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Starting from achiral closo-carborane and using natural amino acid as chiral auxiliary, individual (RP)- and (SP)-enantiomers of C-monosubstituted nido-carboranes were obtained.

(R)-2-Phenoxypropanoate ester was efficient chiral resolving agent in acylative KR of racemic cyclic alkylamines; highest selectivity was observed for 2-methylpiperidine with predominant formation of (R,R)-amide, which was confirmed by DFT modelling.

A number of novel amides were synthesized by coupling of 6-[(9H-purin-6-yl)amino]hexanoic acid to heterocyclic amines. The antiviral activity of the obtained compounds, as well as of purine conjugates in which 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine is linked to position 6 of purine through a fragment of ω-amino acids with varying lengths of polymethylene chains against influenza A and B viruses was studied in vitro. Purine derivatives have been shown to have moderate activity against influenza A (H1N1) virus. The antiinfluenza activity and cytotoxicity of conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine depend on the length of the linker fragment.

The deboronation of enantiomers of planar-chiral benzyl (3-formamido-1,2-dicarba-closo-dodecaboran-1-yl)acetate gave the individual (RP)- and (SP)-enantiomers (ee > 98%) of a new amino acid containing a nido-carborane fragment, (3-ammonio-7,8-dicarba-nido-undecaboran-7-yl)acetic acid. Chiral HPLC methods for the analysis of enantiomeric purity of this compound was developed.

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by1H,19F, and 13 C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. Russian Science Foundation, RSF: 19-13-00231-P Funding: This research was funded by the Russian Science Foundation, grant number 19-13-00231-P.

Recent publications on the key preparation methods of the enantiomers of 2-aryloxy carboxylic acids are summarized and comparative analysis of the methods is given. The information is arranged according to the type of the starting compound, being classified into syntheses from enantiomerically pure chiral precursors and syntheses from prochiral precursors, which imply generation of an asymmetric centre in the substrate molecule. Data on the chemical resolution of racemic mixtures of the title compounds are addressed in a separate Section. Attention is focused on the preparation of practically valuable 2-aryloxy acids. Examples of biologically active derivatives of 2-aryloxy carboxylic acids are given. The bibliography includes 121 references.

A comparative study of the kinetic resolution of racemic derivatives of 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine using racemic 2-aryloxypropionyl chlorides was performed. It was found that the acylation of racemic amines with racemic 2-(1-naphthyloxy)propionyl chloride leads to amides enriched with (3R*,2′R*)-diastereomers, while the acylation with 2-phenoxypropionyl chloride gives predominantly (3R*,2′S*)-amides. Quantum chemical modeling of the process of kinetic resolution at the COSMO-CH2Cl2-B3LYP-D3-gCP/def2-TZVP//B3LYP-D3-gCP/def2-SVP level of theory was performed. The computational results are in a good agreement with the experimental data.

A comparative study of the kinetic resolution of racemic 3-tert-butyl-3,4-dihydro-2H-[1,4]-benzoxazine through the acylation by various chiral acyl chlorides was carried out. A preparative method for obtaining enantiomerically pure (S)-3-tert-butyl-3,4-dihydro-2H-[1,4]benzoxazine can be based on the acylation with N-phthaloyl-(S)-phenylalanyl or (R)-2-phenoxypropionyl chlorides, followed by the acid hydrolysis of the corresponding diastereomerically pure amides.

The enantiomerically pure N- and C-protected derivatives of planar-chiral (3-amino-1,2-dicarba-closo-dodecaboran-1-yl)acetic acid (>99% ee) have first been obtained in good yields via a combination of HPLC separation and synthetic procedures. Assignment of absolute configuration of the carborane fragments has been made based on the X-ray diffraction data of diastereoisomeric derivatives of (S)-amino acids.

