Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold.

The synthesis of tripeptides incorporating new fluorinated heterocyclic hydrazino acids, based on the tetrahydropyridazine scaffold is described. Starting from simple fluorinated hydrazones, these non-proteinogenic cyclic β-amino acids were easily prepared by a zinc-catalyzed aza-Barbier reaction followed by an intramolecular Michael addition. Preliminary conformational studies on tripeptides including this scaffold in the central position show an extended conformation in solution (NMR) and in the solid state (X-ray).

Composition and Conformation of Hetero- versus Homo-Fluorinated Triazolamers Influence their Activity on Islet Amyloid Polypeptide Aggregation.

Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein.

Synthesis, Reactivity, and Antibacterial Activity of -Difluoroalkene, Difluoromethyl, and Trifluoromethyl β-Lactams.

New -difluoroalkenes were synthesized by the dehydrofluorination of the corresponding 4-CF-β-lactams. An unexpected rearrangement mechanism of the ester moiety dependent on a stabilizing negative charge was observed. Hydrogenation to 4-CHF-β-lactams was successful from -difluoro-β-lactams.

Difluoroalanine: Synthesis, Incorporation in Peptides, and Hydrophobic Contribution Assessment.

The straightforward synthesis of chiral ()- and ()-difluoroalanine is reported. The key step is a Strecker-type reaction followed by hydrogenolysis, Fmoc protection, and acidic hydrolysis. Peptide coupling reactions at its N- and C-terminal positions provide diastereomerically pure tripeptides.

Recent Advances in the Syntheses of N-CF Scaffolds up to Their Valorization.

This review provides a recent overview of the different synthetic routes of the N-CF group. This scaffold can be prepared from the desulfurization of thiocabamoyl fluorides or isothiocyanates with fluoride ions. Electrophilic and radical trifluoromethylations are also a great way to generate this motif.

5-Fluoro-1,2,3-triazole motif in peptides and its electronic properties.

The 5-fluoro triazole amino acid scaffold prepared by halogen exchange has been incorporated into peptides. From the X-ray diffraction of the 5-fluoro triazole motif, the main observation was an important localization on one side of the negative potential surface. The fluorine atom reveals a cylindrical shape in its deformation electron density.

Synthesis of -CF hydrazines through radical trifluoromethylation of azodicarboxylates.

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

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

A mild and efficient amination of arenes with azodicarboxylates using potassium bisulfate (KHSO) 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-CF β-Lactams at the C-3 Position.

Mono- and disubstituted 4-CF β-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.

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.

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands.

Pentapeptides having the sequence R-HN-Ala-Val--Val-Leu-OMe, where the central residue is L-serine, L-threonine, (2,3)-L-CF-threonine and (2,3)-L-CF-threonine were prepared. The capacity of (2,3)- and (2,3)-CF-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF-threonine containing pentapeptides are more prone to mimic β-strands than their natural Ser and Thr pentapeptide analogues.

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 β-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.

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.

Designed Glycopeptidomimetics Disrupt Protein-Protein Interactions Mediating Amyloid β-Peptide Aggregation and Restore Neuroblastoma Cell Viability.

How anti-Alzheimer's drug candidates that reduce amyloid 1-42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1-42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1-42.

Benefits of a Dual Chemical and Physical Activation: Direct aza-Michael Addition of Anilines Promoted by Solvent Effect under High Pressure.

The unique combination of hexafluoroisopropanol (HFIP) employed as solvent and hyperbaric conditions (10-15 kbar) allows unprecedented 1,4-addition of poor nucleophiles, such as aromatic amines, onto sluggish (cumbersome) Michael acceptors without any promoter or workup.

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.

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.

Structure-activity relationships of sugar-based peptidomimetics as modulators of amyloid β-peptide early oligomerization and fibrillization.

Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides. Aβ1-42 being the most aggregative and neurotoxic amyloid peptide, we report herein the capacity of sugar-based pentapeptide analogs to modulate the Aβ1-42 aggregation process using thioflavin fluorescence and transmission electron microscopy assays. The importance of the free hydroxyl groups of the sugar moiety, used as a β-breaker element, is confirmed since hydroxylated compounds inhibit the aggregation process while benzylated ones enhance it.

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.

α- and β-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 β-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 μM for molecule 24b).

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 β-sheet formed between the N- and C-ends of the two monomers in the native PR.

The fluorous effect in biomolecular applications.

From being a niche area only a few decades ago, fluorous chemistry has gained momentum and is, nowadays, a fervent area of research. It has brought forth, in fact, numerous applicative innovations that stretch among different fields: from catalysis to separation science, from supramolecular to materials and analytical chemistry. Recently, the unique features of perfluorinated compounds have reached the attention of the biochemists' audience.

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.