Cyclopropanecarboxylic Acid Research Articles

Nitrile Biotransformation for Highly Enantioselective Synthesis of 3‐Substituted 2,2‐Dimethylcyclopropanecarboxylic Acids and Amides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Biological Evaluation of Novel 2‐(1H‐Imidazol‐4‐yl)cyclopropane Carboxylic Acids: Key Intermediates for H3 Histamine Receptor Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Simple Synthesis of 1,1,2‐Tris‐(hydroxymethyl)cyclopropane and Its Dihalo Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Nitrile biotransformation for highly enantioselective synthesis of 3-substituted 2,2-dimethylcyclopropanecarboxylic acids and amides.

Biotransformations of differently configured 2,2-dimethyl-3-substitued-cyclopropanecarbonitriles were studied using a nitrile hydratase/amidase-containing Rhodococcus sp. AJ270 whole-cell catalyst under very mild conditions. Although all of the cis-3-aryl-2,2-dimethylcyclopropanecarbonitriles appeared inert toward the biocatalyst, a number of racemic trans-isomers efficiently underwent a highly enantioselective hydrolysis to produce (+)-(1R,3R)-3-aryl-2,2-dimethylcyclopropanecarboxylic acids and (-)-(1S,3S)-3-aryl-2,2-dimethylcyclopropanecarboxamides in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of 1R-enantioselective nitrile hydratase and amidase, with the later being a dominant factor. The influence of the substrates on both reaction efficiency and enantioselectivity was discussed in terms of steric and electronic effects. Coupled with chemical transformations, biotransformations of nitriles provided convenient syntheses of optically pure geminally dimethyl-substituted cyclopropanecarboxylic acids and amides, including chrysanthemic acids, in both enantiomeric forms.

Development of a DNA Microarray for Toxicology Based on Hepatotoxin-Regulated Sequences

Toxicogenomics is an emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of compounds. One of the main tools used in toxicogenomics is DNA microarrays. We have used a novel strategy to create a library highly enriched for genes expressed in the liver under hepatotoxic conditions. Using this library, we have created a new oligonucleotide microarray dedicated to the study of rat liver function. Oligonucleotide probes for these genes were designed and used in experimental hybridization studies to deduce the correct sequence orientation and to determine those sequences exhibiting differential regulation under a variety of toxicity-related treatments and conditions. The final array was benchmarked on treatments with 3-methylcholanthrene, Aroclor 1254, and cyclopropane carboxylic acid. Our results showed that the subtractive hybridization greatly enriched for genes regulated during a hepatotoxic response. Overall, our strategy for design of a new rat toxicology microarray can be applied to other systems as well and should aid greatly in the development of microarrays targeted for specific scientific areas.

Synthesis and biological evaluation of novel 2-(1 H-imidazol-4-yl)cyclopropane carboxylic acids: key intermediates for H 3 histamine receptor ligands

A new synthetic methodology to provide cis-2-(1H-imidazol-4-yl)-cyclopropane carboxylic acids is described. These cyclopropanes are useful for the preparation of novel H 3 receptor agents.

A Simple Synthesis of 1,1,2-tris-(Hydroxymethyl)-Cyclopropane and Its Dihalo Derivatives

The phase transfer catalytic cyclopropanation of the malonic ester of allylic alcohol or its 3,3-dibromo and 3,3-dichloro derivatives yields bicyclic cyclopropane carboxylic acid lactones; reduction of these lactones with LiAlH4 in boiling THF yields the appropriate 1,1,2-tris-(hydroxymethyl)cyclopropanes in satisfactory yield.

ChemInform Abstract: Highly Selective and Efficient Conversion of Alkyl Aryl and Alkyl Cyclopropyl Ketones to Aromatic and Cyclopropane Carboxylic Acids by Aerobic Catalytic Oxidation: A Free‐Radical Redox Chain Mechanism.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Development of a Practical, Safe, and High-Yielding Process for the Preparation of Enantiomerically Pure trans-Cyclopropane Carboxylic Acid

A practical, safe, and high-yielding process for the cyclopropanation of a chiral epoxide has been developed using the inexpensive and nonhazardous reagents triethylphosphonoacetate and sodium tert-butoxide.