It is well-known that cognitive metaphor can reflect the process of conceptualization of the surrounding world in the human mind. The metaphorical transfer of the source domain’s conceptual features to the target domain shows the essence of the reality perception in the consciousness. This study is focused on the intracultural variation of cognitive metaphors, particularly the phenomenon of the implicit-explicit dispersion in metaphors, dependence of their perception on the occupation, gender, and age of members of a culture, and type of metaphors. Based on conceptual metaphors, associated with the target domain WAR in the Russian culture, the researchers elaborate a novel approach to the analysis of conceptual metaphors, providing full-fledged scrutiny of the reflection of the surrounding realm in the minds of native speakers. The study involved 124 people, some of whom have direct professional experience in the military sphere. The obtained differences in the perception of simulated metaphorical models allow us to talk about intracultural variation of the WAR cognitive metaphor and the significant influence of personal experience on the perception of reality.

Using purine as a scaffold, the methods for preparation of novel 2-aminopurine and purine derivatives substituted at position C6 by the fragments of natural amino acids, short peptides, andN-heterocycles, including enantiopure ones, have been proposed. The methods for determination of the enantiomeric purity of the obtained chiral compounds have been developed. Conjugates exhibiting high antimycobacterial or antiherpesvirus activity against both laboratory and multidrug-resistant strains were revealed among the obtained compounds. © 2020 De Gruyter. All rights reserved. Russian Science Foundation, RSF: 19-13-00231 Funding : The reviewed studies were financially supported by the Russian Science Foundation (project no. 19-13-00231).

New (S)-homocysteine derivatives containing a meta-carborane fragment were synthesized. m-Carboranyl-(S)-homocysteine sulfoxide was obtained as a mixture of diastereoisomers. The reduction of the side-chain carboxy group of N-tert-butoxycarbonyl-(S)-aspartic acid α-tert-butyl ester with sodium tetrahydridoborate was not accompanied by racemization.

Reversed-phase HPLC on chiral stationary phases was used to study the influence of the structure of purine and 2-aminopurine conjugates with chiral heterocyclic amines on the retention times. The optimum conditions for separation of enantiomers were found. The best parameters of separation of stereoisomers of all the compounds examined were achieved on a (S,S)-Whelk-O1 column in weakly alkaline aqueous methanol systems.

The review summarizes the data published over the last 10 – 15 years concerning the key groups of purine derivatives with antituberculosis activity. The structures of purines containing heteroatoms (S, O, N), fragments of heterocycles, amino acids and peptides, in the 6-position, as well as of purine nucleosides are presented. The possible targets for the action of such compounds and structure – activity relationship are discussed. Particular attention is paid to the most active compounds, which are of considerable interest as a basis for the development of efficient antituberculosis drugs. The bibliography includes 99 references.

Stereoselective acylation of racemic 3-methyl-3,4-dihydro-2Н-1,4-benzoxazine and its 7,8-difluoro-substituted analog with racemic 2-alkoxyacyl chlorides was stidied. The reactions of 3-methyl-3,4-dihydro-2H-1,4-benzoxazines with 2-methoxyisopentanoyl chloride were found to be more selective (selectivity factor s 31–32) compared to the acylation with other studied propanoyl chlorides (s 18–21). This fact was probably caused by the significant steric hindrance due to the isopropyl substituent in acyl chloride compared to the methyl group in reagents derived from propanoic acid.

4-Hydroxy-(2S)-prolines bearing 3,4-dihydro-2H-1,4-benzoxazine or 1,2,3,4-tetrahydroquinoline fragments were synthesized and studied as chiral catalysts in the Biginelli reaction. The target product ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate was obtained with 54% enantiomeric excess (ee). An increase in ee values of the reaction product up to 76% was observed in the presence of nanosized oxides SiO2–ZrO2 as heterogeneous promoters.

A series of novel (S)-amino acid derivatives bearing planar-chiral (3-acylamino-1,2-dicarba-closo-dodecaboran-1-yl)acetyl substituents was synthesized. Carboranyl amino esters were obtained in a diastereomerically pure form (according to chiral HPLC). Single crystals of individual diastereomers were studied by optical microscopy, X-ray diffraction analysis and piezoresponse force microscopy. The piezoelectric activity of some compounds was shown to exceed that of most known organic piezoelectrics.

