Search

Pictet–Spengler cyclization method has been adopted for the synthesis of three carboline derived compounds: two compounds with tetrahydro gama- and beta-having CF3 group and amino alkyl chain at delta and alpha position, respectively, and another with guanidine alkyl chain at alpha-position. Structure–activity relationship of the analogues with human serum albumin was studied by fluorescence and Fourier-transform infrared spectroscopy followed by molecular docking. The data showed maximum affinity of human serum albumin with comp7 (S0-820) followed by comp3 (S0-1040) and least with comp1 (S0-728). The compounds were tested for cytotoxic potencies. Comp3, showed maximum cytotoxicity with GI50 6.2 µM, against HCT-116, followed by comp7, and poor cytotoxicity with comp1. Comp3 and 7 induced oxidative stress mediated autophagy led programmed cell death in HCT-116. Furthermore, the compounds effectively inhibit DNA topoisomerase I activity and showed anti-inflammatory actions. In vivo studies regarding therapeutic protective action of Comp3, as a representative carboline analogue, against colon toxicant, 1,2-dimethylhydrazine dihydrochloride (DMH), showed the efficacy of the compound against organ toxicity. The existing studies on biological evaluation showed that these synthetic compounds may have a major role as anticancer agents having myriad of proven therapeutic applications. Communicated by Ramaswamy H. Sarma HighlightsStructure-activity relation showed maximum affinity of HSA with comp7 followed by comp3 and least with comp1.Comp3 and 7 induced oxidative stress mediated autophagy led programmed cell death in HCT-116.The compounds effectively inhibit DNA topoisomerase I activity and showed anti-inflammatory actionsIn vivo studies showed the efficacy of the compound against megacolon condition. Structure-activity relation showed maximum affinity of HSA with comp7 followed by comp3 and least with comp1. Comp3 and 7 induced oxidative stress mediated autophagy led programmed cell death in HCT-116. The compounds effectively inhibit DNA topoisomerase I activity and showed anti-inflammatory actions In vivo studies showed the efficacy of the compound against megacolon condition.

A new method for the synthesis of perfluoroalkylated derivatives of γ-carboline and pyrrolopyrazine was elaborated. Pictet–Spengler reaction of isotryptamine and 2-(pyrrol-1-yl)ethanamine with trifluoromethylated carbonyls and 2-perfluoroalkyl-substituted five-, six-, and seven-membered cyclic imines was studied. It was found that this approach opens efficient access to a family of alkaloid-like compounds bearing a CF3 or C2F5 group in the structure. In the case of the iso-Pictet–Spengler reaction with 2-perfluoroalkyl-substituted cyclic imines, a series of γ-carbolines bearing an aminoalkyl group were prepared.

An efficient three-step synthesis of a novel family of enantiomerically pure isocyanides derived from β3-isocyanopropionic acids was elaborated. Easily available N-formylated α-amino acids were used as starting materials towards this aim. The 3-step sequence (Arndt-Eistert reaction-Wolff rearrangement-dehydration) resulted in target isonitriles in good yields (up to 97%). As a result a new family of isocyanides bearing a fragment of β3-amino acids with different functional groups (amides, esters and short peptides) was obtained. It was demonstrated that these new isonitriles can be used in the Ugi and Passerini reactions to prepare short peptides and depsipeptides having a β-amino acid fragment incorporated.

The Ugi-click-strategy was employed for the synthesis of 12–28 membered 1,2,3-triazole derived macrocyclic peptidomimetics. The Ugi reaction with acid components bearing acetylenic fragments and azidoisocyanides provided the corresponding peptidomimetics in up to 97% isolated yield. The subsequent CuAAC click reaction with these bifunctional substrates containing both acetylene and azide groups was investigated to reveal the influence of the structure of Ugi products on the direction of the click-cyclization. It was demonstrated that this approach allows efficient synthesis of either monomeric (12- and 13-membered) or dimeric (24-, 26- and 28-membered) macrocycles prepared in up to 85% yield. The scope and limitations of this method are discussed.

