Danièle Bonnet-Delpon

One-pot synthesis of non-symmetric tetraoxanes with the H2O2/MTO/fluorous alcohol system☆

Abstract 1,2,4,5-Tetraoxanes, potent antimalarial drugs, were selectively synthesized in fluorous alcohols (2,2,2-trifluoroethanol–TFE and 1,1,1,3,3,3-hexafluoro-2-propanol–HFIP). A use of these solvents enabled for the first time a one-pot synthesis of non-symmetric tetraoxanes in good yields from simple ketones and aldehydes with 2 equiv. of 30% hydrogen peroxide and 0.1 mol% of methyltrioxorhenium (MTO).

Methyltrioxorhenium-catalysed epoxidation of alkenes: enhancement of reactivity in hexafluoro-2-propanol

Abstract Methyltrioxorhenium-catalysed epoxidation of alkenes with hydrogen peroxide can be improved by using hexafluoro-2-propanol as a solvent. Quantitative conversions of cyclic and terminal olefins can be obtained with only 30% H 2 O 2 and 0.1 mol% of catalyst.

Novel fluorinated pseudopeptides as proteasome inhibitors

We have designed novel small inhibitors of rabbit 20S proteasome using a trifluoromethyl-beta-hydrazino acid scaffold. Structural variations influenced their inhibition of the three types of active sites. Proteasome inhibition at the micromolar level was selective, calpain I and cathepsin B were not inhibited.

Synthesis and cytotoxic activity of fluorinated analogues of Goniothalamus lactones. Impact of fluorine on oxidative processes

Novel fluorinated analogues of goniothalamin 1 and howiinol A 2 have been prepared from trifluorocrotonate derivatives. Trifluoromethyl goniothalamin (R/S) 4 showed a slightly lower activity than 1, while the trifluoromethyl howiinol A 16 exhibited similar activities on several cell lines in the micromolar range. Unlike (R) goniothalamin and howiinol A, trifluoromethyl parent compounds remained unchanged when submitted to biomimetic oxidative systems.

Ring-Opening of 1-CF3-Substituted Epoxy Ethers with Carboxylic, Thiocarboxylic, and Phosphinic Acids in Basic Medium and in Hexafluoro-2-propanol

Ring-opening of 1-CF3-substituted epoxy ethers with carboxylic acids was achieved in Et3N as solvent, and α-CF3-substituted acyloins and corresponding esters were obtained in good yields. In hexafluoro-2-propanol (HFIP) as solvent, the carboxylic acids acted as nucleophiles, and α-carbonyloxy trifluoromethyl ketones were isolated in good yields. After reduction, CF3-substituted glycols were obtained as monoesters on one or the other hydroxy group. This reaction also allowed the preparation of α-carbonylsulfanyl- and α-phosphoryloxy trifluoromethyl ketones and corresponding alcohols. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Transport of fluoroalkyl dihydroartemisinin derivatives across rat intestinal tissue

Artemisinin and its derivatives represent an important class of antimalarials. In order to obtain new derivatives with a longer half‐life and better bioavailability, the development of fluorinated analogues has received increasing attention. The purpose of this study was to investigate the permeation of artemisinin and of two fluoroalkyl derivatives of dihydroartemisinin (DHA), namely 10β‐(trifluoropropyloxy)dihydroartemisinin (F1‐DHA) and 10‐trifluoromethyl‐16‐[2‐(hydroxyethyl)piperazine] (F2‐DHA), across rat intestine using Ussing diffusion chambers. Further, the saturation solubility and partition coefficient of the compounds were determined in order to determine whether the substitution of hydrogen atoms by fluorine can induce great changes in these molecular properties. Artemisinin and F2‐DHA permeability coefficients of 27.5 ± 1.6 and 23.2 ± 1.2 (x 10−6, cm s−1), respectively, are predictive of good oral absorption. This indicates that the introduction of a fluoroalkyl group in a compound such as artemisinin in order to prolong its half‐life does not constitute an obstacle for its absorption after oral administration. Moreover, the introduction of a polar substituent into the DHA structural scaffold increased the aqueous solubility of F2‐DHA relative to artemisinin. F1‐DHA permeability measurements showed low transepithelial diffusion across the intestinal mucosa. This indicates that the introduction of a fluorinated substituent at the α‐methylene carbon of DHA ethers in order to provide protection against oxidative processes constitutes an obstacle for the absorption after oral administration.

Biological Impacts of Fluorination: Pharmaceuticals Based on Natural Products

Publisher Summary nThis chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.Publisher Summary This chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.

Biological Impacts of Fluorination

Publisher Summary nThis chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.Publisher Summary This chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.

Chapter 13 – Biological Impacts of Fluorination: Pharmaceuticals Based on Natural Products

Publisher Summary nThis chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.Publisher Summary This chapter focuses on the recent advances in the fluorinated analogues of natural products developed as pharmaceuticals. These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids, and prostaglandins. Among the numerous marketed pharmaceuticals in the world, more than 150 drugs are fluorinated compounds. The specific properties of the fluorine atom, such as its strong electronegativity, small size, and low polarisability of the C–F bond, can have considerable impact on the behavior of a small molecule in a biological environment. The introduction of fluorine atoms into a molecule has an impact on the physical and chemical properties of this molecule, with deep consequences on the biological properties. The absorption, distribution, recognition, and interaction or reaction processes with the biological target, as well as the metabolism and the elimination of this molecule, are affected. This possibility to modify or to modulate the pharmacological profile of a molecule by inserting fluorine atoms clearly explains why bioorganic and medicinal chemistry of fluorine has become so important, and why many drugs and pesticides are fluorinated compounds. Fluorinated groups (F, CF2, etc.) are isosteric or isopolar of various functional groups; they can mimic them in the interaction processes with biological macromolecules. They can also interact afterwards with the target, because of the specific reactivity of the fluorinated molecule. This explains the important role played by the incorporation of fluorine atoms in the design of receptor ligands and enzyme inhibitors: substrate analogues, transition state analogues, and based-mechanism inhibitors.

Cyclisations initiated by solvolyses of α-CF3 sulfonates and α-CF3 alcohols

Abstract The following reactions have been studied: Cyclization occured for R2ue5fbH and C6H5 but failed for R2ue5fbCH3. The results will be discussed in terms of stability of the incipient carbocation R2ue5f8 C + C | ue5f8CF3 related to internal long range participation.