Novel purin-6-yl, 2-aminopurin-6-yl and N-(purin-6-yl)glycyl derivatives of (S)-lysine and (S)-ornithine with free α-functional groups, as well as compounds containing N9-(2-hydroxy-ethoxy)methyl substituent in the purine core have been synthesized and tested for their inhibitory effect against Mycobacterium tuberculosis strains. Among the synthesized conjugates, one compound exhibiting a significant level of antimycobacterial activity has been found.

Studies of the antimycobacterial activity of 2-amino-6-chloropurine and its N-acyl derivatives against laboratory (Mycobacterium tuberculosis H37Rv, M. avium, M. terrae) and clinical Mycobacterium tuberculosis strains (MDR-TB) identified compounds with high tuberculostatic activity (MIC from 0.35 – 1.5 μg/ml). The cytotoxic activities of the compounds with antimycobacterial activity against human embryo fibroblasts were studied in the MTT test, which showed that the study compounds were essentially nontoxic (IC50 > 50 μM). Further chemical modification may yield compounds with potential for creating drugs for the treatment of tuberculosis. With the aim of identifying the possible mechanism of the tuberculostatic activity, the ability of the study compounds to inhibit mycobacterial serine-threonine protein kinases (STPK) was assessed. The tuberculostatic activity of 2-amino-6-chloropurine derivatives was not linked with their inhibition of STPK.

The (S,S)- and (R,R)-enantiomers of dimethyl 2,4-diphthalimidoglutarate were synthesized by nucleophilic substitution of bromine in dimethyl (2S,4RS)-4-bromo-N-phthaloyl-glutamate upon treatment with potassium phthalimide, followed by separation. The crystal structure of the obtained compounds was studied by X-ray diffraction. Crystals of enantiomerically pure dimethyl 4-hydroxy- and 4-phthalimido-N-phthaloylglutamates were found to possess a noticeable piezoelectric activity.

Local morphological features and piezoelectric properties of films and bulk crystals of ortho-carboranyl derivatives of (S)-asparagine and (S)-glutamine have been investigated at nanoscale by atomic force and piezoresponse force microscopies. Both films and bulk crystals of the studied compounds demonstrated a very high piezoelectric response exceeding that of lithium niobate. The crystal structure has been studied by single crystal X-ray diffraction.

The acylative kinetic resolution of racemic heterocyclic amines such as 3,4-dihydro-3-methyl-2H-[1,4]benzoxazines, 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine, 2-methyl-1,2,3,4-tetrahydro-quinolines and 2-methylindoline with enantiopure (R)-2-phenoxypropionyl chloride has been studied. It has been found that acylation of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine proceeds with the best stereoselectively when compared with other racemic amines. An efficient method for the preparation of (S)-3,4-dihydro-3-methyl-2H-[1,4]benzothiazine (99.4% ee) via a kinetic resolution protocol was developed. The possibility of recycling (R)-2-phenoxypropionic acid has been demonstrated.

peer-reviewed The difference in the crystal structure and growth kinetics of microtubes formed from l- and d-enantiomers of diphenylalanine dipeptide is investigated both experimentally and theoretically by computer simulation. The microtubes of l- and d-enantiomers grown simultaneously and under identical experimental conditions possess different crystallographic space groups, have essential difference in sizes, and demonstrate different growth kinetics. Computer simulation by molecular mechanics methods revealed a fundamental difference in the interaction between structural units of microtubes of different chiralities. A model describing chirality-dependent growth of microtubes is proposed. Accepted peer-reviewed

Derivatives of dicarba-closo-dodecaboranes and dicarba-nido-undecaboranes (carboranes) are of increasing interest for modern medicinal chemistry and materials science. The combination of carborane residues and amino acid fragments in one structure can serve as a basis for obtaining promising medicinal agents (primarily, for boron neutron capture therapy), as well as for design the materials with unique properties. For the first time, this review summarizes and analyzes information on the methods of preparation and possible applications of compounds combining in their structure amino acid and peptide residues and carborane clusters, their biological and physicochemical properties. Special attention is paid to the preparation of enantiopure conjugates, the chirality of which is due to both the presence of an asymmetric carbon atom in amino acid fragments and the planar chirality of the carborane cluster. We believe that this review provides comprehensive information about carborane-containing amino acids and peptides and will give a new impetus to the in-depth fundamental research in this field.