Enantioselective synthesis of α-perfluoroalkylated cyclic amino acids and their derivatives was elaborated using the organocatalytic Strecker reaction with 5-7 membered cyclic ketimines. The prepared amino nitriles could be transformed into chiral Rf-prolines and their 6,7-membered homologues as well as their corresponding amides and diamines (yields up to 99%, up to >99% ee).

Three sets of carboline derived compounds were prepared by Pictet-Spengler cyclization. These tetrahydro β- and γ-carbolines have CF3 group with an additional amino alkyl chains (α- or δ-position) and guanidine alkyl chains (α-position), of varying length. Structure–activity relationship of these molecules with calf thymus DNA was emphasized by fluorescence, ITC, FTIR and viscosity. Binding with DNA resulted in dramatic enhancement and quenching in the fluorescence emission. Gamma-carboline analogs showed maximum DNA binding followed by beta-carboline compounds with amino alkyl chain and least with guanidine alkyl chain compounds. It decreased with increasing chain length. The bindings were entropically driven being more with guanidine alkyl chain analogs. Site preference and mode of binding with partial intercalation and external binding was supported by FTIR and viscosity. Cytotoxic potencies of the compounds were tested on seven different cancer cell lines. The smallest alkyl chain analog attached to gamma position, Comp3, showed maximum cytotoxicity with GI50 6.2 µM, against HCT-116 causing apoptosis, followed by the guanidine alkyl chain compounds, but amino alkyl chain compounds to beta position showed poor cytotoxicity. These results may be of prospective use in a framework to design novel carboline derivatives as antitumor drugs for improved therapeutic applications in future.

The reaction between 2-trimethylsilyloxyfuran and perfluoroalkylated cyclic ketimines with different ring sizes affords 5-(2-perfluoroalkyl-1-azacycloalk-2-yl)furan-2(5H)-ones in yields up to 89% and with excellent rel-(R,R)-diastereoselectivity.

CF3-Substituted ketimines synthesized from trifluoroacetone, hexafluoroacetone, and trifluoroacetophenones were studied in aza-Henry reactions with nitroalkanes. We found that nitromethane and nitropropane react with CF3-substituted ketimines to form the target β-nitroamines in high yield. The aza-Henry reaction proceeded under mild conditions in the presence of an appropriate base. A new simple method for the synthesis of β-nitroamines bearing CF3 group was developed. α-CF3-β-nitroamines can easily be converted into trifluoromethylated 1,2-diamines, α-aminooximes, and imidazolidinones.

The reaction of 2-perfluoroalkyl-substituted cyclic imines with arylhydrazines was investigated. We found that 2-perfluoroalkylated cyclic imines are highly reactive electrophiles that form, through ring opening, the corresponding hydrazones bearing an amine group at the end of the alkyl chain. Subsequent acidic treatment resulted in a Fischer rearrangement. Thus, a new synthesis of 2-perfluoroalkylated tryptamines and their homologues through a Fischer reaction was developed. The possibility of modification of the indole core of the 2-CF3-substituted tryptamine products was demonstrated, and various 2-trifluoromethylated tryptamines substituted at the 5-position were prepared.

The challenges of the modern society and the growing demand of high-technology sectors of industrial production bring about a new phase in the development of organic synthesis. A cutting edge of modern synthetic methods is introduction of functional groups and more complex structural units into organic molecules with unprecedented control over the course of chemical transformation. Analysis of the state-of-the-art achievements in selective organic synthesis indicates the appearance of a new trend — the synthesis of organic molecules, biologically active compounds, pharmaceutical substances and smart materials with absolute selectivity. Most advanced approaches to organic synthesis anticipated in the near future can be defined as 'atomic precision' in chemical reactions. The present review considers selective methods of organic synthesis suitable for transformation of complex functionalized molecules under mild conditions. Selected key trends in the modern organic synthesis are considered including the preparation of organofluorine compounds, catalytic cross-coupling and oxidative cross-coupling reactions, atom-economic addition reactions, methathesis processes, oxidation and reduction reactions, synthesis of heterocyclic compounds, design of new homogeneous and heterogeneous catalytic systems, application of photocatalysis, scaling up synthetic procedures to industrial level and development of new approaches to investigation of mechanisms of catalytic reactions. The bibliography includes 840 references.