Measurements of Vapor Pressure, Heat Capacity, and Density along the Saturation Line for Cyclopropane Carboxylic Acid, N,N-Diethylethanolamine, 2,3-Dihydrofuran, 5-Hexen-2-one, Perfluorobutanoic Acid, and 2-Phenylpropionaldehyde

This paper reports measurements made for DIPPR Research Project 821 in the 1997 Project Year. Vapor pressures were measured to a pressure limit of 270 kPa or lower decomposition point for all six compounds using a twin ebulliometric apparatus. Liquid-phase densities along the saturation line were measured for each compound over a range of temperatures (ambient to a maximum of 448 K). A differential scanning calorimeter was used to measure two-phase (liquid + vapor) heat capacities for each compound in the temperature region ambient to the critical temperature or lower decomposition point. The results of all the measurements were combined to derive a series of thermophysical properties including critical temperature, critical density, critical pressure, acentric factor, enthalpies of vaporization [within the temperature range (±50 K) of the vapor pressures], solubility parameter, and heat capacities along the saturation line. Wagner-type vapor-pressure equations were derived for each compound. In addition, the liquid-phase densities were compared with values derived using a four-term power series in [(1 − Tr)n/3]. All measured and derived values were compared with those obtained in a search of the literature.

Internal rotations of vinylcyclopropane, cyclopropanecarboxaldehyde, and cyclopropanecarboxylic acid: a DFT B3LYP study

The internal rotations around the C–C linkage in vinylcyclopropane (VCP), cyclopropanecarboxaldehyde (CPAL), and cyclopropanecarboxylic acid have been studied by performing the DFT B3LYP calculations with triple split-valence basis sets including polarization and diffuse functions. The general features of the B3LYP internal rotation potential energy curves are in line with experiment. The discrepancies between the B3LYP and experimental relative energy values for the stationary points along the curves are in general within 0.7kcalmol−1. Compared with available experimental data the B3LYP calculations predict accurate values for the bond lengths and bond angles in the stationary-point structures, but less accurate values for the torsion angles in the transition state structure of CPAL and the gauche conformer of VCP. The conjugative interaction between the quasi-π Walsh orbit (ea) of CP and the π-orbit of the substituents in the three molecules has been discussed in relation to the features of the potential energy curves and the variations of geometric parameters with the rotational angles. The previous orbital interaction analysis for conjugation in s-trans VCP has been examined at ab initio HF level, and no (ea+π∗) orbital is found in the electronic structure. The ea–π orbital interaction in s-trans VCP corresponds to the two-orbital four-electron case, but it does not cause a net destabilizing consequence due to the involvement of the π∗ orbital.

Highly Selective and Efficient Conversion of Alkyl Aryl and Alkyl Cyclopropyl Ketones to Aromatic and Cyclopropane Carboxylic Acids by Aerobic Catalytic Oxidation: A Free-radical Redox Chain Mechanism.

An efficient and convenient method has been developed for the oxidation of aryl alkyl and cyclopropyl alkyl ketones to aromatic and cyclopropane carboxylic acids by molecular oxygen at atmospheric pressure, catalysed by Mn(NO3)2 in combination with Co(NO3)2 or Cu(NO3)2. This simple, cheap and highly selective process has a general character for the synthesis of carboxylic acids and it is particularly suitable for industrial applications.

Cerium oxide-based catalysts for production of ketones by acid condensation

Cerium oxide-based catalysts proved superior in activity, selectivity, and stability to several other oxides for the condensation of two carboxylic acids to produce non-symmetric ketones. The effects of CeO 2 loading on the catalysts and the addition of more basic or acidic oxides to CeO 2 were also studied. The catalysts were characterized by surface area, XRD, and redox behavior using TGA. CeO 2-based catalysts began deactivating after >12 h operation at WHSV∼4, but could be completely regenerated by high temperature air. The optimum temperature range for methylcyclopropylketone (MCPK) production from acetic and cyclopropanecarboxylic acids (CCA) were 690–730 K, and 670–680 K for methylnonylketone (MNK) production from acetic and decanoic acids. The optimal loadings of CeO 2 on supports approached a monolayer, but the maximum yield appeared almost independent of support. Both acidic and basic oxide additives to CeO 2 increased the rates to isomers of both CCA and MCPK, and to aldol condensation products. Catalyst performance improved with respect to time on stream and the number of regeneration cycles. This behavior resulted from the gradual dispersion of CeO 2 on the support during reduction/oxidation cycles. Acetic acid/air could also be used to activate the catalysts prior to feeding the second acid.