Local piezoelectric and ferroelectric properties as well as morphology of single crystals and films of two novel chiral organic compounds derived from chiral 2-methoxy and 2-amino acids have been investigated. The crystals demonstrated piezoelectric response exceeding that of lithium niobate. The piezoelectric response was registered also in compound films. Piezoelectric properties and domain structure of single crystals and films have been studied by piezoresponse force microscopy.

Novel purine and 2-aminopurine conjugates containing fragments of (S)-aspartic and (S)-glutamic acids with free α-functional groups attached via a 1,2-ethylenediamine linker at 6-position of the purine core, as well as their analogues with N9-(2-hydroxyethoxy)methyl substituent have been synthesized. Among the conjugates obtained, compounds exhibiting a significant antimycobacterial activity have been found.

A series of ribo- and deoxyribonucleosides bearing 2-aminopurine as a nucleobase with 7,8-difluoro- 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (conjugated directly or through an aminohexanoyl spacer) was synthesized using an enzymatic transglycosylation reaction. Nucleosides 3-6 were resistant to deamination under action of adenosine deaminase (ADA) Escherichia coli and ADA from calf intestine. The antiviral activity of the modified nucleosides was evaluated against herpes simplex virus type 1 (HSV-1, strain L2). It has been shown that at sub-toxic concentrations, nucleoside (S)-4-[2-amino-9-(β-D-ribofuranosyl)-purin-6-yl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine exhibit significant antiviral activity (SI > 32) on the model of HSV-1 in vitro, including an acyclovir-resistant virus strain (HSV-1, strain L2/R).

A series of novel N-(purin-6-yl)- and N-(2-aminopurin-6-yl) derivatives of heterocyclic amines was synthesized. It was found that preferred preparative method for N-(purin-6-yl) derivatives of heterocyclic amines is interaction of 6-chloropurine with heterocyclic amines without any catalyst; whereas N-(2-aminopurin-6-yl) derivatives were obtained in the moderate-to-high yields while heating 2-amino-6-chloropurine and heterocyclic amines in water in the presence of sulfuric acid.

In the search for novel efficient chiral resolving agents, we have studied the diastereoselective acylation of 3,4-dihydro-3-methyl-2 H -[1,4]benzoxazine and 7,8-difluoro-3,4-dihydro-3-methyl-2 H -[1,4]benzoxazine with acyl chlorides of 2-phenoxy carboxylic acids (2-phenoxypropionic, 2-phenoxyisovaleric, and 2-phenoxy-3-phenylpropionic) in toluene and dichloromethane at different temperatures. HPLC analysis of the acylation products showed the predominant formation of ( R ∗ , S ∗ )-diastereoisomeric amides in all cases. It was found that acylation with the studied acyl chlorides was highly stereoselective; 2-phenoxyisovaleryl chloride demonstrated the highest stereoselectivity (selectivity factor s up to 499). A model for the diastereoisomeric transition states in the interaction between racemic amine and acyl chloride is proposed.

It has been found that acyl chlorides of (S)-naproxen, N-phthaloyl-(S)-leucine, and N-tosyl-(S)-proline are efficient chiral resolving agents for the acylative kinetic resolution of racemic 3-methyl- and 3-phenyl-3,4-dihydro-3-methyl-2H-[1,4]benzothiazines. Based on the experimental results, a preparative protocol comprising the acylative kinetic resolution followed by isolation of a single (major) diastereoisomeric amide and subsequent hydrolysis of amide bond was proposed. Using this approach with various chiral resolving agents, (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine (ee >99%) were obtained. The oxidation of the corresponding diastereoisomers of the amides followed by deacylation led to the (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-dioxide (ee >97%). This method proved to be less suitable for the preparation of the (S)-enantiomer of 3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine (ee up to 93%) and its sulfone (ee 82%) which were both obtained in low yields. The loss of enantioselectivity for (S)-3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine and its sulfone occurred during hydrolysis of the corresponding diastereoisomerically pure amides.