Optically active α-(tetrazol-1-yl)-substituted carboxylic acid OBO-esters were synthesized from the corresponding a-isocyano OBO-esters and trimethylsilyl azide in up to 92% yield. Subsequent acidic hydrolysis proceeds without epimerization and makes it possible to prepare enantiomerically pure α-(tetrazol-1-yl)-substituted carboxylic acids in up to 89% yield.

The reaction of 2-alkyl-substituted 5-, 6- and 7-membered cyclic imines with a-bromo ketones in the presence of Hunig's base affords 2,3-dihydro-1 H -pyrrolizines, 5,6,7,8-tetrahydroindolizines and 6,7,8,9-tetrahydro-5 H -pyrrolo[1,2- a ]azepines, respectively.

The aza-Henry addition of nitroalkanes at ketimines derived from trifluoropiruvate affords the corresponding α-nitro amines in up to 98% yields.

Aza-Henry reaction of 5-, 6- and 7-membered cyclic imines bearing perfluorinated group with nitroalkanes affords the corresponding nitro amines in up to 95% yield. Subsequent reduction of nitro group gives perfluoroalkyl-equipped vicinal diamines.

The application of perfluoroalkylated cyclic imines in azido-Ugi reactions was studied. It was shown that the reaction allows access to five-, six- and seven-membered perfluoroalkylated cyclic amines connected to a tetrazole ring. The scope and limitations of this approach are discussed. When benzyl isocyanide was used in the azido-Ugi reaction, it was shown that the tetrazole products could easily be debenzylated by catalytic hydrogenation to form 1H-tetrazoles in excellent yields.

A Friedel–Crafts-type alkylation reaction was studied between various pyrroles and α-polyfluoroalkylated cyclic imines that were activated by Lewis acids. The reaction proceeded under mild conditions and provided a high yielding synthesis of α-CF3-substituted pyrrolidines and piperidines as well as seven-membered analogues that contained a pyrrole ring. The unpredictably high β-selectivity for the aminoalkylation of both 1H-pyrrole and N-substituted pyrrole was observed as a result of a thermodynamically-controlled electrophilic substitution reaction. The computational data are in full agreement with the experimental results, which confirmed the observed regioselectivity as a result of the lower energy of the β-substituted pyrroles that contain α-trifluoromethyl-substituted pyrrolidine, piperidine, and azepane rings.

The reaction of cyclic ketimines with indoles was studied. A dramatic difference between the electrophilicity of perfluoroalkyl-substituted and non-fluorinated imines was demonstrated. In good agreement with our calculations, the Friedel–Crafts-type alkylation of indoles only takes place with α-polyfluoroalkylated cyclic imines that are activated by boron trifluoride–diethyl ether. The reaction proceeds under mild conditions and provides the opportunity to obtain promising alkaloid-like structures that contain a fluoroalkyl group. As a result, α-CF3- and α-C2F5-substituted pyrrolidines, piperidines, and azepanes that contain an indole moiety can be prepared efficiently.

We have evaluated a range of functionalized isocyanides in the aziridine aldehyde-driven multicomponent synthesis of piperazinones. High diasteroselectivity for each isocyanide was observed. A theoretical evaluation of the reaction course corroborates the experimental data. Moreover, the reactivity of cis- and trans-configured aziridine aldehyde dimers has been compared. This study further probes the dimer-driven mechanism of cyclization and enables an efficient access to a wide range of chiral piperazinones bearing functionalized side chains.

