Octane Carboxylic Acids Research Articles

Synthesis of Azabicyclic Isosteres of Piperazine 2S-Carboxylic Acid.

Methods have been developed for the stereocontrolled synthesis of bicyclic diaza [3.3.0] octane carboxylic acids as possible isosteres of piperazine 2S-carboxylic acid. In the first approach, l-pyroglutamic acid was functionalized adopting new as well as documented reaction sequences via Michael and aza-Michael reactions, leading to two of the four intended isosteres. An alternative shorter route relying on enolate chemistry starting with N-Pf 4-keto l-proline methyl ester led to two other isosteres. Calculated pKa values and density functional theory (DFT) calculations have provided some insights into the relative basicities of the nitrogen atoms in these diaza [3.3.0] octane carboxylic acids in relation to piperazine 2S-carboxylic acid.

ChemInform Abstract: N‐Pyrrolidine‐Based α/β‐Peptides Incorporating ABOC, a Constrained Bicyclic β‐Amino Acid, for Asymmetric Aldol Reaction Catalysis.

AbstractCatalytic properties of 15 N‐pyrrolidine‐based α,β‐peptides incorporating a constrained 2‐aminobicyclo[2.2.2]octane carboxylic acid (ABOC) are evaluated in the asymmetric aldol reaction from acetone and some p‐substituted benzaldehydes.

N-Pyrrolidine-based α/β-peptides incorporating ABOC, a constrained bicyclic β-amino acid, for asymmetric aldol reaction catalysis

A series of N-pyrrolidine-based α,β-peptide catalysts incorporating a constrained 2-aminobicyclo[2.2.2]octane carboxylic acid (ABOC) residue were synthesized and evaluated in the asymmetric aldol reaction from acetone and some p-substituted benzaldehydes. Their catalytic properties were shown to be highly dependent on the amino acid sequences and on the absolute configuration of the ABOC residue that played a determinant role. Among the peptides tested, the heterochiral tripeptide H-Pro-(R)-ABOC-Asp-OCH313, that adopts a turn conformation in the solid state, proved to be the most efficient catalyst affording β-hydroxy ketones in high yields and good enantioselectivities (up to 87%).

Bicyclic naphthenic acids in oil sands process water: Identification by comprehensive multidimensional gas chromatography–mass spectrometry

Although bicyclic acids have been reported to be the major naphthenic acids in oil sands process-affected water (OSPW) and a well-accepted screening assay indicated that some bicyclics were the most acutely toxic acids tested, none have yet been identified. Here we show by comprehensive multidimensional gas chromatography–mass spectrometry (GC×GC–MS), that >100 C8–15 bicyclic acids are typically present in OSPW. Synthesis or purchase allowed us to establish the GC×GC retention times of methyl esters of numerous of these and the mass spectra and published spectra of some additional types, allowed us to identify bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.3.0]nonane, bicyclo[3.3.1]nonane and bicyclo[4.4.0]decane acids in OSPW and a bicyclo[2.2.2]octane acid in a commercial acid mixture. The retention positions of authentic bicyclo[3.3.0]octane and bicyclo[4.2.0]octane carboxylic acid methyl esters and published retention indices, showed these were also possibilities, as were bicyclo[3.1.1]heptane acids. Bicyclo[5.3.0]decane and cyclopentylcyclopentane carboxylic acids were ruled out in the samples analysed, on the basis that the corresponding alkanes eluted well after bicyclo[4.4.0]decane (latest eluting acids). Bicyclo[4.2.1]nonane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, bicyclo[4.2.2]decane and spiro[4.5]decane carboxylic acids could not be ruled out or in, as no authentic compounds or literature data were available. Mass spectra of the methyl esters of the higher bicyclic C12–15 acids suggested that many were simply analogues of the acids identified above, with longer alkanoate chains and/or alkyl substituents. Our hypothesis is that these acids represent the biotransformation products of the initially somewhat more bio-resistant bicyclanes of petroleum. Although remediation studies suggest that many bicyclic acids can be relatively quickly removed from suitably treated OSPW, examination by GC×GC–MS may show which isomers are affected most. Knowledge of the structures will allow the toxicity of any residual isomers to be calculated and measured.

