A one-pot synthesis of 3-trifluoromethyl-2-isoxazolines from trifluoromethyl aldoxime.

Functionalized 3-trifluoromethyl-2-isoxazolines and 3-trifluoromethylisoxazoles were easily prepared from trifluoromethyl aldoxime 2 under mild conditions by using DIB as oxidant. Theoretical studies of the reactivity of trifluoroacetonitrile oxide 4 toward olefins and alkynes were carried out. The 3-trifluoromethyl-2-isoxazolines were ring-opened with NaBH4 and NiCl2 to yield the corresponding trifluoromethylated γ-amino alcohols.

Fluorous tagging of DABCO through halogen bonding: recyclable catalyst for the Morita-Baylis-Hillman reaction.

The halogen-bonded adduct between DABCO and two molecules of perfluorooctyl iodide (DABCO·(C(8)F(17)I)(2)) acts as a recyclable organocatalyst for the Morita-Baylis-Hillman reaction. This "supramolecular fluorous catalyst" is readily accessible and can be recovered by simple precipitation/filtration.

Nonmetal catalyzed insertion reactions of diazocarbonyls to acid derivatives in fluorinated alcohols.

The insertion reaction of diazocarbonyls to acids could be performed smoothly in fluorinated alcohols in the absence of metal catalyst. This new procedure allowed the chemoselective preparation of various functionalized compounds such as acyloxyesters, depsipeptides, and sulfonate, phosphonate, or boronate derivatives.

Influence of the structure of polyfluorinated alcohols on Brønsted acidity/hydrogen-bond donor ability and consequences on the promoter effect.

The influence of substituents on the properties of tri- and hexafluorinated alcohols derived from 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was examined. Measurements of specific solvent-solute interactions revealed that H-bond donation (HBD) of fluorinated alcohols is sensitive to the steric hindrance of the OH group, whereas their Brønsted acidity is dependent only on the number of fluorine atoms. For hexafluorinated alcohols (HFAs), their association with amines characterized by X-ray diffraction showed that the balance between HBD and acidity is influenced by their structure.

Synthesis of substituted 8-aminoquinolines and phenanthrolines through a Povarov approach.

The synthesis of 8-aminoquinolines and 1,10-phenanthrolines with substituents in α of the nitrogen has been performed through an inverse-demanding aza-Diels-Alder (Povarov reaction) in the fluoroalcohols TFE or HFIP. This path involves simple starting materials: 1,2-phenylenediamines, enol ethers and aldehydes.

Trifluoromethyl nitrones: from fluoral to optically active hydroxylamines.

Trifluoromethyl nitrones were obtained in high yields by condensation of various hydroxylamines with trifluoroacetaldehyde hydrate. The nucleophilic diastereoselective additions of organometallic reagents to these nitrones afforded the corresponding optically active trifluoroethyl hydroxylamines in good yields.

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.

Solvent-promoted and -controlled aza-Michael reaction with aromatic amines.

1,4-Addition of anilines onto Michael acceptors proceeds easily in specific polar protic solvents, without any promoting agent. According to the solvent and to the electrophile, the selectivity of the reaction can be finely tuned. With methyl acrylate as electrophile, only monoaddition takes place in water, while the diadduct is yielded in hexafluoroisopropyl alcohol (HFIP).

Non Lewis acid catalysed epoxide ring opening with amino acid esters.

The ring opening of epoxides by various amino acid esters is described in refluxing trifluoroethanol without any catalyst. Under these simple conditions the corresponding beta-amino alcohols are obtained in good to excellent yields in relatively short reaction times compared to previously reported methods.

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.

Solubility switch of gold nanoparticles through hydrogen bond association.

Gold nanoparticles (AuNPs) coated with hexafluoroisopropanol moieties were prepared, and their surface was changed through simple hydrogen bond association with various amines, which allow orientation of the solubility of these AuNPs in determined organic solvents.

In vitro antileishmanial activity of fluoro-artemisinin derivatives against Leishmania donovani.

The antileishmanial activity of 19 fluoro-artemisinin derivatives was evaluated in vitro against the promastigote forms of Leishmania donovani. The most active compound BB 201, an amino derivative, exhibited an IC50 at about 1microM and no cross-resistance was found on miltefosine-resistant and sitamaquine-resistant lines. Despite these promising data, no activity was observed on intramacrophage amastigote stage.

