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At least 19 recordsLinked to original sources

PubMed2003

Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure.

A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.

Animals↗

PubMed2002

Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine.

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.

Chromatography↗

PubMed1980

Studies on cyclopropane fatty acid synthesis. Effect of carbon source and oxygen tension on cyclopropane fatty acid synthetase activity in Pseudomonas denitrificans.

The cyclopropane fatty acid, methylene hexadecanoic acid, constituted from 1% to upwards of 30% of the total lipid fatty acids of the bacterium, Pseudomonas denitrificans. The amount of this component varied along with the levels of the enzyme, cyclopropane synthetase (unsaturated-phospholipid methyltransferase, EC 2.1.1.16). When P. denitrificans was grown on succinate in a culture medium saturated with oxygen, cyclopropane synthetase remained repressed while cell densities were low. As cell densities increased, the enzyme was induced and the activity rose to a maximum over a period of 4-6 h. Cyclopropane synthetase could also be induced by rapidly limiting the oxygen supply to cells growing in conditions where oxygen was in excess. This phenomenon was independent of the phase of growth and could be prevented by addition of chloramphenicol to the medium. Growth on glucose was also shown to repress the synthesis of cyclopropane synthetase under similar conditions. However, once maximum levels of cyclopropane synthetase were reached, they remained constant for at least the following 15 h irrespective of the source of carbon in the medium. Methylene hexadecanoic acid accumulated in a linear manner throughout this period until a maximum level was achieved, the rate of accumulation being related to the activity of cyclopropane synthetase detected in vitro. The rate of conversion of total fatty acid to methylene hexadecanoic acid was approximately 1.3-1.5% per h, the methylene hexadecanoic acid being metabolically stable - the relative percentage of methylene hexadecanoic acid to total fatty acid in repressed cells, falling linearly with increase in cell number. Repression of enzyme synthesis was further investigated by growing cells on various sources of carbon other than glucose. The results indicated that succinate was unique amongst tricarboxylic acid cycle intermediates in depressing cyclopropane synthetase under limited oxygen conditions.

Carbon↗

PubMed2002

A density functional theory investigation of the Simmons-Smith cyclopropanation reaction: examination of the insertion reaction of zinc into the C-I bond of CH(2)I(2) and subsequent cyclopropanation reactions.

The insertion reaction of zinc into the C-I bond of CH(2)I(2) and subsequent cyclopropanation reactions with CH(2)CH(2) have been investigated using B3LYP level density functional theory calculations. The Simmons-Smith cyclopropanation reaction of olefins does not proceed easily due to the relatively large barriers on the insertion and cyclopropanation pathways. The computed results indicate that the IZnCH(2)I molecule is the active reagent in the Simmons-Smith reaction. This is consistent with the IZnCH(2)I reactive species being generated from diiodomethane and a Zn-Cu couple as proposed by several other research groups. The Simmons-Smith IZnCH(2)I carbenoid and CH(2)I-I carbenoid cyclopropanation reactions with olefins are compared. The reactions of olefins with the radicals from the decomposition of the IZnCH(2)I and CH(2)I-I species were also compared. We found that the chemical reactivity of the carbenoid species is dependent on its electrophilic behavior, steric effects, the leaving group character and the mechanism of the cyclopropanation reactions.

Cyclization↗

PubMed1982

Relationship between cyclopropane synthetase and the formation of cyclopropane fatty acids by Proteus vulgaris grown under various respiratory conditions.

In medium saturated with oxygen, the cyclopropane synthetase (unsaturated-phospholipid methyltransferase; EC 2.1.1.16) of Proteus vulgaris was generally synthesized after the mid-exponential phase of growth. The enzyme could also be induced by rapidly limiting the oxygen supply, or by initiating respiration on nitrate or thiosulphate following an initial period of growth in a highly aerobic environment. In each of these 'step-down' situations the specific activity of cyclopropane synthetase rose to a maximum prior to the stationary phase of growth and subsequently decreased. The cyclopropane fatty acids, methylene hexadecanoic acid and methylene octadecanoic acid accumulated throughout exponential growth following the induction of the enzyme. During a 12 h period in the stationary phase there was little synthesis of either of the fatty acids, despite detectable cyclopropane synthetase activity in the cells, indicating that essentially all the fatty acid synthesis was complete prior to entering the stationary phase. When nitrate was used as a respiratory electron acceptors a twofold increase in octadecenoic acid was observed, giving rise to an increase in methylene octadecanoic acid. This increase in octadecanoic acid was not apparent in mutants unable to respire on nitrate.

