Carbocyclic Moiety Research Articles

Polynorbornenes with carbocyclic substituents: A perspective approach to highly permeable gas separation membranes

Gas transport properties of two sets of polynorbornenes bearing carbocyclic substituents of different nature (cyclohexyl, norbornyl, phenyl groups, and framed oligocyclic moieties) were systematically studied. The influence of side chain carbocyclic substituents on gas permeability and separation selectivity for CO2-containing gas pairs and gaseous hydrocarbons was evaluated. It was found that the presence of carbocyclic moieties in side chains of polynorbornenes promotes the increase in gas permeability similarly to that of SiMe3 groups, with this effect being enhanced by the increase in the number of cycles in the substituents. As a result, P(CO2) of the metathesis polymer with pentacene-based substituents is equal to 1200 Barrer. Studied polynorbornenes with carbocyclic substituents displayed promising gas separation selectivities: CO2/N2 separation selectivity up to 41 (above the 2008 upper bound in the Robeson diagram) and solubility-controlled hydrocarbon separation selectivity up to 16 for the n-butane/methane gas pair. For the polymer with pentacene-based substituents, the separation of the mixture of hydrocarbons and aging were studied. The studies revealed that the mixed gas C4/C1 separation selectivity of this polymer reaches 4, and a two-time reduction of permeability occurs in 8.5 months. Therefore, the incorporation of carbocyclic groups in the side chains of polynorbornenes can be considered as an efficient strategy for the design of polymeric gas separation membrane materials.

InCl3-catalyzed intramolecular carbonyl-olefin metathesis.

An efficient and novel synthetic strategy for the generation of different carbocyclic moieties by ring closing carbonyl-olefin metathesis is reported. Herein, we describe a sustainably attractive protocol for one of the most powerful carbon-carbon bond-forming reactions, based on solvent-reduction, use of InCl3 catalyst, and microwave irradiation, affording target compounds with yields up to 96%.

Recent Advances in the Synthesis of 5'-deoxynucleoside Phosphonate Analogs.

The present review focuses on the synthesis of cyclic 5'-deoxynucleoside phosphonate analogs. The formation of various phosphonate alkyl moieties is accomplished through (i) Wittig (or HWE) type condensation to the nucleoside aldehyde moiety; (ii) nucleophilic displacement reaction using phosphonate anion or Lewis acid; (iii) Arbuzov reaction; (iv) olefin cross-metathesis between vinyl phosphonates and vinylated nucleosides; and (v) radical reaction and Pd catalyzed alkyne. For the coupling of nucleobases with cyclic moieties, the Mitsunobu reaction and Sonogashira-type cross-coupling are usually applied. For the coupling of furanose moieties with nucleobases, Vorbrüggentype condensation is generally applied. Addition reactions mediated by selenium ions are mainly applied for the coupling of carbocyclic moieties. Their biological activity results have been summarized.

Design, synthesis, AChE/BChE inhibitory activity, and molecular docking of spiro[chromeno[4,3-b]thieno[3,2-e]pyridine]-7-amine tacrine hybrids

A new series of 12 examples of spiro[chromeno[4,3-b]thieno[3,2-e]pyridine]-7-amines tacrine hybrids (3) were designed and synthesized as cholinesterase inhibitors. These new compounds were synthesized at 20-33% yields by a one-pot two-step cyclocondensation reaction of 2-aminothiophene-3-carbonitriles (1) with spiro[chroman-2,10-cycloalkan]-4-ones (2) using AlCl3 as the catalyst without solvent and under conventional thermal heating. Subsequently, these new tacrine hybrids were subjected to AChE and BChE inhibitory activity evaluation and molecular docking studies. In vitro cholinesterase assays and in silico docking indicated that all new tacrine analogs 3 were not AChE inhibitors. However, the molecules without a carbocyclic moiety geminated to the thiophene ring, i.e., spiro scaffolds that originated from cyclopentanone (3aa), cyclohexanone (3ba), and cycloheptanone (3ca) showed the highest inhibitory potency against the BChE enzyme, thereby proving to be promising candidates for evaluation in Alzheimer's disease synthetic models.

