Oxygen, nitrogen, sulfur and other heteroatoms are critical to the biological function of pharmaceuticals and other biologically active organic molecules. In this context, oxidation reactions are among the most important transformations in organic chemistry because they increase the chemical complexity of and incorporate heteroatom substituents into carbon-based molecules. In this project, we will develop Pd-catalyzed methods for selective oxidation of alkenes that are capable of using O2 as the stoichiometric oxidant. Intramolecular oxidative amination reactions will be developed for diastero- and enantioselective synthesis of nitrogen heterocycles and for the modular coupling of primary amines with allylic amines or allylic alcohols enroute to versatile vicinial diamine and aminoalcohol products. Highly active catalysts recently discovered in the course of this work will be used to pursue the development of regio- and stereoselective methods for intermolecular oxidative amination of alkenes. The key to the success of these intra- and intermolecular reactions is the discovery and development of novel ligands for Pd that support high catalyst stability, activity and selectivity. Experimental and DFT computational methods will be used to characterize the mechanism of these reactions and provide a foundation for the design of more effective catalysts. Most of these oxidative amination reactions are expected to proceed via a mechanism involving aminopalladation of the alkene;however, we have recently discovered a novel catalyst system that enables selective oxidation of allylic C-H bonds. The utility of these reactions will be expanded through the mechanism-based design of improved catalyst systems and the development of new synthetic applications of allylic C-H oxidation. Finally, we will apply our insights into aerobic oxidation catalysis to develop an efficient method for regioselective aerobic oxidative coupling of aryl- and vinyl-boronic acid derivatives with electronically unbiased alkenes. Overall, the catalytic reactions will lead to highly efficient and atom- economical methods for the formation of new C-N, C-O and C-C bonds in pharmaceutically relevant building blocks and complex organic molecules.

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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Lees, Robert G
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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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
Diao, Tianning; Stahl, Shannon S (2014) O2-Promoted Allylic Acetoxylation of Alkenes: Assessment of "Push" vs. "Pull" Mechanisms and Comparison between O2 and Benzoquinone. Polyhedron 84:96-102
Weinstein, Adam B; Stahl, Shannon S (2014) Palladium Catalyzed Aryl C-H Amination with O2 via In Situ Formation of Peroxide-Based Oxidant(s) from Dioxane. Catal Sci Technol 4:4301-4307
Ye, Xuan; White, Paul B; Stahl, Shannon S (2013) Mechanistic studies of Wacker-type amidocyclization of alkenes catalyzed by (IMes)Pd(TFA)2(H2O): kinetic and stereochemical implications of proton transfer. J Org Chem 78:2083-90
Weinstein, Adam B; Schuman, David P; Tan, Zhi Xu et al. (2013) Synthesis of vicinal aminoalcohols by stereoselective aza-Wacker cyclizations: access to (-)-acosamine by redox relay. Angew Chem Int Ed Engl 52:11867-70
Martinez, Claudio; Wu, Yichen; Weinstein, Adam B et al. (2013) Palladium-catalyzed intermolecular aminoacetoxylation of alkenes and the influence of PhI(OAc)2 on aminopalladation stereoselectivity. J Org Chem 78:6309-15
Redford, Joanne E; McDonald, Richard I; Rigsby, Matthew L et al. (2012) Stereoselective synthesis of cis-2,5-disubstituted pyrrolidines via Wacker-type aerobic oxidative cyclization of alkenes with tert-butanesulfinamide nucleophiles. Org Lett 14:1242-5
Lu, Zhan; Stahl, Shannon S (2012) Intramolecular Pd(II)-catalyzed aerobic oxidative amination of alkenes: synthesis of six-membered N-heterocycles. Org Lett 14:1234-7
McDonald, Richard I; White, Paul B; Weinstein, Adam B et al. (2011) Enantioselective Pd(II)-catalyzed aerobic oxidative amidation of alkenes and insights into the role of electronic asymmetry in pyridine-oxazoline ligands. Org Lett 13:2830-3
Decharin, Nattawan; Popp, Brian V; Stahl, Shannon S (2011) Reaction of O2 with [(-)-sparteine]Pd(H)Cl: evidence for an intramolecular [H-L]+ "reductive elimination" pathway. J Am Chem Soc 133:13268-71

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