Cyclopropanes↗

PubMed1991

Cyclopropane and the Datex Capnomac. Effect of cyclopropane on the single wavelength infrared measurement of volatile anaesthetic agents.

We report the effect of cyclopropane used for induction of anaesthesia in children on the subsequent measurement of maintenance volatile anaesthetic agents with the single wavelength infrared absorption technique. After using cyclopropane to induce anaesthesia we have observed that falsely high readings of the expired maintenance agent occur for up to 60 minutes when using the Datex Capnomac. This is because of the effect of low concentrations of cyclopropane expired from the patient.

Anesthesia, Inhalation↗

PubMed1997

Cyclopropanation Reactions of Enones with Lithiated Sulfoximines: Application to the Asymmetric Synthesis of Chiral Cyclopropanes.

Stabilized lithiated sulfoximines 2 and 9 undergo highly diastereoselective Michael reactions with acyclic enones under kinetically controlled conditions. At rt the initially formed anionic Michael adducts undergo intramolecular displacement of the sulfonimidoyl group, with inversion of stereochemistry at the carbon bearing the nucleofuge, to give cyclopropanes. Lithiated sulfoximines derived from S-alkyl sulfoximines give mixtures of 1,2- and 1,4-adducts with enones under kinetically controlled conditions. However, at rt the 1,2-adducts are in equilibrium with their corresponding 1,4-adducts. The 1,4-adducts are formed in a highly diastereoselective manner and are rapidly converted to diastereomerically pure cyclopropanes in good to excellent yields. Optically active versions of these sulfoximines give cyclopropanes in high enantiomeric purities.

Journal Article↗

PubMed2002

Cyclopropanation with Fischer acyloxycarbene complexes: preparation of cyclopropane and cycloheptane-fused gamma-lactones.

[reaction: see text] A sequential acylation-intramolecular cyclopropanation reaction takes place upon treatment of a series of tetraalkylammonium acylchromates with beta,gamma-unsaturated acyl chlorides at -10 degrees C. The reaction leads to 2-oxabicyclo[3.1.0]hexan-3-ones with exo selectivity in good yields. The diastereoselectivity of the reaction allows the preparation of cis-divinyl cyclopropanes, which evolve via Cope sigmatropic reaction toward cycloheptadiene derivatives. Furthermore, the aromatic Cope rearrangement of a series of cis-aryl vinyl cyclopropanes prepared by means of this methodology has been studied.

Journal Article↗

PubMed2004

Cyclopropane-annelated azaoligoheterocycles by Ti-mediated intramolecular reductive cyclopropanation of cyclic amino Acid amides.

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.

Amides↗

PubMed2002

In search of high stereocontrol for the construction of cis-disubstituted cyclopropane compounds. Total synthesis of a cyclopropane-configured urea-PETT analogue that is a HIV-1 reverse transcriptase inhibitor.

[reaction: see text] A new azetidine-ligated dirhodium(II) catalyst that possesses a l-menthyl ester attachment provides significant diastereocontrol and high enantiocontrol for the formation of cis-cyclopropane products from reactions of substituted styrenes with diazo esters.

Cyclopropanes↗

PubMed2001

Catalytic asymmetric cyclopropanation of allylic alcohols with titanium-TADDOLate: scope of the cyclopropanation reaction.

A substoichiometric amount of titanium-TADDOLate complex was effective at catalyzing the cyclopropanation reaction of allylic alcohols in the presence 1 equiv of bis(iodomethyl)zinc. After initial optimization of the catalyst structure, excellent yields and enantiomeric ratios were obtained for 3-aryl- or 3-heteroaryl-substituted allylic alcohols (up to 97:3). Alkyl-substituted allylic alcohols gave modest yields and enantiomeric ratios (up to 87:13) but these compare favorably with those observed with other substoichiometric chiral ligands. The full synthetic scope of the reaction is presented in this paper.

Journal Article↗

PubMed1965