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The data on the reactions of various classes of functionalized alkynyl cyclopropanes that proceed with simultaneous participation of triple bond, three-membered ring, and functional group at a cyclopropane ring are systematized. The syntheses of polysubstituted and fused furans and indoles based on electrophile-induced and catalytic transformations of alkynyl cyclopropyl carbonyl compounds and their derivatives are considered separately. The methods for isomerization of 1-alkynyl cyclopropanols and their ethers to 3-methylenecyclobutanones are described. Information on the reactions of other types of alkynyl cyclopropanes containing one or more functional groups at three-membered ring leading to different acyclic, carbo-, and heterocyclic compounds is given. Transformations of alkynyl cyclopropanes lacking the functional groups, which simultaneously involved the cyclopropane ring and the alkynyl fragment, are also discussed. [ABSTRACT FROM AUTHOR]

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. While numerous synthetic approaches exist, the development of atom-/step-economic and practical methods for the chemodivergent assembly of diverse ortho-functionalized phenols based on fixed catalyst/substrates remains challenging. Here, by selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3-dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Experimental and computational mechanistic studies reveal that distinct catalytic modes involving selective β-C/β-H elimination, π-allylation, inter-/intramolecular nucleophilic substitution cascade and β-H' elimination processes enabled by different solvent-mediated and coupling partner-controlled reaction conditions are crucial for achieving chemodivergence, among which a structurally distinct Rh(V) species derived from a five-membered rhodacycle is proposed as the corresponding active intermediates. Ortho functionalisation of phenols can be achieved using N-phenoxy amide directing groups. Here a method for chemodivergent C-H alkenylation, alkylation, carboetherification, or [3 + 2] annulation is presented, with product selectivity determined by the choice of solvent. [ABSTRACT FROM AUTHOR]

HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PRWT) and highly-multi-PI-resistance-associated PRDRVRP51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier. [ABSTRACT FROM AUTHOR]

Rationale: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.Objective: In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.Methods: Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.Results: ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.Conclusions: These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens. [ABSTRACT FROM AUTHOR]

Recently, a number of fentanyl analogs have been implicated in overdose deaths in Europe and in the US. So far, little is known of the molecular behavior of the structurally related subgroup; the alicyclic fentanyls. In this study, reference standards of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2,2,3,3-tetramethylcyclopropyl fentanyl (TMCPF) at a final concentration of 5 µM were incubated with cryopreserved human hepatocytes (1 × 106 cells/mL) for 0, 1, 3 and 5 h. The metabolites formed were identified by liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. The most abundant biotransformation found was N-dealkylation (formation of normetabolites) and oxidation of the alicyclic rings. As ring size increased, the significance of N-dealkylation decreased in favor of alicyclic ring oxidation. An example of this was cyclopropyl fentanyl, with a three-carbon ring, whose normetabolite covered 82% of the total metabolic peak area and no oxidation of the alicyclic ring was observed. In contrast, TMCPF, with a seven-carbon ring structure, rendered as much as 85% of its metabolites oxidized on the alicyclic ring. Other biotransformations found included oxidation of the piperidine ethyl moiety and/or the phenethyl substructure, glucuronidation as well as amide hydrolysis to form metabolites identical to despropionyl fentanyl. Taken together, this study provides a base for understanding the metabolism of a number of structurally related fentanyl analogs formed upon intake. [ABSTRACT FROM AUTHOR]

In order to track the source of duplicated peaks in the 1H-NMR spectrum of Ticagrelor, variable-temperature NMR (VT-NMR) experiment was carried out with temperature increasing from 300 to 343 K. The result showed that the phenomenon was brought forth by coexistence of conformational isomers. Subsequently, conformational search was carried out by molecular mechanics (MM) stimulations associating with quantum mechanics (QM) calculations. The results revealed that the isomers resulting in duplicated proton peaks were introduced by the rotation of 2,4-diflurophenyl group on C3’position of cyclopropyl. Finally, noncovalent interaction (NCI) topological analysis of the conformers exhibited that CH-π interactions and H-bonds play important roles in controlling the population of conformers of ticagrelor. [ABSTRACT FROM AUTHOR]

