Samuel Couve-Bonnaire

Syntheses and Applications of Monofluorinated Cyclopropanes

The combination of a fluorine atom and a cyclopropane ring, which both possess unique structural and chemical features, can generate new relevant building blocks for the discovery of efficient fluorinated biologically active agents. In this review, we report the different strategies to access monofluorocyclopropanes and highlight some of their attractive biological applications.

Pd‐ and Cu‐Catalyzed Stereo‐ and Regiocontrolled Decarboxylative/CH Fluoroalkenylation of Heteroarenes

Pd/Cu-catalyzed decarboxylative/direct C-H alkenylations of heteroarenes with α-fluoroacrylic acid is reported. This method offers step-economical and stereocontrolled access to valuable heteroarylated monofluoroalkenes as both Z and E isomers, which are known to be useful in the synthesis of fluorinated biomolecules.

Fluorinated Pseudopeptide Analogues of the Neuropeptide 26RFa: Synthesis, Biological, and Structural Studies

A series of four fluorinated dipeptide analogues each containing a fluoro‐olefin moiety as peptide bond surrogate has been designed and synthesized. These motifs have been successfully introduced into the bioactive C‐terminal heptapeptide of the neuropeptide 26RFa by conventional SPPS. We then evaluated the ability of the generated pseudopeptides to increase [Ca2+]i in GPR103‐transfected cells. For these fluorinated analogues, greater stability in human serum was observed. Their conformations were also investigated, leading to the valuable identification of differences depending on the position of the fluoro‐olefin moiety in the sequence.

One-step synthesis of highly functionalized monofluorinated cyclopropanes from electron-deficient alkenes.

The unique combination of Zn/LiCl allowed generation of reactive zinc enolate from ethyl dibromofluoroacetate. This fluorinated enolate reacts efficiently with a wide range of functionalized electron-deficient alkenes to afford the corresponding monofluorinated cyclopropylcarboxylates in good yields.

Stereospecific Synthesis of Tri- and Tetrasubstituted α-Fluoroacrylates by Mizoroki-Heck Reaction.

Ligand-free, efficient, palladium-catalyzed Mizoroki-Heck reaction between methyl α-fluoroacrylate and arene or hetarene iodides is reported for the first time. The reaction is stereospecific and provides fair to quantitative yields of fluoroalkenes. The Mizoroki-Heck reaction starting from more hindered and usually reluctant trisubstituted acrylate, to access tetrasubstituted fluoroalkenes, is also reported. Finally, the use of a three-step synthesis sequence, including Mizoroki-Heck reaction, allows the synthesis of fluorinated analogues of therapeutic agents with high yield.

Asymmetric Synthesis of Cyclopropanes with a Monofluorinated Quaternary Stereocenter

New chiral fluorinated reagents (N-(dibromofluoroacetyl)oxazolidinones) were easily synthesized and used in an asymmetric cyclopropanation process. The Michael initiated ring closure reaction provided chiral cyclopropanes bearing a fluorinated quaternary stereocenter. Various electron-deficient alkenes can be used to efficiently obtain chiral polysubtituted fluorinated cyclopropanes in good yields. Moderate to very good cis/trans ratios were obtained with a high level of diastereoselectivity for each isomer.

Indium-Promoted Diastereoselective Addition of Fluorinated Haloallylic Derivatives to Imines

We report herein the first general access to fluorinated homoallylic amines by means of an addition of fluorinated organoindium reagent. The corresponding amines were obtained in good to excellent yield with excellent diastereoisomeric ratio. A plausible mechanism is proposed to explain the stereochemical outcome of the reaction based on the X-ray structure of the products.

Ethyl dibromofluoroacetate: a versatile reagent for the synthesis of fluorinated molecules

Graphical abstract

Effect of Fluorination on Skin Sensitization Potential and Fragrant Properties of Cinnamyl Compounds

A series of three α‐ and three β‐fluorinated representatives of the family of cinnamate‐derived odorants (cinnamaldehyde (1), cinnamyl alcohol (2), and ethyl cinnamate (3)) as used as fragrance ingredients is described. Olfactive evaluation shows that the fluorinated compounds exhibit a similar odor profile to their parent compounds, but the olfactive detection thresholds are clearly higher. In vitro evaluation of the skin sensitizing properties with three different assays indicates that α‐fluorination of Michael acceptor systems 1 and 3 slightly improves the skin sensitization profile. α‐Fluorocinnamyl alcohol 2b is a weaker skin sensitizer than cinnamyl alcohol 2a by in vitro tests and the fluorinated product drops below the sensitization threshold of the KeratinoSens® assay. On the other hand, β‐fluorination of compounds 1 – 3 results in highly reactive products which display a worsened in vitro skin sensitization profile.