Chemoenzymatic transglycosylation of 2-aminopurine conjugates with enantiomerically pure 7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazines under the action of recombinant E. coli purine nucleoside phosphorylase afforded the corresponding arabinofuranosides, yields of the target compounds being dependent on both the structure and configuration of the fragment of heterocyclic amine attached at C-6 position of purine moiety.

A comparative study on the kinetic resolution of racemic amines (2,3-dihydro-4H-1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline derivatives) via diastereoselective acylation with N-tosyl-(S)-prolyl chloride and its structural analogs was performed. The effect of resolving agent structure on the stereoselectivity of heterocyclic amine acylation was examined. The highest stereoselectivity was achieved in the case of acylation with acyl chlorides bearing a conformationally restricted pyrrolidine ring and an aromatic substituent in the protecting group at the nitrogen atom.

The kinetic resolution of racemic heterocyclic amines via acylation with N-tosyl-(S)-prolyl chloride was systematically investigated. It was established that racemic mixtures of aromatic amines could be resolved with high efficiency, while the acylation of 2- and 3-methylpiperidines occurred with low diastereoselectivity. A method for the preparation of enantiomerically pure (3R)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine was developed.

Novel conjugates of purine and 2-aminopurine linked with heterocyclic amines, including chiral derivatives of 3,4-dihydro-2 H -[1,4]benzoxazine, 3,4-dihydro-2 H -[1,4]benzothiazine and 1,2,3,4-tetrahydroquinoline, by 6-aminohexanoyl fragment at the 6-position of purine moiety were obtained. For this purpose, replacement of the chlorine atom in 2-amino-6-chloropurine or 6-chloropurine by direct nucleophilic substitution reaction with 6-aminohexanamides or the coupling of 6-(purin-6-ylamino)-6-hexanoic acid with nitrogen heterocycles were used.

A comparative study of the acylative kinetic resolution of racemic 2-methyl-1,2,3,4 tetrahydroquinoline and 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine using N-phthaloyl-(S)-amino acyl chlorides with alkyl side chains has been carried out. The influence of steric factors on the stereoselectivity of the acylation was demonstrated. The (S)-enantiomers of the heterocyclic amines (ee >99%) were obtained in good yields via a kinetic resolution protocol using N-phthaloyl-(S)-leucyl chloride.

The fundamental possibility of acylative kinetic resolution of racemic heterocyclic amines was demonstrated by the example of all- cis -5-(4-bromophenyl)-4- tert -butoxycarbonyl-2-methoxycarbonylpyrrolidine. Individual enantiomers ( ee >99%) were obtained in high yields via preparative chiral HPLC.

Synthetic routes to novel N-(purin-6-yl)- and N-(2-aminopurin-6-yl) conjugates with amino acids and glycine-containing dipeptides were developed. In vitro testing of 42 new and known compounds made it possible to reveal a series of N-(purin-6-yl)- and N-(2-aminopurin-6-yl) conjugates exhibiting significant antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant M. tuberculosis strain isolated from tuberculosis patients in the Ural region (Russia). N-(2-Aminopurin-6-yl)- and N-(purin-6-yl)-glycyl-(S)-glutamic acids were the most active compounds.

A series of novel N-(purin-6-yl)- and N-(2-aminopurin-6-yl) derivatives of heterocyclic amines was synthesized. It was found that preferred preparative method for N-(purin-6-yl) derivatives of heterocyclic amines is interaction of 6-chloropurine with heterocyclic amines without any catalyst; whereas N-(2-aminopurin-6-yl) derivatives were obtained in the moderate-to-high yields while heating 2-amino-6-chloropurine and heterocyclic amines in water in the presence of sulfuric acid.