α,ß-Disubstituted CF3-Enones as a Trifluoromethyl Building Block: Regioselective Preparation of Totally Substituted 3-CF3-Pyrazoles.

An efficient pathway toward a novel class of trifluoromethyl building blocks was elaborated. The reaction of α-CF3-enamines with arylaldehydes resulted in direct synthesis of α,ß-diaryl-CF3-enones isolated in up to 93% yield as E-isomers. The possible reaction mechanism was proposed using the Zimmerman-Traxler model. The reaction of α,ß-diaryl-CF3-enones with hydrazines opens a novel pathway to trifluoromethylated pyrazolines. Oxidation of pyrazolines with DDQ opened access to totally regioselective preparation of 3-CF3-pyrazoles isolated in high yield. Using this strategy, 4-arylated derivatives of known drugs Celebrex, Mavacoxib, and SC-560 can be synthesized.

Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines.

A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF3-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF3-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF3-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed.

Experimental and Theoretical Study of an Intramolecular CF3-Group Shift in the Reactions of α-Bromoenones with 1,2-Diamines.

The reactions of trifluoromethylated 2-bromoenones and N,N'-dialkyl-1,2-diamines have been studied. Depending on the structures of the starting compounds, the formation of 2-trifluoroacetylpiperazine or 3-trifluoromethylpiperazine-2-ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting α-bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated.

Fliposomes: pH-controlled release from liposomes containing new trans-2-morpholinocyclohexanol-based amphiphiles that perform a conformational flip and trigger an instant cargo release upon acidification.

A new type of pH-sensitive liposome (fliposomes) was designed based on the amphiphiles that are able to perform a pH-triggered conformational flip (flipids). This flip disrupts the liposome membrane and causes rapid release of the liposome cargo, specifically in the areas of increased acidity. The flipids (1-3) are equipped with a trans-2-morpholinocyclohexanol conformational switch, pH-Sensitive fliposomes containing one of these flipids, POPC and PEG-ceramide (molar ratio 50/45/5) were constructed and characterized. These compositions were stable at 4 degrees C and pH 7.4 for several months. Fliposomes loaded with ANTS/DPX demonstrated an unusually quick content release (in a few seconds) at pH below 5.5, which was more efficient in the case of flipid 1 with the shorter linear C12-tails. The pH-titration curve for the fliposome leakage paralleled the curve for the acid-induced conformational flip of 1-3 studied by 1H NMR. A plausible mechanism of the pH-sensitivity starts with an acid-triggered conformational flip of 1, 2 or 3, which changes the molecular size and shape, shortens the lipid tails, and perturbs the liposome membrane resulting in the content leakage.

Porphyrin-based peptide receptors: syntheses and NMR analysis.

The synthesis and purification of a water-soluble host compound that contains three pyridinium units and one spacer-connected benzocrown ether unit in the meso-positions of porphyrin and of its Zn(II) or Cu(II) complexes is described. Metalation leads to small (compared to the apo-derivative) changes of selectivities with different peptides, with complexation constants in water of above 10(5)M(-1). One complex containing the tripeptide Gly-Gly-Phe is analyzed in detail by COSY, HSQC, HMBC, and NOESY NMR experiments. Temperature-dependent spectra show activation energies for a intramolecular hydrogen exchange of amide protons with valence isomerization of the porphyrin ring, in accordance with the literature. Sharp signals for the spin system are only found at elevated temperature. Vicinal coupling constants within the crown ether moiety indicate stronger puckering than that reported for benzocrowns. All NMR signals of the complexed peptide are shielded, in particular those of the terminal phenylalanine unit, in line with its stacking on the porphyrin surface. A corresponding structural model, obtained by CHARMm simulation, is also in line with the observed intermolecular NOE cross peaks.