Use of molecular electrostatic potential for quantitative assessment of inductive effect

Density functional theory computations at the B3LYP/6-31G(d,p) level have been carried out for three types of model compounds, viz. (i) 4-substituted bicyclo[2.2.2]octane carboxylic acids, (ii) anions of 4-substituted bicyclo[2.2.2]octane carboxylic acids and (iii) 4-substituted quinuclidines where the substituents are NO(2), CN, Cl, Br, CF(3), F, CHO, CH(2)Cl, COOH, COCH(3), CONH(2), OH, OCH(3), C(6)H(5), NH(2), H, CH(3), CH(2)CH(3), CH(CH(3))(2), and C(CH(3))(3) to study the dependencies between molecular electrostatic potential minimum (V(min)) and the inductive substituent constant sigma(I). All the three model systems show excellent linear correlation between V(min) and sigma(I) suggesting that the calculation of V(min) parameter in these systems offers a simple and efficient computational approach for the evaluation of inductive substituent constants. The calculated linear equation for the models (i), (ii), and (iii) are V(min) = 12.982 sigma(I)- 48.867, V(min) = 13.444 sigma(I)- 182.760, and V(min) = 18.100 sigma(I)- 65.785, respectively. Considering the simplicity of the quinuclidine model, V(min) value at the nitrogen lone pair region of a 4-substituted quinuclidine system is recommended for the evaluation of sigma(I). Further, the additivity effect of sigma(I) is tested on multiply substituted quinuclidine and bicyclo[2.2.2]octane carboxylic acid derivatives using the V(min) approach and the results firmly supported the additivity rule of inductive effect. The systems showing considerable deviations from the additivity rule are easily recognized as those showing either steric effect or intramolecular hydrogen bond interactions at the V(min) response site. However, the distance relation of sigma(I) is not well represented in the caged molecular systems.

Aza-bicyclic amino acid sulfonamides as α 4β 1/α 4β 7 integrin antagonists

The design, synthesis, and biological activity of novel α 4β 1 and α 4β 7 integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent α 4β 1-selective and dual α 4β 1/α 4β 7 antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma. ©2003 Elsevier Science Ltd. All rights reserved.

Enantiospecific synthesis of 3-aza-6,8-dioxa-bicyclo[3.2.1]octane carboxylic acids from erythrose

New methodology for the synthesis of enantiopure 3-aza-6,8-dioxa-bicyclo[3.2.1]octane-carboxylic acids belonging to 7- endo-BTAa sub-class of γ/δ amino acids is described. The novelty is the use of 2,3- O-isopropylidene-erythrose instead of meso-tartaric acid derivative, thus allowing us to perform an enantiospecific synthesis. Reductive amination of erythrolactol with aminoacetaldehyde diethylacetal or benzylamine, and subsequent acid cyclisation gave directly the amino alcohol scaffold. Protection of nitrogen as urethane and final alcohol oxidation afforded the Fmoc-, Boc-, and Cbz-amino acids. The new synthetic route was applied to multigram scale, thus resulting in a marked improvement of the synthesis of enantiopure 7- endo-BTG and 7- endo-BTK amino acids.

Substituent effects on the acidity of weak acids. 1. Bicyclo[2.2.2]octane-1-carboxylic acids and bicyclo[1.1.1]pentane-1-carboxylic acids.

The acidities of 3- and 4-substituted bicyclooctane-1-carboxylic acids and 3-substituted bicyclo[1.1.1]pentane-1-carboxylic acids have been calculated at the MP2/6-311++G** theoretical level. There is good agreement between the calculated and observed gas-phase acidities. The acidities of the 4-substituted bicyclooctane acids were found to be linearly dependent on the C-X bond dipoles, as expected from a field effect. The substituents had a negligible effect on the electron density at C1. The difference in acidity between 4-chlorobicyclo[2.2.2]octane-1-carboxylic acid and the parent acid (6.2 kcal/mol) is reproduced by the Kirkwood-Westheimer treatment of substituent effects on acidity, but only if the bicyclooctane ring is given an effective dielectric constant of unity. The acidities of the 3-substituted bicyclooctane acids are linearly related to the corresponding 4-substituted acids with a slope of 0.9. The acidities of the 3-substituted bicyclo[1.1.1]pentane-1-carboxylic acids are linearly related to the C-X bond dipoles for this ring system (which are different than those for the bicyclooctanes), and they are also linearly related to the acidity of the 4-substituted bicyclo[2.2.2]octanecarboxylic acids with a slope of 1.34. The larger slope is due to the smaller bridgehead-bridgehead distance in the bicyclopentane ring than in bicyclo[2.2.2]octane.

Liquid crystals comprising hydrogen-bonded organic acids II. Heterodimers in mixed mesogenic acids

Nematic mesophase stability, as determined by the excess mesophase range in mixtures of organic acids (supramesogen derived from par a-substituted phenyl, 4-substituted cyclohexane and bicyclo[2.2.2]octane carboxylic acids), is increased in mixtures of disparate species - mixed acids with differing substituent sizes (different supramesogen tail lengths) and different acid types (aliphatic and aromatic supramesogen cores). These trends enable one to estimate contributions to mesophase stability stemming from tail disparity and core differences, contributions that appear to carry over into analogous covalent mesogens. IR measurements of solid mixtures of acids suggest that the heterodimer acids population dominates, and deuterium NMR studies of labelled acids in the nematic phase emphasize the dynamic character of this class of supramesogens: dimer lifetimes are shorter than microseconds.

