Pavel K. Mykhailiuk

Controlling biological activity with light: diarylethene-containing cyclic peptidomimetics.

Photobiological processes in nature are usually triggered by nonpeptidic chromophores or by modified side chains. A system is presented in which the polypeptide backbone itself can be conformationally switched by light. An amino acid analogue was designed and synthesized based on a reversibly photoisomerizable diarylethene scaffold. This analogue was incorporated into the cyclic backbone of the antimicrobial peptide gramicidin S at several sites. The biological activity of the resulting peptidomimetics could then be effectively controlled by ultraviolet/visible light within strictly defined spatial and temporal limits.

In Situ Generation of Difluoromethyl Diazomethane for [3+2] Cycloadditions with Alkynes†

A novel approach to agrochemically important difluoromethyl-substituted pyrazoles has been developed based on the elusive reagent CF2 HCHN2 , which was synthesized (generated in situ) for the first time and employed in [3+2] cycloaddition reactions with alkynes. The reaction is extremely practical as it is a one-pot process, does not require a catalyst or the isolation of the potentially toxic and explosive gaseous intermediate, and proceeds in a common solvent, namely chloroform, in air. The reaction is also scalable and allows for the preparation of the target pyrazoles on gram scale.

“Reported, but Still Unknown.” A Closer Look into 3,4-Bis- and 3,4,5-Tris(trifluoromethyl)pyrazoles

Straightforward practical synthetic approaches to 3,4-bis- and 3,4,5-tris(trifluoromethyl)pyrazoles have been developed. The key step of the both syntheses is a transformation of the carboxylic group in a pyrazole core into the trifluoromethyl group by sulfur tetrafluoride. The elaborated synthetic protocols allow gram-scale preparation of the target products. The obtained compounds are comprehensively characterized by means of crystallographic analysis, determination of pK(a) values and fluorescence measurements.

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Structure analysis of the cell-penetrating peptide transportan 10 (TP10) revealed an exemplary range of different conformations in the membrane-bound state. The bipartite peptide (derived N-terminally from galanin and C-terminally from mastoparan) was found to exhibit prominent characteristics of (i) amphiphilic α-helices, (ii) intrinsically disordered peptides, as well as (iii) β-pleated amyloid fibrils, and these conformational states become interconverted as a function of concentration. We used a complementary approach of solid-state 19F-NMR and circular dichroism in oriented membrane samples to characterize the structural and dynamical behaviour of TP10 in its monomeric and aggregated forms. Nine different positions in the peptide were selectively substituted with either the L - or D -enantiomer of 3-(trifluoromethyl)-bicyclopent-[1.1.1]-1-ylglycine (CF3 -Bpg) as a reporter group for 19F-NMR. Using the L -epimeric analogs, a comprehensive three-dimensional structure analysis was carried out in lipid bilayers at low peptide concentration, where TP10 is monomeric. While the N-terminal region is flexible and intrinsically unstructured within the plane of the lipid bilayer, the C-terminal α-helix is embedded in the membrane with an oblique tilt angle of ∼55° and in accordance with its amphiphilic profile. Incorporation of the sterically obstructive D -CF3 -Bpg reporter group into the helical region leads to a local unfolding of the membrane-bound peptide. At high concentration, these helix-destabilizing C-terminal substitutions promote aggregation into immobile β-sheets, which resemble amyloid fibrils. On the other hand, the obstructive D -CF3 -Bpg substitutions can be accommodated in the flexible N-terminus of TP10 where they do not promote aggregation at high concentration. The cross-talk between the two regions of TP10 thus exerts a delicate balance on its conformational switch, as the presence of the α-helix counteracts the tendency of the unfolded N-terminus to self-assemble into β-pleated fibrils.

Generation of C2F5CHN2 In Situ and Its First Reaction: [3+2] Cycloaddition with Alkenes

The novel chemical reagent, C2 F5 CHN2 , is generated in situ from C2 F5 CH2 NH2 ⋅HCl and sodium nitrite. It reacts with mono- and disubstituted electron-deficient alkenes at room temperature to afford C2 F5 -pyrazolines in excellent yields.

Silver(I) and Copper(I) Adducts of a Tris(pyrazolyl)borate Decorated with Nine Trifluoromethyl Groups

Silver and copper ethylene adducts and the silver carbonyl complex of the tris(pyrazolyl)borate [HB(3,4,5-(CF(3))(3)Pz)(3)](-) (which is based on one of the most acidic pyrazoles known) have been synthesized. (13)C NMR resonance signals of metal-bound ethylene carbon atoms of [HB(3,4,5-(CF(3))(3)Pz)(3)]Ag(C(2)H(4)) and [HB(3,4,5-(CF(3))(3)Pz)(3)]Cu(C(2)H(4)) appear at δ 111.6 and 94.9, respectively. The CO stretching frequency of the silver adduct [HB(3,4,5-(CF(3))(3)Pz)(3)]Ag(CO) is significantly higher than that of free CO, but it appears at a region less sensitive to the ligand electronic effects of tris(azolyl)borate silver adducts.

4-Fluoro-2,4-methanoproline.

The first fluorinated analogue of the naturally occurring 2,4-methanoproline, 4-fluoro-2,4-methanoproline, has been synthesized in five steps from commercially available methyl 2-fluoroacrylate through a photochemical cyclization as a key step in generating a 2-azabicyclo[2.1.1]hexane skeleton.

Three-component synthesis of C2F5-substituted pyrazoles from C2F5CH2NH2·HCl, NaNO2 and electron-deficient alkynes

Summary A one-pot reaction between C2F5CH2NH2·HCl, NaNO2 and electron-deficient alkynes gives C2F5-substituted pyrazoles in excellent yields. The transformation smoothly proceeds in dichloromethane/water, tolerates the presence of air, and requires no purification of products by column chromatography. Mechanistically, C2F5CH2NH2·HCl and NaNO2 react first in water to generate C2F5CHN2, that participates in a [3 + 2] cycloaddition with electron-deficient alkynes in dichloromethane.

Approach to the library of fused pyridine-4-carboxylic acids by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles.

A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.

Unexpected Reactivity of Trifluoromethyl Diazomethane (CF3CHN2): Electrophilicity of the Terminal N-Atom

After more than 70 years since its discovery, CF3CHN2 was found to possess a novel reactivity mode: N-terminal electrophile. With C-nucleophiles it gives hydrazones that are easily transformed into valuable CF3-heterocycles.