The efficient production of small organic molecules and chemical processes impacts pharmaceutical research, both drug discovery and process chemistry. Chiral compounds make up a substantial portion of bioactive small organic molecules. Their enantioselective synthesis minimizes use of chiral separation technology, which can be time and resource intensive, and the production of undesired enantiomers, which are often considered chemical waste. New copper-catalyzed alkene difunctionalization reactions that enable efficient and stereoselective synthesis of chiral amine derivatives and ethers, including saturated heterocycles, are being developed. The products of these reactions readily map on to structures contained in bioactive organic small molecules such as natural products and pharmaceuticals.
In Aim 1, enantioselective aerobic copper-catalyzed alkene oxidative difunctionalizations will be explored for the direct synthesis of 2-formyl pyrrolidines and 2-formyl tetrahydrofurans. Application of these aerobic cyclizations to the streamlined synthesis of bioactive natural products and small molecule intermediates useful to drug discovery will test the practical utility of the methods. The focus of Aim 2 is the development of methods for the enantioselective synthesis of chiral bridged bicyclic ketals and other saturated heterocycles that contain fully substituted carbon stereocenters. A number of these transformations are enabled by a radical group transfer strategy. Mechanistic aspects of these reactions will be explored, which will enable their rational optimization and predictable application. The focus of Aim 3 is on the development of copper-catalyzed 2- and 3-component reactions that involve the coupling of alcohol and amine derivatives with styrenes or dienes, and alkyl radicals formed in situ. Mechanistic aspects of these reactions, especially related to stereoselectivity, will be investigated. Development of these chemical transformations will enable their use in multi-step organic synthesis in drug discovery and chemical biology applications. Their invention enables new options for synthetic organic chemists, which may enable diverse small molecule candidates to be synthesized efficiently. Lessons learned in reaction engineering for efficiency and selectivity will be applicable to the invention and development of related useful chemical processes.

Public Health Relevance

Organic molecules containing oxygen and nitrogen are ubiquitous in biomedical research and in the treatment of a range of human ailments including mental health conditions, cancer and diabetes as well as cardiovascular, infectious and neurodegenerative diseases. This project is centered on the development of efficient, catalytic and stereoselective methods for C-O, C-N and C-C bond formation, useful in the efficient construction and structural optimization of bioactive compounds. These methods will facilitate drug discovery by enabling the synthesis of new, potentially useful, small molecules, as well as pharmaceutical process development, by enabling the streamlined synthesis of known bioactive compounds.

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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Brown, Patrick
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State University of New York at Buffalo
Schools of Arts and Sciences
United States
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Shikora, Jonathan M; Chemler, Sherry R (2018) Synthesis of Benzyl Amines via Copper-Catalyzed Enantioselective Aza-Friedel-Crafts Addition of Phenols to N-Sulfonyl Aldimines. Org Lett 20:2133-2137
Chemler, Sherry R; Karyakarte, Shuklendu D; Khoder, Zainab M (2017) Stereoselective and Regioselective Synthesis of Heterocycles via Copper-Catalyzed Additions of Amine Derivatives and Alcohols to Alkenes. J Org Chem 82:11311-11325
Khoder, Zainab M; Wong, Christina E; Chemler, Sherry R (2017) Stereoselective Synthesis of Isoxazolidines via Copper-Catalyzed Alkene Diamination. ACS Catal 7:4775-4779
Wdowik, Tomasz; Chemler, Sherry R (2017) Direct Synthesis of 2-Formylpyrrolidines, 2-Pyrrolidinones and 2-Dihydrofuranones via Aerobic Copper-Catalyzed Aminooxygenation and Dioxygenation of 4-Pentenylsulfonamides and 4-Pentenylalcohols. J Am Chem Soc 139:9515-9518
Um, Chanchamnan; Chemler, Sherry R (2016) Synthesis of 2-Aryl- and 2-Vinylpyrrolidines via Copper-Catalyzed Coupling of Styrenes and Dienes with Potassium ?-Aminoethyl Trifluoroborates. Org Lett 18:2515-8
Chemler, Sherry R (2015) Copper catalysis in organic synthesis. Beilstein J Org Chem 11:2252-3
Casavant, Barbara J; Khoder, Zainab M; Berhane, Ilyas A et al. (2015) Copper(II)-Promoted Cyclization/Difunctionalization of Allenols and Allenylsulfonamides: Synthesis of Heterocycle-Functionalized Vinyl Carboxylate Esters. Org Lett 17:5958-61
Karyakarte, Shuklendu D; Sequeira, Fatima C; Zibreg, Garrick H et al. (2015) Copper-promoted synthesis of 1,4-benzodiazepinones via alkene diamination. Tetrahedron Lett 56:3686-3689
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

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