Efficient methods for the incorporation of nitrogen functional groups into organic molecules are critical for the discovery, development and production of pharmaceuticals and related biologically active molecules. This proposal addresses the oxidative coupling of alkenes and nitrogen nucleophiles (amides, imides and carbamates), which represents a long-standing challenge in synthetic organic chemistry. Recent results in our lab have led to several important breakthroughs in this area. Efficient palladium-catalyzed methods have been developed for the intramolecular oxidative amination of alkenes with molecular oxygen (and, in some cases, ambient air) as the stoichiometric oxidant. Unlike early precedents of this chemistry, these reactions are compatible with the use of well-defined palladium catalysts coordinated by oxidatively stable ancillary ligands. The latter property creates the opportunity to pursue enantioselective catalytic methods. Separately, the first methods for intermolecular aerobic oxidative amination of alkenes were developed. This proposal outlines a comprehensive program to expand the scope and utility of aerobic oxidative amination reactions and to develop enantioselective methods for the synthesis of nitrogen-containing heterocycles. The first thorough mechanistic studies of this class of reactions will be undertaken in order to gain insights into the factors that promote efficient product formation and contribute to substrate- and catalyst-controlled stereoselectivity. The mechanistic work will utilize a number of complementary approaches, including gas-uptake kinetic methods, in-situ spectroscopic analysis of catalytic reactions, the use of suitably designed substrate probes and density functional theoretical calculations to illuminate fundamental features of the reaction pathway. Mechanistic insights provide the basis for our synthetic efforts to expand the scope of Pd-catalyzed aerobic oxidation reactions, including the development of new methods for oxidative difunctionalization of alkenes (aminooxygenation and aminoalkylation). Diversely functionalized and stereochemically defined substrates for these reactions will be accessed via the Ireland-Claisen rearrangement and via condensation of chiral allylic and homoallylic alcohols with isocyanates. Use of these substrates in the synthesis of target structures such as small pyrrolidine alkaloids and aminosugar derivatives will enable us to probe important issues related to the diastereoselectivity and functional group compatibility of these methods. New chiral palladium catalysts have been designed to pursue enantioselective catalysis. The goals in this area include the development of a completely new class of N-heterocyclic-carbene ligands based on a seven-membered heterocyclic framework that exhibits axial chirality. Insights from recent mechanistic studies suggest that chiral anionic ligands represent additional promising targets for the catalytic asymmetric synthesis of nitrogen heterocycles.

Public Health Relevance

The development of efficient methods for the synthesis of organic molecules is critical for the discovery, development and commercial production of pharmaceuticals and therapeutic agents. The research outlined in this proposal will lead to new catalytic methods for the preparation of such biologically active molecules.

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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Schwab, John M
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Tereniak, Stephen J; Stahl, Shannon S (2017) Mechanistic Basis for Efficient, Site-Selective, Aerobic Catalytic Turnover in Pd-Catalyzed C-H Imidoylation of Heterocycle-Containing Molecules. J Am Chem Soc 139:14533-14541
Jaworski, Jonathan N; McCann, Scott D; Guzei, Ilia A et al. (2017) Detection of Palladium(I) in Aerobic Oxidation Catalysis. Angew Chem Int Ed Engl 56:3605-3610
Wang, Dian; Stahl, Shannon S (2017) Pd-Catalyzed Aerobic Oxidative Biaryl Coupling: Non-Redox Cocatalysis by Cu(OTf)2 and Discovery of Fe(OTf)3 as a Highly Effective Cocatalyst. J Am Chem Soc 139:5704-5707
Clagg, Kyle; Hou, Haiyun; Weinstein, Adam B et al. (2016) Synthesis of Indole-2-carboxylate Derivatives via Palladium-Catalyzed Aerobic Amination of Aryl C-H Bonds. Org Lett 18:3586-9
White, Paul B; Jaworski, Jonathan N; Zhu, Geyunjian Harry et al. (2016) Diazafluorenone-Promoted Oxidation Catalysis: Insights into the Role of Bidentate Ligands in Pd-Catalyzed Aerobic Aza-Wacker Reactions. ACS Catal 6:3340-3348
White, Paul B; Jaworski, Jonathan N; Fry, Charles G et al. (2016) Structurally Diverse Diazafluorene-Ligated Palladium(II) Complexes and Their Implications for Aerobic Oxidation Reactions. J Am Chem Soc 138:4869-80
Zultanski, Susan L; Stahl, Shannon S (2015) Palladium-Catalyzed Aerobic Acetoxylation of Benzene using NOx-Based Redox Mediators. J Organomet Chem 52:97-102
Osterberg, Paul M; Niemeier, Jeffry K; Welch, Christopher J et al. (2015) Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry. Org Process Res Dev 19:1537-1543
Zheng, Changwu; Stahl, Shannon S (2015) Regioselective aerobic oxidative Heck reactions with electronically unbiased alkenes: efficient access to ?-alkyl vinylarenes. Chem Commun (Camb) 51:12771-4
Wang, Dian; Izawa, Yusuke; Stahl, Shannon S (2014) Pd-catalyzed aerobic oxidative coupling of arenes: evidence for transmetalation between two Pd(II)-aryl intermediates. J Am Chem Soc 136:9914-7

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