New Methods for Nitrogen Heterocycle Synthesis New enabling technologies for the synthesis of nitrogen and oxygen heterocycles using copper-catalyzed reactions is proposed. The heterocycles formed can be useful for application as ligands and catalysts in the chemical industry and as modulators of biological function and intermediates in the synthesis of bioactive compounds in the pharmaceutical industry. One or more stereocenter is present in the products of most of the reactions and these stereocenters can be predictably formed with high enantio- and diastereoselectivity in most cases. The selective synthesis of chiral compounds impacts the pharmaceutical industry, enabling the optimization of activity while minimizing dosing and side-effects. Originating chirality from catalysts instead of stoichiometric amounts of chiral substrates is an efficient practice that greatly expands substrate scope while reducing cost. This proposal involves the optimization (reaction conditions, selectivity, catalyst loading), expansion (wide substrate scope and several new reactions proposed) and application (the synthesis of commercial drugs and bioactive natural products) of the new copper-catalyzed reactions. The starting compounds are stable, readily available amines, alcohols and alkenes. The reaction methodology enables the versatile stereoselective synthesis of various alkene difunctionalization products (diamination, carboamination, aminooxygenation, aminohalogenation, hydroamination, carboetherification) by judicious choice of reaction components. Several of the catalytic enantioselective methods being developed in this program are the first and only examples of such technology in the scientific community (e.g. the first and only catalytic enantioselective intramolecular alkene aminooxygenation, diamination and aminohalogenation reactions), and thus fill a recognized technology gap.

Public Health Relevance

The efficient synthesis of chiral organic compounds is important to drug discovery and development. The discovery and development of the new synthetic methods described in this proposal will expand the tools available for drug discovery. Application of these methods in the synthesis of an anti-cancer natural product, an antipsychotic medication and a clinically used diuretic are proposed.

National Institute of Health (NIH)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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State University of New York at Buffalo
Schools of Arts and Sciences
United States
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Casavant, Barbara J; Hosseini, Azade S; Chemler, Sherry R (2014) 6-Azabicyclo[3.2.1]octanes Via Copper-Catalyzed Enantioselective Alkene Carboamination. Adv Synth Catal 356:2697-2702
Bovino, Michael T; Liwosz, Timothy W; Kendel, Nicole E et al. (2014) Enantioselective copper-catalyzed carboetherification of unactivated alkenes. Angew Chem Int Ed Engl 53:6383-7
Belding, Lee; Chemler, Sherry R; Dudding, Travis (2013) A computational study of the copper(II)-catalyzed enantioselective intramolecular aminooxygenation of alkenes. J Org Chem 78:10288-97
Liwosz, Timothy W; Chemler, Sherry R (2013) Copper-catalyzed oxidative amination and allylic amination of alkenes. Chemistry 19:12771-7
Paderes, Monissa C; Keister, Jerome B; Chemler, Sherry R (2013) Mechanistic analysis and optimization of the copper-catalyzed enantioselective intramolecular alkene aminooxygenation. J Org Chem 78:506-15
Chemler, Sherry R; Bovino, Michael T (2013) Catalytic Aminohalogenation of Alkenes and Alkynes. ACS Catal 3:1076-1091
Liwosz, Timothy W; Chemler, Sherry R (2013) Copper-catalyzed oxidative Heck reactions between alkyltrifluoroborates and vinyl arenes. Org Lett 15:3034-7
Paderes, Monissa C; Belding, Lee; Fanovic, Branden et al. (2012) Evidence for alkene cis-aminocupration, an aminooxygenation case study: kinetics, EPR spectroscopy, and DFT calculations. Chemistry 18:1711-26
Bovino, Michael T; Chemler, Sherry R (2012) Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer. Angew Chem Int Ed Engl 51:3923-7
Chemler, Sherry R (2011) Evolution of copper(II) as a new alkene amination promoter and catalyst. J Organomet Chem 696:150-158

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