Bisulfate Salt-Catalyzed Friedel-Crafts Benzylation of Arenes with Benzylic Alcohols.

We report here a method of direct Friedel-Crafts benzylation of arenes with benzylic alcohols using cheap and readily available bisulfate salt as the catalyst in hexafluoroisopropanol. The catalytic system is powerful with a quite diverse group of functionalized arenes and benzylic alcohols. These mild conditions provide a straightforward synthesis of a variety of unsymmetrical diarylmethanes in high yield with good to high regioselectivity. An SN1 mechanism involving activation of the hydroxy group through a hydrogen bond is proposed.

Regioselective Halogenation of Arenes and Heterocycles in Hexafluoroisopropanol.

Regioselective halogenation of arenes and heterocycles with N-halosuccinimides in fluorinated alcohols is disclosed. Under mild condition reactions, a wide diversity of halogenated arenes are obtained in good yields with high regioselectivity. Additionally, the versatility of the method is demonstrated by the development of one-pot sequential halogenation and halogenation-Suzuki cross-coupling reactions.

Electrophilic amination of fluoroalkyl groups on azodicarboxylate derivatives.

The formation of an NCF3 bond or an NCF2R bond still remains scarce. An efficient direct electrophilic amination of fluoroalkyl groups was developed. Difluoroenoxysilanes reacted easily on azodicarboxylate derivatives. These results led to a novel family of NCF3 and NCF2 hydrazine derivatives.

Synthesis of N-CF3 hydrazines through radical trifluoromethylation of azodicarboxylates.

We report here the synthesis of a novel family of N-CF3 hydrazines from a direct way involving the available and cheap Langlois reagent (CF3SO2Na). These derivatives have shown very high stability whatever the conditions used and are excellent precursors for building previously inaccessible N-CF3 functionalized compounds, such as substituted hydrazides, hydrazine-amino-acids, hydrazones, N-aziridines and pyrazoles.

Fluorinated Triazole Foldamers: Folded or Extended Conformational Preferences.

The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for José Laxio Arenas. The China Scholarship Council is thanked for financial support for Yaochun Xu. The authors thank Pr. Vadim Soloshonok and TOSOH F-TECH, Inc. for the kind gift of N-terbutyl-sulfinylimine.

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.

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.

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.

Direct Amination of Arenes with Azodicarboxylates Catalyzed by Bisulfate Salt/HFIP Association.

A mild and efficient amination of arenes with azodicarboxylates using potassium bisulfate (KHSO4) as the catalyst in 1,1,1,3,3,3-hexafluoro-2-propanol has been developed. This protocol allowed the amination of a broad range of arenes leading to corresponding hydrazides in good to excellent yields.

Direct Access to Substituted 4-CF3 ß-Lactams at the C-3 Position.

Mono- and disubstituted 4-CF3 ß-lactams at the C-3 position have been obtained stereoselectively under basic conditions. A wide range of function such as alcohols, alkyls, aryls, esters, and double and triple bonds have been introduced.

Synthesis of new triazole-based trifluoromethyl scaffolds.

Trifluoromethyl propargylamines react with various azide derivatives to afford 1,4-disubstituted 1,2,3-triazoles through a Huisgen 1,3-dipolar cycloaddition. The reaction is catalyzed by a Cu(I) species in acetonitrile, and the corresponding products are obtained in good yields. This process thus offers an entry to new trifluoromethyl peptidomimetics as interesting scaffolds.

Friedel-Crafts alkylation reaction with fluorinated alcohols as hydrogen-bond donors and solvents.

An effective and clean FC alkylation of indoles and electron-rich arenes with ß-nitroalkenes in HFIP was reported. The desired products are formed rapidly in excellent yields under mild conditions without the need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot synthesis of biologically active tryptamine derivatives.

Reactivity of carbon dioxide in hydrofluoroethers: a facile access to cyclic carbonates.

The high solubility of CO2 in hydrofluoroethers led to various cyclic carbonates with excellent selectivities and yields. The fluorinated phase increased the amount of CO2 in contact with the reagents. Reactions could be realized under mild conditions at 80 °C, under atmospheric pressure or under 5 bar.

α- and ß-hydrazino acid-based pseudopeptides inhibit the chymotrypsin-like activity of the eukaryotic 20S proteasome.

We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a ß-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 µM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies.

Carbonylhydrazide-based molecular tongs inhibit wild-type and mutated HIV-1 protease dimerization.

We have designed and synthesized new molecular tongs based on a rigid naphthalene scaffold and evaluated their antidimer activity on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide (azatide) fragments into their peptidomimetic arms to reduce hydrophobicity and increase metabolic stability. These fragments are designed to disrupt the protein-protein interactions by reproducing the hydrogen bond pattern found in the antiparallel ß-sheet formed between the N- and C-ends of the two monomers in the native PR. Kinetic analyses and fluorescent probe binding studies showed that several molecular tongs can inhibit PR dimerization. The best nonpeptidic molecular tongs to date were obtained with an inhibition constant K(id) of 50 nM for PR and 80 nM for the multimutated protease ANAM-11. The PR inhibition was selective, the aspartic proteases renin and pepsin were not inhibited.

Structural and biological effects of a beta2- or beta3-amino acid insertion in a peptide.

Molecular mechanics calculations on conformers of Ac-HGly-NHMe, Ac-beta2-HAla-NHMe and Ac-beta3-HAla-NHMe indicate that low-energy conformations of the beta-amino acids backbone, corresponding to gauche rotamers around the Calpha-Cbeta bond, may overlap canonical backbone conformers observed for alpha-amino acids. Therefore, Substance P (SP) was used as a model peptide to analyse the structural and biological consequences of the substitution of Phe7 and Phe8 by (R)-beta2-HPhe and of Gly9 by HGly (R)-beta2-HAla or (S)-beta3-HAla. [(R)-beta2-HAla9]SP has pharmacological potency similar to that of SP while [HGly9]SP and [(S)-beta3-HAla9]SP show a 30- to 50-fold decrease in biological activities. The three analogues modified at position 9 are more resistant to degradation by angiotensin converting enzyme than SP and [Ala9]SP. NMR analysis of these SP analogues suggest that a beta-amino acid insertion in position 9 does not affect the overall backbone conformation. Altogether these data suggest that [HGly9]SP, [(S)-beta3-HAla9]SP and [(R)-beta2-HAla9]SP could adopt backbone conformations similar to that of SP, [Ala9]SP and [Pro9]SP. In contrast, incorporation of beta2-HPhe in position 7 and 8 of SP led to peptides that are almost devoid of biological activity. Thus, a beta-amino acid could replace an alpha-amino acid within the sequence of a bioactive peptide provided that the additional methylene group does not cause steric hindrance and does not confine orientations of the side chain to regions of space different from those permitted in the alpha-amino acid.