Konstantin V. Kudryavtsev

Probing of the cis-5-phenyl proline scaffold as a platform for the synthesis of mechanism-based inhibitors of the Staphylococcus aureus sortase SrtA isoform

cis-5-Phenyl prolinates with electrophilic substituents at the fourth position of a pyrrolidine ring were synthesized by 1,3-dipolar cycloaddition of arylimino esters with divinyl sulfone and acrylonitrile. 4-Vinylsulfonyl 5-phenyl prolinates inhibit Staphylococcus aureus sortase SrtA irreversibly by modification of the enzyme Cys184 and could be used as hits for the development of antibacterials and antivirulence agents.

1,3-dipolar cycloaddition of schriff bases and electron-deficient alkenes, catalyzed by α-Amino acids

L-α-Amino acids catalyze 1,3-dipolar cycloaddition of methyl α-benzylideneamino acids to electron-deficient olefins in different solvents at room temperature. L-α-Amino acids ensure stereoselective formation of the corresponding syn,syn-azomethine ylides. The subsequent reaction with an active dipolarophile is stereospecific; it occurs as endo-cycloaddition with low asymmetric induction (up to ee 12%.). 3,4-Substituted 5-arylprolines were obtained in preparative yields using L-pyroglutamic acid or L-proline as catalyst.

Alternating Asymmetric Self‐Induction in Functionalized Pyrrolidine Oligomers

Artificial structurally well-defined polymers have excited interest as functional mimetics of natural biomacromolecules, exhibiting additional properties not occurring in the living world. Specific conformational organization of natural and synthetic polymeric objects leading to unique folding accounts for the molecular recognition, which is one of the driving principles in important natural processes. Some nonnatural oligomeric species adopt specific and well-defined conformations dictated by the structure of monomeric units and intramolecular interactions and are defined as foldamers. One of the most studied unnatural foldamer types are bpeptides that adopt stable folded helical, sheet, and turn-like conformations. b-Peptides are stable towards natural enzymes, and appropriate design leads to discovery of bpeptide ligands for complicated pharmaceutical targets, such as protein–protein interactions. The application of pyrrolidine-3-carboxylic acid (Pca) for the construction of bpolypeptide chain rigidifies the molecular backbone and provides additional stabilization of the secondary structure of the oligomer in solution. The typical synthesis of a b-peptide backbone is based on the arsenal of peptide chemistry methods, including routine sequences of amino group protection–deprotection steps and multiple activations of carboxylic functionality for amide bond construction. Herein we disclose a fundamentally novel synthetic method towards well-defined highly functionalized short b-peptides that avoids protection, deprotection, and activation procedures and allows to generate efficiently stereoregular oligomeric pyrrolidine-based molecules. The developed method, called cycloadditive oligomerization, has been used for the synthesis of a set of racemic and enantiopure oligomers containing a Pca backbone. The realized approach determines highly diverse structural characteristics of b-peptide oligomers, which are characterized by various physicochemical methods, including X-ray analysis. The oligomerization utilized azomethine ylide 1,3-dipolar cycloaddition as a chain-growth approach (Scheme 1). 5Arylpyrrolidine-2,4-dicarboxylate units serve both as linked elements and as auxiliaries to determine stereoand enantioselectivities of the cycloaddition process. The starting 5arylpyrrolidine-2,4-dicarboxylic acid diesters 3a (X=H, Br) for oligomer synthesis were obtained from iminoesters 1 and tert-butyl acrylate in racemic and enantiopure forms by 1,3-dipolar cycloaddition using Lewis acids for the azomethine ylide generation step (Scheme 1, Table 1). Asymmetric synthesis of the monomer ( )-3a-H was effectively conducted with the enantiopure ligand 4 on a gram scale, and single recrystallization provided the target compound with more than 99% ee. Subsequent N-acryloylation of monomers 3a with acryloyl chloride transformed them into dipolarophiles 2b with a sterically hindered amide residue connected to the ethylene fragment. We supposed that these unique dipolarophiles would induce good diastereoand enantioselectivities under iterative cycloaddition steps with iminoesters 1 (Scheme 1). Indeed, dimers 3b were effectively synthesized by cycloaddition of acrylamides 2b with Schiff bases 1 (X=H, Br) in presence of AgOAc as a Lewis acid agent for azomethine ylide generation (Table 1, entries 4–6). Comparison of H NMR spectra of the cycloaddition reaction mixtures and