One-pot Preparation and Characterisation of Five-membered Cyclic Alcohols

Background: Over the last few years, one of the primary focuses of our research group has been the synthesis and biological evaluation CANs featuring structural and/or configurationally alterations on the carbocyclic moiety. We previously reported an enlarged group of diversely functionalized amino cyclopentenols, cyclopentenols and cyclopentenones as useful precursors in the synthesis and pos-terior biological evaluation of CANs featuring structural and/or configurationally alterations on the carbo-cyclic moiety; moreover the five-membered carbocycles are common structural units in other natural products and bioactive compounds, for this reason, these compounds presented great interest for their use as building blocks in the development of compounds with potential pharmacological activities. Method: The conversion of benzyl cyclopent-3-enocarboxylate into a mixture of the corresponding hydroxy allylic esters 5a and 5b was efficiently achieved by the employed diphenyl diselenide, H2O2 in dry CH2Cl2 for the synthesis of phenylselenenic acid and electrophilic addition to double bond of 3, and 90% tert-butyl hydroperoxide subsequently being added. Results: The mixture of compounds 5 was obtained in good yields under these conditions, and this was readily separated by column chromatography. Isolated components were identified by1H and13C NMR spectral, as well as by its EI HRMS. The corresponding alcohols 5a or 5b were easily transformed in the corresponding 3,5-dinitrobenzoyl derivatives, 6a and 6b, from which single crystals were obtained, permitting unequivocal identification. Conclusion: Using a one-pot method, benzyl cyclopent-3-enecarboxylate was turned into a mixture of corresponding hydroxy allylic derivatives 5a and 5b, employing diphenyl diselenide, H2O2 and tert-butyl hydroperoxide for the formation and subsequent oxidation/elimination of the first-generated alkyl phenyl selenides. The use of these oxidants corresponds to modern trends in organic synthesis, because they are easily available and environmentally friendly reagents, which can be used at a large scale.

Peptide carbocyclic derivatives as inhibitors of the viroporin function of RNA-containing viruses

New carbocyclic derivatives of amino acids, peptides, and other compounds have been synthesized, and their antiviral activity toward the influenza A/H5N1 and hepatitis C viruses has been studied in vitro. It has been shown that the aminoacyl derivatives of aminoadamantane are capable of inhibiting the replication of the highly virulent strain of the avian influenza virus (H5N1), which is resistant to aminoadamantanes amantadine and rimantadine. The effect of the configuration of the carbocyclic moiety of the dipeptide H-Pro-Trp-OH on the antiviral properties toward the hepatitis C virus has been studied. The cyclohexyloxycarbonyl derivative of the H-Pro-Trp-OH dipeptide strongly inhibited the replication of HCV in vitro. Some compounds have been found to exhibit a high virucidal activity toward influenza A/H5N1 and HCV virions.

Fused 1,2,3-Dithiazoles: Convenient Synthesis, Structural Characterization, and Electrochemical Properties.

A new general protocol for synthesis of fused 1,2,3-dithiazoles by the reaction of cyclic oximes with S2Cl2 and pyridine in acetonitrile has been developed. The target 1,2,3-dithiazoles fused with various carbocycles, such as indene, naphthalenone, cyclohexadienone, cyclopentadiene, and benzoannulene, were selectively obtained in low to high yields. In most cases, the hetero ring-closure was accompanied by chlorination of the carbocyclic moieties. With naphthalenone derivatives, a novel dithiazole rearrangement (15→13) featuring unexpected movement of the dithiazole ring from α- to β-position, with respect to keto group, was discovered. Molecular structure of 4-chloro-5H-naphtho[1,2-d][1,2,3]dithiazol-5-one 13 was confirmed by single-crystal X-ray diffraction. Electrochemical properties of 13 were studied by cyclic voltammetry and a complex behavior was observed, most likely including hydrodechlorination at a low potential.