Interactions and natural bond orbital analysis of cyclopropylpiperazine(cppp) and B- or Al-doped C60 fullerenes are investigated by quantum mechanical calculations. The structural and electronic properties, such as NH stretching vibrations, nuclear magnetic shielding tensors of 27Al and 11B nuclei or the energy gap are also investigated. All calculations are carried out in the gas phase and water media. Results of the bond order and the binding energy suggest that chemisorption occurs between the cppp nitrogen atom and boron or aluminum atoms of fullerenes. The Alcomplex in water is foundto have the highest binding energy. Further, AlC59...cppp complexes have a slightly higher kinetic stability and a low chemical reactivity. However, BC59...cppp works as a function-type sensor for cppp. [ABSTRACT FROM AUTHOR]

New schemes of synthesis of (2S)-4-methyl- and (2S)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-carbaldehydes have been developed with the goal of obtaining C22-C27 fragments of fijianolides and their synthetic analogs on the basis of transformations of cyclopropanol intermediates. The C22-C27 block of fijianolides A and B has been synthesized. [ABSTRACT FROM AUTHOR]

The molecular structure and conformational behavior of 3-cyclopropyl-1,2-dimethyldiaziridine have been for the first time experimentally studied by gas-phase electron diffraction and quantum chemical calculations. The two most stable conformers at 298 K possess anti and gauche mutual ring orientation (with prevalence of the anti conformer) whereas only one anti conformer is observed in solution. The determined structural parameters of gaseous 3-cyclopropyl-1,2-dimethyldiaziridine have been compared with those for 3,3-bidiaziridine structural analogues in the crystal phase. The simple and convenient procedure for the synthesis of 3-cyclopropyl-1,2-dimethyldiaziridine comprising cyclopropane and diaziridine rings in one molecule was developed. The standard enthalpy of formation of 3-cyclopropyl-1,2-dimethyldiaziridine in the gas phase was calculated using Gaussian-4 theory, yielding value of 281.9 ± 5.0 kJ/mol. [ABSTRACT FROM AUTHOR]

The reduction of 2-cyclopropylcarbonyl-, 2-(thiophen-2-yl)carbonyl-, and 2-arylcarbonylbenzonitriles with sodium tetrahydridoborate afforded 3-cyclopropyl-, 3-(2-thiophen-2-yl)-, and 3-arylphthalides, respectively, in high yields. Under analogous conditions, 3-cyanobenzophenones were converted to the corresponding 3-cyanobenzhydrols. [ABSTRACT FROM AUTHOR]

In the scope of a broader study focused on glutamate receptors regulators, we have been engaged in synthesis, analysis and pharmacological characterization of rigid analogues of glutamic acid. These compounds exhibited the bioisosteric replacement of the distal carboxylic group with the sulfonic one. Besides the sophisticated synthetic approach, we targeted preparation of a series of cyclopropyl-containing sulfonyl amino acids and development of a chromatographic enantioselective method suitable for distinguishing and quantifying the resulting isomers. Due to chelating ability, the chiral ligand-exchange chromatography (CLEC) was used for diastereo- and enantioseparation of the synthesized compounds. The CLEC-based enantioseparation was achieved by using a chiral mobile phase (CMP) system with N,N-dimethyl-( S)-phenylalanine [(S)-DMP] as the chiral selector. Only one of the investigated enantiomeric pairs was undiscriminated with the employed CLEC-CMP system which, very importantly, produced the simultaneous diastereo- and enantioseparation of two compounds of the series. Furthermore, the large α and RS values computed for three enantiomer pairs could be a good basis for a successful scale-up to a semi-preparative level. [ABSTRACT FROM AUTHOR]

The crystal structures of 4-cyclopropyl-1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole, 1, and ethyl 1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole-4-carboxylate, 2, are reported. The two molecules are non-planar as indicated by the dihedral angles between the heteroaryl rings of 53.94 (7)° in 1 and 70.68 (12)° in 2. Considerable delocalization of π -electron density within the triazole ring is indicated by the pattern of bond distances in 1. By contrast to 1, localization of π -electron density within the triazole ring in 2 is apparent. In both molecules, the nitro group takes part in N-O···π(imidazole) interactions. Compound 1 crystallizes in the orthorhombic space group P222 with a = 7.8053(3) Å, b = 8.5264(3) Å, c = 15.7343(11) Å and Z = 4. Compound 2 crystallizes in the monoclinic space group, P2/ c wit h a = 5.2740(4) Å, b = 8.9695(5) Å, c = 26.0080(18) Å, β = 92.622(2)° and Z = 4. Graphical Abstract: The bond lengths indicate more bond fixation in the triazole rings of ethyl 1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole-4-carboxylate and more delocalization in 4-cyclopropyl-1-(1-methyl-4-nitro-1 H-imidazol-5-yl)-1 H-1,2,3-triazole. [ABSTRACT FROM AUTHOR]

