The ever-increasing demand for chiral compounds and the impressive prevalence of fluorinated pharmaceuticals on the US drug market generate compelling motivation for the development of synthetic methods that yield practical access to multifunctional organofluorines. The introduction of strategies that provide control over the unique stability and reactivity patterns of fluorinated species offers invaluable opportunities to streamline chemical synthesis of current and future drugs. The versatile chemistry of terminal ynamides which have been barely investigated to date and new C- F functionalization methodology recently discovered in our lab bear similar promise. The goals of the proposed research are to introduce asymmetric methods for catalytic carbon-carbon bond formation with fluorinated nucleophiles generated either by mild deacylative C-C cleavage of readily available precursors or from multifunctional prenucleophiles, to continue our spearheading efforts with asymmetric ynamide addition reactions, and to develop new C-F functionalization chemistry. The general feasibility of the planned activities and the synthetic utility prospects are highlighted with ample proof- of-concept results and mechanistic insights. Considerable emphasis will be placed on the introduction of currently elusive reactions and new methodologies, for example unprecedented asymmetric Michael addition/Nef reactions, C-F activation for selective carbon-carbon and carbon-heteroatom bond formation, and base-free ynamide additions. In addition, the overall usefulness of the proposed multifunctional chiral building blocks for the total synthesis of biologically active compounds will be explored. The reaction development efforts will be guided by detailed mechanistic studies and include screening and systematic optimization of a variety of organocatalysts and chiral ligands, including bisoxazolidines which have been developed previously in our laboratory. Altogether, the anticipated outcomes of this proposal are likely to afford new tools and directions for asymmetric catalysis with organofluorines and terminal ynamides as well as general reaction insights and synthetic opportunities that will be of interest to a wide range of synthetic and medicinal chemists.

Public Health Relevance

Chiral fluoroorganic compounds have received increasing attention during the past decade due to their significant role in the health sciences. This steadily growing popularity stems at least in part from a variety of beneficial effects of the carbon-fluoride moiety on the pharmacological profile of biologically active compounds; and it is therefore very important to develop synthetic routes producing multifunctional chiral building blocks, in particular if these lead to the emerging class of fluorinated pharmaceuticals. We therefore aim to introduce asymmetric methods that allow efficient production of current and future drugs with a strong emphasis on organofluorine chemistry.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1)
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Bond, Michelle Rueffer
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Georgetown University
Schools of Arts and Sciences
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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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