Incorporating solvation effects into density functional theory: Calculation of absolute acidities

An approach to the calculation of molecular electronic structures, solvation energies, and pKa values in condensed phases is described. The electronic structure of the solute is described by density functional quantum mechanics, and electrostatic features of environmental effects are modeled through external charge distributions and continuum dielectrics. The reaction potential produced by a mode of the molecular charge distribution is computed via finite-difference solutions to the Poisson-Boltzmann equation and incorporated into the self-consistent field procedure. Here we report results on three sets of organic acids, whose pKa values range over 16 pH units. The first set provides models for ionizable side chains in proteins; the second set considers the effects of substituting one to three chlorine atoms for hydrogens in acetic acid; and the final set consists of 4-substituted-bicyclo-[2.2.2]-octanecarboxylic acids. Successful prediction of “absolute” pKa values places stringent requirements on the computation of gas-phase proton affinities and on the response to solvation. In some cases the current model shows substantial errors, but overall the results and trends are in good agreement with experiment. Prospects for extending this approach to more complex systems such as proteins are briefly discussed. © 1997 John Wiley & Sons, Inc.

Synthesis and conformational studies of Zabicipril (S 9650-3), a potent inhibitor of angiotensin converting enzyme

The synthesis of the title compound 8c is described. The inhibitor of Angiotensin Converting Enzyme (ACE) contains aza-2 bicyclo [2, 2, 2] octane-carboxylic acid, a bulky cyclic amino acid replacing the proline moiety present in most ACE inhibitors described in the literature. Structural analysis of 8c supports the hypothesis of preferred conformations for this type of pseudo peptidic molecule, in solution ( 1H, 13C NMR) and in the solid state (X- Ray).

The indirect action of ions upon amino acid transport system L in the S37 cell

The uptake into S37 ascites cells of an L-system specific analog, 2-amino-bicyclo-(3,2,1)-octanecarboxylic acid (ABOCA), wasinconsistently inhibited by deletion of sodium ion from the incubation medium. We note that there have been conflicting reports from various other laboratories as to the effect of sodium ion on the transport of L-system specific analogs. The uptake of labeled exo-2-aminobicyclo-(2.2,1)-heptane-2-carboxylic acid (BCH) wasalso diminished by the removal of sodium from the medium. The K m values for these substrates were increased and ν max values decreased as the sodium ion concentration was decreased or abolished. Transport behavior was also found to be affected by varying the medium potassium ion concentration with valinomycin present. The sodium effect was abolished by preincubation with cyanide and deoxyglucose. The results suggest an indirect effect of sodium ion upon transport system L: system L is energetically supported by a membrane potential.

ChemInform Abstract: SYNTHESIS OF 4‐ALKYL‐ AND 4‐PHENYLBICYCLO(2.2.2)OCTANECARBOXYLIC ACIDS

Chemischer InformationsdienstVolume 12, Issue 14 Isocyclic Compounds ChemInform Abstract: SYNTHESIS OF 4-ALKYL- AND 4-PHENYLBICYCLO(2.2.2)OCTANECARBOXYLIC ACIDS R. KH. GEIVANDOV, R. KH. GEIVANDOVSearch for more papers by this authorE. I. KOVSHEV, E. I. KOVSHEVSearch for more papers by this author R. KH. GEIVANDOV, R. KH. GEIVANDOVSearch for more papers by this authorE. I. KOVSHEV, E. I. KOVSHEVSearch for more papers by this author First published: April 7, 1981 https://doi.org/10.1002/chin.198114166AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume12, Issue14April 7, 1981 RelatedInformation

A Comparison of the Properties of Some Liquid Crystal Materials Containing Benzene, Cyclohexane, and Bicyclo[2.2.2]octane Rings

Abstract A preliminary study of the properties of nine cyanoaryl esters of various 40-alkylbicyclo [2.2.2] octane-carboxylic acids has been extended and results are now presented for a wider range of 4-cyanophenyl, 2-cyano-6-naphthyl, and 4-cyano-4-biphenyl 4-alkylbicyclo [2.2.2]octane-1-carboxylates.

13C NMR Chemical shifts in bicyclo[2.2.2]octanes—iii : Hydroxy acids and lactones

A number of hydroxybicyclo[2.2.2]octane carboxylic acids and the corresponding delta lactones have been prepared, and the 13C NMR spectra show trends that, together with some deuteration experiments, provide a self consistent and unambiguous assignment of the resonance peaks. The effects produced by the substituents and the changes in chemical shifts brought about by the lactonization process are analysed.