ChemInform Abstract: Synthesis and Separation of Substituted Cyclopropane Carboxylic Acid Amide Isomers.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Development of a class-specific immunoassay for the type I pyrethroid insecticides

A general enzyme-linked immunosorbent assay was developed for the type I pyrethroid insecticides, such as permethrin, phenothrin, resmethrin and bioresmethrin. Polyclonal antibodies were generated by immunizing with a permethrin derivative, 2,2-dimethyl-3-(5′-carboxy-pent-1′-en-yl)cyclopropanecarboxylic acid-(3-phenoxybenzyl)ester conjugated with thyroglobulin, bovine serum albumin or ovalbumin. Antisera were screened against eight different coating antigens. The antibody–antigen combination with the lowest background, and highest sensitivity for permethrin was further optimized and tested for solvent and detergent tolerance. The I 50’s of the optimized immunoassay were 30 μg/l for permethrin and 20 μg/l for phenothrin, respectively. No cross-reactivities were measured to the type II pyrethroids, such as esfenvalerate, cyfluthrin, cypermethrin, deltamethrin, fenvalerate and fluvalinate. This assay can be used in monitoring studies to distinguish between types I and II pyrethroids.

ChemInform Abstract: Reduction of Cyclopropanecarboxylic Acids by Borane, a Chemoselective Reduction Sensitive to Steric Interactions and Reaction Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and separation of substituted cyclopropane carboxylic acid amide isomers

The phase-transfer-catalyzed cyclization of optically active malonic acid allylic ester amides yields bicyclic cyclopropane carboxamide lactone derivatives. The two diastereomers obtained could be separated in some cases by simple column chromatography yielding the pure isomers.

Metabolic, idiosyncratic toxicity of drugs: overview of the hepatic toxicity induced by the anxiolytic, panadiplon

Preclinical drug safety evaluation studies, typically conducted in two or more animal species, reveal and define dose-dependent toxicities and undesirable effects related to pharmacological mechanism of action. Idiosyncratic toxic responses are often not detected during this phase in development due to their relative rarity in incidence and differences in species sensitivity. This paper reviews and discusses the metabolic idiosyncratic toxicity and species differences observed for the experimental non-benzodiazepine anxiolytic, panadiplon. This compound produced evidence of hepatic toxicity in Phase 1 clinical trial volunteers that was not predicted by rat, dog or monkey preclinical studies. However, subsequent studies in Dutch-belted rabbits revealed a hepatic toxic syndrome consistent with a Reye's Syndrome-like idiosyncratic response. Investigations into the mechanism of toxicity using rabbits and cultured hepatocytes from several species, including human, provided a sketch of the complex pathway required to produce hepatic injury. This pathway includes drug metabolism to a carboxylic acid metabolite (cyclopropane carboxylic acid), inhibition of mitochondrial fatty acid β-oxidation, and effects on intermediary metabolism including depletion of glycogen and disruption of glucose homeostasis. We also provide evidence suggesting that the carboxylic acid metabolite decreases the availability of liver CoA and carnitine secondary to the formation of unusual acyl derivatives. Hepatic toxicity could be ameliorated by administration of carnitine, and to a lesser extent by pantothenate. These hepatocellular pathway defects, though not directly resulting in cell death, rendered hepatocytes sensitive to secondary stress, which subsequently produced apoptosis and hepatocellular necrosis. Not all rabbits showed evidence of hepatic toxicity, suggesting that individual or species differences in any step along this pathway may account for idiosyncratic responses. These differences may be roughly applied to other metabolic idiosyncratic hepatotoxic responses and include variations in drug metabolism, effects on mitochondrial function, nutritional status, and health or underlying disease.

Reduction of Cyclopropanecarboxylic Acids by Borane, a Chemoselective Reduction Sensitive to Steric Interactions and Reaction Conditions

A number of cyclopropanecarboxylic acids have been reduced by BH3 reagents in THF to the corresponding cyclopropyl alcohols; the yield is sensitive to the steric influence of the substituents attached to the ring, the reaction temperature, and the nature of the borane reagent.

Cyclopropane-derived peptidomimetics. design, synthesis, and evaluation of novel Ras farnesyltransferase inhibitors.

Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.