Permethrin, cypermethrin and cyfluthrin are three important pyrethroids with similar structures and contain four, eight and eight stereoisomers, respectively. All the stereoisomers were completely resolved by a combination of achiral and chiral high-performance liquid chromatography with hexane/isopropanol as the mobile phase. The absolute configurations for the stereoisomers were also assigned on the basis of enantioselective resolution of permethrinic acid. For cypermethrin and cyfluthrin, although there is the only difference being one F atom substitution in cyfluthrin, the cis-I diastereomer exhibited a reversal of enantiomer order. Three specific stereoisomers were further isolated to investigate the photolysis and chiral stability of synthetic pyrethroids at the enantiomeric level. The results clearly revealed that significant isomerization occurred along with the photolysis process. The isomerization occurred at chiral 1-C position, 3-C position or both in the cyclopropyl ring, and the chiral 3-C exhibited a higher inversion tendency. [ABSTRACT FROM AUTHOR]

Novel extended fluorescent styryl derivatives were synthesized from (E)-3-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)acrylaldehyde containing quinoline ring with 4-fluorophenyl ring at the 4-position as an electron donor and different active methylene compounds as electron acceptors by conventional Knoevenagel condensation reaction. The UV-Visible absorption and fluorescence emission spectra of the dyes were studied in solvents of differing polarity and the compounds showed polarity sensitive emission properties. The dyes were characterized by the spectral analysis. Thermogravimetric analysis showed these dyes are thermally stable up to 250 °C. Density Functional Theory computations have been used to derive more understanding of structural, molecular, electronic and photophysical parameters of the push-pull dyes. The computed absorption wavelength values are found to be in good agreement with the experimental results. The second order hyperpolarizability ( β) values were computed by Density Functional Theory and found to be in the range of 116.61 × 10 to 898.48 × 10 e.s.u. [ABSTRACT FROM AUTHOR]

Bicyclo[4.1.0]heptenes, which are readily accessible molecules via the transition metal-catalyzed cycloisomerization of 1,6-enynes, and have served as useful building blocks in organic synthesis. These molecules can undergo a variety of ring-opening reactions given that the release of the cyclopropyl ring strain (27.5 kcal/mol) may serve as a thermodynamic driving force for reactions, and the double bond within the skeleton can afford the kinetic opportunity to initiate the ring-opening via a coordination to a metal species. Even though the chemistry of the cyclopropyl group has been widely explored in organic chemistry, less attention has been paid to the chemistry of bicyclo[4.1.0]heptenes. However, during the past 5 years, we have been engaged in the exploration of the chemistry of bicyclo[4.1.0]heptenes. This review describes the chemistry developed in our laboratory. Depending upon the position, number, and identity of the substituent(s), the identity of the tether group, and the nature of the catalytic system, bicyclo[4.1.0]heptenes can undergo a variety of transformations. Our studies have revealed the reaction patterns of bicyclo[4.1.0]heptenes which include thermal reactions, nucleophilic addition, and rhodium-catalyzed reactions, that can proceed both with and without opening of the cyclopropyl ring. The chemistry described in this review can be used to produce a variety of new compounds such as 2,4-pentadienals, 3-methylene-4-vinylcyclohex-1-enes, bicyclo[3.2.2]nonadienes, 1,6,7,9a-tetrahydrocyclohepta[c] pyrans and -pyridines, hexahydroisoquinolines, 4-oxa-6-azatricyclo[3.3.0.0]octanes, and heterotricyclo[3.3.1.0]nonanes. [ABSTRACT FROM AUTHOR]

