving high catalytic activity (turnover frequencies and turnover numbers) for the target reactions, (3) design chiral Lewis bases that will impart high stereoselectivity and high chemical conversion for the introduction of new carbon and heteroatom substituted stereocenters, and (4) carry out detailed mechanistic (kinetic, spectroscopic, crystallographic, computational) investigations of the newly invented catalytic reactions described below. The first major effort will be the expansion of catalytic, enantioselective sulfenofunctionalization reactions to many substrate classes. Direct functionalization and cyclofunctionalization of alkenes bearing a tethered nu- cleophile (oxygen, nitrogen, carbon) is a powerful method for creating stereodefined chains, heterocycles, and carbocycles. Lewis basic catalysts of novel topology that can effect the stereoselective sulfenofunctionalization of E- and Z-alkenes will be designed and evaluated in many of these transformations. The second major effort, divided into two sub goals, is the development of catalytic, enantioselective halo- functionalization reactions. The development of catalysts for these extremely important transformations is guided by our demonstration that chloriranium ions are configurationally stable whereas bromiranium and iodiranium ions are not. Thus, the design criteria for these transformations diverge into two sub goals: (1) the design of catalysts that provide enantiotopic face differentiation for the delivery of a chlorenium ion, and (2) the design of catalysts that provide enantiotopic face differentiation for the delivery of a bromenium (iodenium) ion AND stabilize the intermediate against racemization prior to capture.

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. 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 to invent chemical reactions for which, currently general, enantioselective catalytic process do not exist.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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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; 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; 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
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; Jaunet, Alex (2013) Catalytic, enantioselective, intramolecular carbosulfenylation of olefins. J Am Chem Soc 135:6419-22
Denmark, Scott E; Cresswell, Alexander J (2013) Iron-catalyzed cross-coupling of unactivated secondary alkyl thio ethers and sulfones with aryl Grignard reagents. J Org Chem 78:12593-628
Denmark, Scott E; Ueki, Yusuke (2013) Lewis Base Activation of Lewis Acids - Group 13. In Situ Generation and Reaction of Borenium Ions. Organometallics 32:
Denmark, Scott E; Kornfilt, David J P; Vogler, Thomas (2011) Catalytic asymmetric thiofunctionalization of unactivated alkenes. J Am Chem Soc 133:15308-11
Denmark, Scott E; Kalyani, Dipannita; Collins, William R (2010) Preparative and mechanistic studies toward the rational development of catalytic, enantioselective selenoetherification reactions. J Am Chem Soc 132:15752-65
Denmark, Scott E; Burk, Matthew T (2010) Lewis base catalysis of bromo- and iodolactonization, and cycloetherification. Proc Natl Acad Sci U S A 107:20655-60