Rac-BINAP-PdCl2 catalyzed Heck reactions of 3-formylquinolin-2-yl chlorides with methyl acrylate: synthesis of methyl 3-(3-formylquinolin-2-yl) acrylates

rac-BINAP-PdCl2 catalytic system catalyzed Heck reaction of 3-formylquinolin-2-yl chlorides with methyl acrylate in DMA is described to the synthesis of methyl 3-(3-formyl-quinolin-2-yl)-acrylates, in good to excellent yields. The reaction could be also extended with other activated alkenes to afford Heck products. Fused-benzene ring in heterocyclic and carbocyclic moieties was found to enhance the yields.

ChemInform Abstract: Advances in the Enantioselective Synthesis of Carbocyclic Nucleosides

AbstractReview: 60 refs.

The Role of the Chiral cis‐1,3‐Disubstituted 2,2‐Dimethylcyclobutane Motif in the Conformational Bias of Several Types of γ‐Peptides

AbstractThree series of new γ‐peptides have been synthesized by starting from conveniently protected cis‐3‐amino‐2,2‐dimethylcyclobutane‐1‐carboxylic acid derivatives. The first series is constructed with only one enantiomer of this γ‐amino acid, whereas in the second one both enantiomeric cyclobutane residues are joined in alternating fashion. The high degrees of rigidity in these γ‐peptides induce the adoption of extended but sterically constrained conformations in both cases. The third series is the product of alternation of a cyclobutane residue with linear γ‐aminobutyric acid (GABA). Conformational bias in these three systems accounts for the cyclobutane being a major disrupting factor to the formation of strong intramolecular hydrogen bonds, leading to extended conformations. In contrast, investigation of cyclobutane/GABA hybrid γ‐peptides of a fourth series, in which the carbocyclic moiety is not a part of the polyamide skeleton but acts as a chiral polyfunctional platform, reveals that these peptides are able to produce intramolecular hydrogen bonds leading to well defined folded conformations.

Advances in the enantioselective synthesis of carbocyclic nucleosides

Carbocyclic nucleosides are nucleoside analogues in which the furanosidic moiety has been replaced by a carbocycle. Several members of this family have been isolated from natural sources and include a 5-membered ring carbocycle. The aim of this review is to examine critically the different methodologies for the enantioselective construction of 3- to 6-membered rings, with a particular focus on 5-membered rings and their modifications. The procedures for bonding the heterocyclic moiety and the carbohydrate are treated separately. The methods for synthesising the carbocyclic moiety mainly focus on the construction of the cycle, although precise details about the functionalisation are provided in some cases. The selected methods aim to provide an overview of the synthesis of carbocycles related to the synthesis of carbocyclic nucleosides. The methods of synthesis of 5-membered rings are classified into two types: methods in which the cyclopentane ring is formed by ring closing reactions (C=C and C-C formation) and methods that start from preformed 5-membered rings, based mainly on cycloaddition reactions. With respect to the methods of synthesis of 3-, 4- and 6-membered ring carbocyclic nucleosides, a selection of the more relevant enantioselective procedures is presented in a systematic manner.

Synthesis of amino derivatives of 1,3,5-triazines containing hetero- and carbocyclic moieties

Reactions of chloro-sim-triazines with secondary amines containing 1,3-dioxolane and hemdichlorocyclopropane moieties were studied. Structures of amino derivatives of 1,3,5-triazines containing cyclic acetal and cyclopropane moieties were examined.