An efficient (one- and two-step) synthesis of trifluoromethylated derivatives of the natural alkaloids nazlinine, trypargine, and homotrypargine was elaborated. Trifluoromethyl-substituted 5–7-membered cyclic imines were used as a masked carbonyl component in the Pictet–Spengler reaction with various tryptamines. As a result, this approach opens access to a family of alkaloid-like compounds bearing a CF3 group at position 1 of tetrahydro-β-carboline.

We have evaluated a range of functionalized isocyanides in the aziridine aldehyde-driven multicomponent synthesis of piperazinones. High diasteroselectivity for each isocyanide was observed. A theoretical evaluation of the reaction course corroborates the experimental data. Moreover, the reactivity of cis- and trans-configured aziridine aldehyde dimers has been compared. This study further probes the dimer-driven mechanism of cyclization and enables an efficient access to a wide range of chiral piperazinones bearing functionalized side chains.

CF3-Substituted ketimines synthesized from trifluoroacetone, hexafluoroacetone, and trifluoroacetophenones were studied in aza-Henry reactions with nitroalkanes. We found that nitromethane and nitropropane react with CF3-substituted ketimines to form the target β-nitroamines in high yield. The aza-Henry reaction proceeded under mild conditions in the presence of an appropriate base. A new simple method for the synthesis of β-nitroamines bearing CF3 group was developed. α-CF3-β-nitroamines can easily be converted into trifluoromethylated 1,2-diamines, α-aminooximes, and imidazolidinones.

The reaction of 2-perfluoroalkyl-substituted cyclic imines with arylhydrazines was investigated. We found that 2-perfluoroalkylated cyclic imines are highly reactive electrophiles that form, through ring opening, the corresponding hydrazones bearing an amine group at the end of the alkyl chain. Subsequent acidic treatment resulted in a Fischer rearrangement. Thus, a new synthesis of 2-perfluoroalkylated tryptamines and their homologues through a Fischer reaction was developed. The possibility of modification of the indole core of the 2-CF3-substituted tryptamine products was demonstrated, and various 2-trifluoromethylated tryptamines substituted at the 5-position were prepared.

Treatment of 5-, 6- and 7-membered cyclic ketimines bearing alkyl or aryl group with m-chloroperbenzoic acid proceeds as C=N epoxidation and affords bicyclic oxaziridines in good yields, whose subsequent rearrangement gives nitrones.

Oxidative Nef reaction of 2-nitroalkanamines or N -(2-nitroalkyl)carboxamides bearing trifluoromethyl group affords amino acids, amino ketones or hydroxyhydantoins depending on structure of the starting compounds.

A new route to tetrazole-derived cyclic amines based on the TMSN3-modified Ugi reaction with 2-substituted cyclic imines was elaborated. The reaction allows the direct preparation of five-, six-, and seven-membered cyclic amines substituted with a tetrazole ring, which are important types of organocatalysts. The scope and limitations of this method are discussed. In the case of the Ugi reaction with benzyl isocyanide, the N-substituted tetrazoles can be easily debenzylated under catalytic hydrogenation conditions to form NH-tetrazoles in quantitative yields. It was demonstrated that both enantiomers of tetrazole-derived cyclic amines can be prepared by resolution with tartaric acid, thereby initiating a simple route to chiral derivatives. One of the obtained chiral tetrazoles was efficiently used as an organocatalyst in the amination reaction.

The reaction of natural amino acid-derived pyrroles of type (I) with CF3-substituted cyclic imines of type (II) proceeds selectively at the β-position of the pyrrole moiety.

Natural amino acid-derived ethyl 2-(1-pyrrolyl)alkanoates react with 2-trifluoromethyl-1-azacycloalkenes selectivity at the b-position of the pyrrole moiety to afford ethyl 2-[3-(1-trifluoromethyl-2-azacycloalkyl)pyrrol-1-yl]alkanoates.