The ever-increasing demand for synthetic methods that expand currently accessible chemical space and provide efficient access to biologically active compounds has begun to shift attention toward the development of largely unexplored Csp3-F bond functionalization chemistry. Despite considerable progress, in particular with hydrodefluorinations, this task remains quite challenging because the profound electron-withdrawing and stereoelectronic effects of fluorine often interfere with established synthetic protocols and dramatically alter reaction outcomes compared to nonfluorinated analogues. Given the abundance and diversity of readily available fluorinated compounds, the introduction of strategies that provide control over the unique stability and reactivity patterns of the aliphatic carbon-fluorine bond are expected to set the stage for extremely powerful synthetic venues that streamline the production of current and future drugs. The goals of the proposed research are to introduce new Csp3-F bond activation chemistry that is complementary to existing methodologies by enabling unprecedented carbon-carbon and carbon-heteroatom bond formation and an array of new synthetic opportunities with exceptional reaction control, scope and functional group tolerance. The Csp3-F bond, typically considered chemically inert, will become a strategically useful entity representing a latent carbon nucleophile or electrophile, for example via unique Umpolung pathways that allow selective manipulation of orthogonal reactivity modes, with multiple applications including late-stage functionalization. In addition, the Csp3-F bond activation methodology will be extended to catalytic asymmetric cross- coupling chemistry and the (organo)catalytic enantio- and diastereoselective synthesis of a variety of multifunctional organofluorines carrying two contiguous chirality centers from the challenging class of fluoronitriles will be pioneered. While emphasis lies on the development of new synthetic methodologies and asymmetric catalysis, the usefulness of the proposed transformations and reaction products in the total synthesis of biologically active compounds will also be explored. The general feasibility and the synthetic prospects are highlighted with ample proof-of-concept results and mechanistic insights that underscore the broad impact of asymmetric catalysis with fluoronitriles and of strikingly diverse C-F bond functionalization pathways which altogether will exploit organofluorines in currently not possible ways.

Public Health Relevance

The importance of fluorinated organic chemicals in the health sciences is a result of the unique stability of the carbon-fluoride bond and its beneficial effects on the pharmacological properties of biologically active compounds. The synthetic potential and general utility of organofluorines, however, are far from being fully explored. This proposal is aimed at the development of new synthetic methodology that exploits the large variety of readily available fluoroorganic building blocks to generate unprecedented access to multifunctional compounds and ultimately to current and future drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Brown, Patrick
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Georgetown University
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Ding, Ransheng; Wolf, Christian (2018) Organocatalytic Asymmetric Synthesis of ?-Oxetanyl and ?-Azetidinyl Tertiary Alkyl Fluorides and Chlorides. Org Lett 20:892-895
Moskowitz, Max; Balaraman, Kaluvu; Wolf, Christian (2018) Organocatalytic Stereoselective Synthesis of Fluorinated 3,3'-Linked Bisoxindoles. J Org Chem 83:1661-1666
Ding, Ransheng; Bakhshi, Pegah R; Wolf, Christian (2017) Organocatalytic Insertion of Isatins into Aryl Difluoronitromethyl Ketones. J Org Chem 82:1273-1278
Balaraman, Kaluvu; Wolf, Christian (2017) Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3-Fluorinated and All-Carbon Quaternary Oxindoles. Angew Chem Int Ed Engl 56:1390-1395
Balaraman, Kaluvu; Ding, Ransheng; Wolf, Christian (2017) Stereoselective Synthesis of 3,3'-Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution. Adv Synth Catal 359:4165-4169
Cook, Andrea M; Wolf, Christian (2016) Efficient Access to Multifunctional Trifluoromethyl Alcohols through Base-Free Catalytic Asymmetric C-C Bond Formation with Terminal Ynamides. Angew Chem Int Ed Engl 55:2929-33
Ding, Ransheng; Wolf, Christian (2016) Catalytic insertion of aldehydes into dihalonitroacetophenones via sequential bond scission-aldol reaction-acyl transfer. Chem Commun (Camb) 52:3576-9
Balaraman, Kaluvu; Moskowitz, Max; Liu, Yang et al. (2016) Detrifluoroacetylative Generation of Halogenated Enolates: Practical Access to Perhalogenated Ketones and Alkenes. Synthesis (Stuttg) 48:2376-2384
Cook, Andrea M; Wolf, Christian (2015) S3S63 Terminal Ynamides: Synthesis, Coupling Reactions and Additions to Common Electrophiles. Tetrahedron Lett 56:2377-2392
Cook, Andrea M; Wolf, Christian (2014) Catalytic enantioselective nucleophilic addition of ynamides to aldehydes. Chem Commun (Camb) 50:3151-4

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