Synthesis of Chiral Organofluorines via Catalytic Asymmetric C-C Bond Formation with Fluoroenolates, Alkynes and Ynamides The ever-increasing demand for chiral compounds and the rapid rise of fluoroorganic pharmaceuticals call for the development of new synthetic methods that provide practical access to a wide variety of fluorinated chiral building blocks. The introduction of new strategies that allow control of the unique stability and reactivity patterns of fluorinated nucleophiles and electrophiles offers invaluable opportunities to streamline chemical syntheses of current and future fluoroorganic drugs. We will develop a method for asymmetric catalysis with fluorinated nucleophiles generated in-situ and under mild conditions from readily available trifluoroacetyl derived precursors. The feasibility and practicality of this approach are demonstrated with ample preliminary results obtained by a copper-bisoxazoline catalyzed reaction using aliphatic and aromatic aldehydes. Continued ligand development and the planned mechanistic investigations will further improve the enantioselectivity of this reaction and extend this methodology to a range of currently elusive fluorinated nucleophiles. Using bisoxazolidine ligands recently developed in our laboratories we have found an entry towards a practical catalytic asymmetric alkynylation of trifluoromethyl ketones. Further ligand and method development will go hand-in-hand with mechanistic studies and screening of promising reaction parameters. We have made substantial progress with this important reaction and this experience provides a unique opportunity to introduce ynamides and ynesulfonamides to catalytic C-C bond formation. Our preliminary investigations provide promising proof-of-concept results obtained with a tosylated ynamide and show that this research direction will provide unprecedented access to a diverse range of new versatile chiral building blocks. The planned catalyst and reaction developments will be guided by detailed mechanistic studies and lead to in-depth investigations of the scope and applications of the proposed methods. Our multifaceted efforts will introduce in-situ generated fluoroenolates to asymmetric catalysis (Aim 1), a practical method for the alkynylation of trifluoromethyl ketones (Aim 2), and catalytic enantioselective addition reactions with ynamides and derivatives thereof (Aim 3). Additional emphasis will be given to the synthetic use and reactions of the new building blocks that will be generated by the wide range of electrophiles and nucleophilic species made available during this work.

Public Health Relevance

Chiral fluoroorganic compounds have received increasing attention during the past decade due to their significant role in drug discovery. This steadily growing popularity stems from a variety of beneficial effects of the fluorine moiety on the pharmacological profiles of drugs;and it is therefore very important to develop synthetic routes towards new chiral building blocks, in particular if these lead to the emerging class of fluorinate pharmaceuticals. We aim to develop new catalytic methods for the asymmetric synthesis of a wide range of organofluorinated compounds which promise practical access 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 A Study Section (SBCA)
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Lees, Robert G
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Georgetown University
Schools of Arts and Sciences
United States
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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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