Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

Fluorine in Pharmaceuticals: Looking Beyond Intuition.

Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

The use of visible light sensitization as a means to initiate organic reactions is attractive due to the lack of visible light absorbance by organic compounds, reducing side reactions often associated with photochemical reactions conducted with high energy UV light. This tutorial review provides a historical overview of visible light photoredox catalysis in organic synthesis along with recent examples which underscore its vast potential to initiate organic transformations.

Visible light photoredox catalysis: applications in organic synthesis

The Many Roles for Fluorine in Medicinal Chemistry

Fluorine is the most electronegative element in the periodic table. When bound to carbon it forms the strongest bonds in organic chemistry and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of speciality materials. Although highly polarised, the C–F bond gains stability from the resultant electrostatic attraction between the polarised Cδ+ and Fδ– atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C–F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighbouring bonds or lone pairs. In this tutorial review these fundamental aspects of the C–F bond are explored to rationalise the geometry, conformation and reactivity of individual organofluorine compounds.

Understanding organofluorine chemistry. An introduction to the C–F bond

Department of Chemistry, Tianjin University, Tianjin 300072, China; Department of Applied Chemistry, China Agricultural University, Beijing 100193, China; UMR 6014 CNRS, Laboratoire COBRA de l’IRCOF, Université et INSA de Rouen, Rue Tesniere, F-76130 Mont Saint Aignan, France; and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China

Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates.

Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions.

Update 1 of: Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions

Strategies for nucleophilic, electrophilic, and radical trifluoromethylations

The design and development of new high-performance catalysts for applications in asymmetric catalytic reactions is of ongoing interest in organic chemistry. The combination of a Lewis acid and a Lewis base working in concert is now considered state of the art in stereoselective syntheses. The synergistic activation by two or more reactive centers allows high reaction rates and excellent transfer of stereochemical information. Despite the self-quenching reaction between Lewis acids and Lewis bases that might lead to an inactive catalyst, considerable effort has been directed towards the development of the dual-activation concept. The ultimate goal is to mimic nature by the discovery of catalytic systems analogous to enzymatic processes that involve metal-ion cocatalysts. With this aim, the dual activation concept greatly broadens the range of artificial catalysts. The most efficient catalytic systems are reviewed, and the mechanisms of action are discussed.

Dominique Cahard

Papers

Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates.

Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions.

Update 1 of: Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions

Strategies for nucleophilic, electrophilic, and radical trifluoromethylations

Towards perfect catalytic asymmetric synthesis: dual activation of the electrophile and the nucleophile.