[Fluorine, an essential element for medicinal chemistry].

Because of the intrinsic properties of the fluorine atom, organic fluoride compounds have unique properties of particular importance in the pharmaceutical industry. The effect of fluorine is illustrated by selected examples of medicinal chemistry.

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 10beta-(trifluoropropyloxy)dihydroartemisinin (F(1)-DHA) and 10-trifluoromethyl-16-[2-(hydroxyethyl)piperazine] (F(2)-DHA), across rat intestine using Ussing diffusion chambers.

Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives.

This report is an overview on the design, preparation, and evaluation of metabolically stable artemisinins, using fluorine substitution. The chemical challenges encountered for the incorporation of fluorine-containing elements and the preparation of a large range of 10-trifluoromethyl artemisinin derivatives are detailed. Impact of the fluorine substitution on the antimalarial activity is also highlighted.

Synthesis and antimalarial activities of novel 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes.

The oxidative system H2O2/fluorinated alcohol (TFE, HFIP) was used for direct acid- and MeReO3-catalyzed synthesis of 1,2,4,5-tetraoxanes from cyclic (C6, C7, and C12) and acyclic ketones. The influence of ring size and alkyl chain length were studied and antimalarial activities of synthetic 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes were determined. Variations in their antimalarial activities were significant, although they share similar electrochemical properties of the peroxide bond.

S(N)/S(N)' competition: selective access to new 10-fluoro artemisinins.

In this paper, we report a simple route to accede to a new family of C-10 fluorinated derivatives of artemisinin 7. We demonstrated that nucleophilic substitution of the allylic bromide 6 with alcohols can occur at carbon 10 (compounds 7) under solvolytic conditions (S(N)'/S(N) ratio, 87:13). Furthermore, using the particular properties of hexafluoroisopropanol (HFIP), we are able to increase the selectivity of the substitution.

Synthesis of new artemisinin-derived dimers by self-cross-metathesis reaction.

[reaction: see text] New artemisinin-derived dimers, fluorinated or not, have been prepared by a self-cross metathesis reaction in the presence of first- or second-generation ruthenium catalysts without degradation of the endoperoxide bridge and with a good E/Z selectivity (up to 100:0).

The chemistry of trifluoromethyl imines and related acetals derived from fluoral.

Trifluoromethylated nitrogen-containing molecules have been shown to have important biological effects and their synthesis is in the focus of the pharmaceutical industry. In the last few years, simple nitrogen derivatives of fluoral, i.e.

Analogues of key precursors of aspartyl protease inhibitors: synthesis of trifluoromethyl amino epoxides.

The synthesis of the title compound is described through original and tailored synthetic protocols. The addition of vinylmagnesium bromide to CF(3)-N-aryl and N-alkyl aldimines was efficient and did not require an activating N-substituent. The resultant CF3-allylamines were converted in an efficient and completely stereoselective route to syn CF3-epoxides 3 via formation of bromhydrins 8.

Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate.

The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with methanol, ethanol, or succinic acid allowed the access of C-10 CF(3) analogues of beta-artemether, beta-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF(3) group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions.

Orally active antimalarials: hydrolytically stable derivatives of 10-trifluoromethyl anhydrodihydroartemisinin.

New fluoroartemisinin derivatives containing polar or water-soluble functionalities at C-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. The substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with N-, O-, and C-nucleophiles. Among them, amines 11a-c appeared to be highly in vivo efficient antimalarials on mice infected with Plasmodium berghei, more than the reference sodium artesunate 1d.

Preparation of 10-trifluoromethyl artemether and artesunate. Influence of hexafluoropropan-2-ol on substitution reaction.

To prepare 10-trifluoromethyl analogues of important antimalarials such as artemether and artesunate, the substitution reaction of the 10-trifluoromethyl hemiketal 6 and bromide 4 derived from artemisinin was investigated. While 6 appeared to be unreactive under various conditions, bromide 4 could easily undergo substitution with methanol under electrophilic assistance or noncatalyzed conditions. Optimization of the reaction revealed the role of CH(2)Cl(2) as solvent to avoid the competitive elimination process and the crucial influence of hexafluoro-2-propanol (HFIP) in increasing the rate and the stereoselectivity of the substitution reaction (de >98%).