Synthesis of bridged heterocycles from cis-pyrrolidine-2,4-dicarboxylic acids: I. 3,6-Diazabicyclo[3.2.1]octanes

Abstractcis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensation with formation of bicyclic imides having a 3,6-diazabicyclo[3.2.1]octane skeleton. The use of copper(I) cyanide as catalyst ensures high yields of 3,6-diazabicyclo[3.2.1]octane-2,4-diones substituted at the 3-, 5-, 6-, and 7-positions. (1R*,5R*,7S*)-7-(4-Chlorophenyl)-5,6-dimethyl-3,6-diazabicyclo[3.2.1]octane-2,4-dione was found to inhibit thrombin in a buffer solution at a millimolar concentration.

Novel Reaction: Brominative Aromatization of 2-Alkyl(aryl)thio Cyclohexanones

Abstract 2-Alkyl(aryl)thio cyclohexanones are transformed into o-alkyl(aryl)thio phenols by treatment with bromine or N-bromosuccinimide.

Stereoselective synthesis of functional derivatives of 2-(2-carboxyethyl)pyrrolidine-2-carboxylic acid

Azomethine ylides generated from dimethyl 2-(arylmethylideneamino)pentanedioates by the action of AgOAc and Et3N reacted with dipolarophiles in regio-and stereoselective fashion to form 5-aryl-2-(2-carboxyethyl)pyrrolidine-2-carboxylic acid derivatives. 1,3-Dipolar cycloaddition of divinyl sulfone to the azomethine ylide generated from the Schiff base derived from methyl (S)-2-phthalimido-4-oxobutanoate and dimethyl glutamate gave chiral simplified kaitocephalin analogs.

Menthols as Chiral Auxiliaries for Asymmetric Cycloadditive Oligomerization: Syntheses and Studies of β-Proline Hexamers

To produce a novel class of structurally ordered poly-β-prolines, an emergent method for synthesizing chiral β-peptide molecular frameworks was developed based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Functionalized short β-peptides with up to six monomeric residues were efficiently synthesized in homochiral forms using a cycloadditive oligomerization approach. X-ray, NMR, and CD structural analyses of the novel β-peptides revealed secondary structure features that were generated primarily by Z/E-β-peptide bond isomerism. Anticancer in cellulo activity of the new β-peptides toward hormone-refractory prostate cancer cells was observed and was dependent on the absolute configuration of the stereogenic centers and the chain length of the β-proline oligomers.

Pharmacological Correction of Stress-Induced Gastric Ulceration by Novel Small-Molecule Agents with Antioxidant Profile

This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.

Structural Studies and Anticancer Activity of a Novel Class of β‐Peptides

Functionalized oligomeric organic compounds with well-defined β-proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β-peptides was investigated by NMR spectroscopic and X-ray methods determining the conformational shapes of the β-proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β-peptide bonds between 5-arylpyrrolidine-2-carboxylic acid units existing in Z/E configurations. The whole library of short β-peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone-refractory prostate cancer cell line PC-3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine-substituted dimeric and trimeric acrylamides induced caspase-dependent apoptosis of PC-3 cells through cell-cycle arrest and mitochondrial damage.

Three-Component Synthesis of Polysubstituted Homoproline Analogs

Tetrasubstituted pyrrolidines representing analogs of homoproline were synthesized by three-component condensation of aryl(heteroaryl)aldehydes, asparagine and N-methylmaleimide (NMM). Compounds with (1S*, 3R*, 3aS*, 6aR*)-configuration at the corresponding carbon positions of the bicyclic pyrrolidine ring could be isolated on a preparative scale.