Fine Tuning of Electrostatics around the Internucleotidic Phosphate through Incorporation of Modified 2′,4′-Carbocyclic-LNAs and -ENAs Leads to Significant Modulation of Antisense Properties

In the antisense (AS) and RNA interference (RNAi) technologies, the native single-stranded 2'-deoxyoligonucleotides (for AS) or double-stranded RNA (for RNAi) are chemically modified to bind to the target RNA in order to give improved downregulation of gene expression through inhibition of RNA translation. It is shown here how the fine adjustment of the electrostatic interaction by alteration of the substituents as well as their stereochemical environment around the internucleotidic phosphodiester moiety near the edge of the minor grove of the antisense oligonucleotides (AON)-RNA heteroduplex can lead to the modulation of the antisense properties. This was demonstrated through the synthesis of various modified carbocyclic-locked nucleic acids (LNAs) and -ethylene-bridged nucleic acids (ENAs) with hydroxyl and/or methyl substituents attached at the carbocyclic part and their integration into AONs by solid-phase DNA synthesis. The target affinity toward the complementary RNA and DNA, nuclease resistance, and RNase H elicitation by these modified AONs showed that both the nature of the modification (-OH versus -CH(3)) and their respective stereochemical orientations vis-a-vis vicinal phosphate play a very important role in modulating the AON properties. Whereas the affinity to the target RNA and the enzymatic stability of AONs were not favored by the hydrophobic and sterically bulky modifications in the center of the minor groove, their positioning at the edge of the minor groove near the phosphate linkage resulted in significantly improved nuclease resistance without loss of target affinity. On the other hand, hydrophilic modification, such as a hydroxyl group, close to the phosphate linkage made the internucleotidic phosphodiester especially nucleolytically unstable, and hence was not recommended. The substitutions on the carbocyclic moiety of the carba-LNA and -ENA did not affect significantly the choice of the cleavage sites of RNase H mediated RNA cleavage in the AON/RNA hybrid duplex, but the cleavage rate depended on the modification site in the AON sequence. If the original preferred cleavage site by RNase H was included in the 4-5nt stretch from the 3'-end of the modification site in the AON, decreased cleavage rate was observed. Upon screening of 52 modified AONs, containing 13 differently modified derivatives at C6' and C7' (or C8') of the carba-LNAs and -ENAs, two excellent modifications in the carba-LNA series were identified, which synergistically gave outstanding antisense properties such as the target RNA affinity, nuclease resistance, and RNase H activity and were deemed to be ideal candidates as potential antisense or siRNA therapeutic agents.

An Efficient Synthesis of Phosphonate Derivatives of 1,2-Disubstituted Carbocyclic Purine Nucleosides with a Cyclopentane Ring

The synthesis of phosphonate 1,2-disubstituted carbocyclic nucleosides with a cyclopentane ring is described following two different strategies: inclusion of the phosphonomethyl group before or after coupling of the carbocyclic moiety with the heterocyclic base. The diethyl [(trifluoromethanesulfonyl)oxy]methanephosphonate is the key phosphonylating agent for both the strategies.

Convergent or Linear? A Challenging Question in Carbocyclic Nucleoside Chemistry

North-methanocarbathymidine (N-MCT) is a carbocyclic nucleoside analogue with potent anti-HSV and KSHV activity. The critical step in the synthesis of N-MCT and other carbocyclic nucleoside analogues is the introduction of the nucleobase into the carbocyclic moiety. For this, convergent and linear strategies were compared side by side. In the convergent approach, the base was coupled to the carbocyclic moiety by either a Mitsunobu reaction or by displacement of a mesylate. This strategy leads to the formation of various amounts of the O 2 -regioisomer, depending on the applied procedure. Additionally, by-products of the Mitsunobu reaction have to be separated from the coupling products. Although lengthier, the linear strategy leads selectively to the target compound N-MCT with overall yields comparable to the convergent approaches, making this strategy more compatible for future large-scale syntheses.

Regioselective synthesis of O2- and O6-cyclopyrimidine nucleoside analogues

Regioselective synthesis of two new series of cyclonucleoside analogues from the 1,2-carbonucleoside of uracil 1a: O 2,7′-cyclonucleosides ( 3a– c) and O 6,7′-cyclonucleosides ( 4a– c), analogues of pyrimidine (cyclohexane derivatives) is reported. Synthesis of O 2-cyclonucleoside analogues was performed by activation of the hydroxymethyl group of carbocyclic moiety and using the carbonyl group at position 2 of the heterocyclic base as a nucleophile. Synthesis of O 6-cyclonucleoside analogues was achieved by nucleophilic attack of the 7′-hydroxyl group on the electron-deficient 6-position and subsequently dehydrohalogenation in basic conditions.