A flexible method for synthesis of laurencione, a marine natural product, and its benzyl and tert-butyl-methylsilyl-protected precursors was developed utilizing 3-hydroxypropionic acid ethyl ester as a starting material. The synthetic route consists of Kulinkovich cyclopropanation of a hydroxyl-protected ester, followed by oxidation of the resulting cyclopropanol to the appropriate oxiranyl ketone and its MgBr∙OEt-catalyzed rearrangement to 1,2-diketone. [ABSTRACT FROM AUTHOR]

Simple and efficient asymmetric syntheses of several lactones with the use of methyl (5 R)-5-hydroxy-3-methylidenedecanoate as a polyfunctional building block are described. [ABSTRACT FROM AUTHOR]

Valley-ridge inflection points (VRI) on the potential energy surface for the ring opening of the cyclopropyl radical to the allyl radical are determined using the tool of Newton trajectories (NTs) (Quapp and Schmidt in Theor Chem Acc 128:47, ). The UHF surface is treated in a former paper (Quapp et al. in Theor Chem Acc 129:803, ). This paper is the extension to the more expensive CASSCF(3,3) surface. We compare the results on the UHF surface with the more appropriate calculation: there are quantitative as well as qualitative changes, of course. But many fundamental relations are the same on both surfaces. However, we could detect new pathways on the CASSCF(3,3) surface which highlight the bifurcation problem of this radical. VRIs play a role in the understanding of bifurcating reactions. The region where the bifurcation takes place is governed by a VRI point. Because the transition state of the ring opening is not symmetric, the steepest descent (SD) from the transition state is not along a symmetry axis either, and in this case the SD usually fails a downhill VRI point. The SD from the transition state of the ring opening goes to the disrotatory minimum of the allyl radical. In contrast, we find some pathways which end at the conrotatory minimum, and which go along so-called non steepest descent paths, at least in parts. The region of interest (around the SP of the ring opening) is crossed by electronic intersection seams. Conical intersection points on the seam can be detected by NTs. We use the possibility to explore parts of the intersection seam of the lower CAS surface and we determine connected VRI points being the corner stones of the possible ring opening channels in the disrotatory and the conrotatory case. [ABSTRACT FROM AUTHOR]

Edessa meditabunda is a secondary pest within the piercing-sucking stink bug complex that attacks soybean crops in Brazil . The behavioral responses of males and females to aeration extracts from conspecifics suggested the presence of a male-produced sex pheromone. Gas chromatographic (GC) analysis of male and female aeration extracts revealed the presence of two male-specific compounds in a ratio of 92:8. Gas chromatographic -electroantennographic detection (GC-EAD) assays indicated that the major component is bioactive for females, supporting the behavioral data. Analysis of the mass and infrared spectra of the male-specific compounds suggested that they were both methyl-branched long-chain methyl esters. On the basis of the mass spectra of the respective hydrocarbons obtained by micro derivatizations, the structures of these methyl esters were proposed to be methyl 4,8,12-trimethylpentadecanoate (major) and methyl 4,8,12-trimethyltetradecanoate (minor). An 11 step synthetic route that was based on a sequence of Grignard reactions, starting from cyclopropyl methyl ketone, was developed to obtain synthetic standards with a 7.9 % overall yield for the major compound and a 9.9 % yield for the minor. The synthetic standards co-eluted with the natural pheromones on three different GC stationary phases. Y-tube olfactometer assays showed that the synthetic standards, including the major compound alone and a mixture of the major and minor compounds in the proportion found in natural extracts, were strongly attractive to females. [ABSTRACT FROM AUTHOR]

Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The α-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters). Methods to prepare small, strained rings are sought after due to the importance of such scaffolds in medicinal chemistry. Here, the authors report a palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. [ABSTRACT FROM AUTHOR]

The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously [ABSTRACT FROM AUTHOR]

The article focuses on the study on the efficiency of regioselective synthesis of 6,7-dihydro-5H-pyrrolo[1,2-c][1,3]thiazol-4-ium bromides IIIa-IIIc compounds. The study examines the mechanism of formation of compounds and was being synthesized including 4-cyclopropyl-substituted 2-aminothiazolium bromide into 3-amino-6,7-dihydro-5H-pyrrolo[1,2-c]- [1,3]thiazolium bromide. Moreover, the proton nuclear magnetic resonance (NMR) spectroscopy were also studied.