Enantiomeric synthesis of carbocyclic analogs ofD- andL-6-azapyrimidine ribonucleosides

An effective and practical synthesis of carbocyclic D- and L-6-azapyrimidine nucleosides (3–8) was described. Starting from D-ribose, a new efficient methodology for the synthesis of L-2,3-O-cyclohexylidene-4-cyclopentenone (23) was developed via a ring-closing metathesis, which was applied for the synthesis of L-cyclopentyl-6-azapyrimidine nucleosides (6–8). The regiospecific introduction of 6-azauracil on the carbocyclic moiety (9 and 25) was also achieved by masking its N3position with a 4-methylthio group.Key words: carbocyclic nucleosides, 6-azapyrimidine nucleosides, enantiomeric synthesis.

O-confusion approach in construction of carbaporphyrinoids

Carbaporphyrinoids provide a suitable macrocyclic platform for organometallic investigations providing unique capabilities for reversible modifications of a macrocyclic structure. Alteration of a coordination core is the route of choice for stabilizing unusual metal ion oxidation states and coordination geometries. This concise review presents the general characteristic of carbaporphyrinoid focusing, however, on oxaporphyrin derivatives. Incorporation of a furan ring into a porphyrin frame results in the formation of 21-oxaporphyrin or its O-confused counterpart. This particular couple, constructed applying the O-confusion concept, was selected to illustrate the developments in the field of carbaporphyrinoids. The coordination chemistry in the O-confused porphyrin surrounding takes advantage of the unique set of four meridional donor atoms (CNNN) constrained in the regular porphyrin-like framework. The subtle interplay between their structural flexibility, perimeter substitution, coordination, and aromaticity was detected for oxacarbaporphyrinoids. The oxidation state of a central metal ion is a factor, which determines the ligand molecular structure. The adjacency of the metal and carbon atom provides the unprecedented route for activation of the carbocyclic moiety, which is built into a metalloporphyrin-like structure. The perspectives of the field have also been briefly discussed including feasible applications as a new class of building blocks applied to control both the architecture and electronic properties of oligoporphyrinic nanostructures.

SYNTHESIS OF A NEW N-9 RIBITYL ANALOGUE OF CYCLIC INOSINE DIPHOSPHATE RIBOSE (cIDPR) AS A MIMIC OF CYCLIC ADP RIBOSE (cADPR)

A new analogue of cyclic inosine diphosphate ribose (cIDPR), in which the N-1 and N-9 ribosyl moieties were substituted by a carbocyclic moiety and a hydroxyl-alkyl chain, has been synthesized and characterized.

Effect of sulfide structure on enantioselectivity in catalytic asymmetric epoxidation of aldehydes: mechanistic insights and implications.

Bridged bicyclic sulfide 1 was originally found to provide high levels of asymmetric induction in sulfur ylide-mediated epoxidations. This sulfide possesses chirality in the [2.2.1] thioether moiety and the [2.2.1] camphor-derived carbocyclic moiety. To determine whether the optimal sulfide had been used, a diastereomer of sulfide 1 in which the stereochemistry of the [2.2.1] carbocycle was reversed (sulfide 5) was prepared and studied as an epoxidation catalyst. This diastereomer gave considerably lower levels of asymmetric induction than the original sulfide 1. From computational and x-ray studies it was found that sulfide 5 gave rise to a more hindered ylide, which reacted more reversibly with aldehydes leading to lower enantioselectivity. Conditions that reduced reversibility were also tested and high enantioselectivities were returned for sulfide 5 (similar to sulfide 1). The implications for the synthesis of chiral sulfides for asymmetric epoxidations are discussed.