Cyclopropyl Ring Research Articles

ChemInform Abstract: Formation of Three-Membered Rings by SHi Displacement. Reverse of Cyclopropyl Ring Opening.

ChemInform 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.

Dibromido{2-[1-(cyclopropylimino)ethyl]pyridine}zinc(II)

In the title compound, [ZnBr2(C10H12N2)], the Zn2+ ion is coordinated by the N,N′-bidentate Schiff base ligand and two bromode ions in a distorted tetra­hedral arrangement. The dihedral angle between the pyridine and the cyclo­propyl rings is 95.4 (8)°.

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

We report the synthesis of a novel analogue of Alogliptin via condensation of two key intermediates one of which is an aminopiperidine derivative bearing a spirocyclic ring on the piperidine moiety. Preparation of the aminopiperidine intermediate was carried out by constructing the cyclopropyl ring prior to assembling the piperidine ring.

Crystal and Molecular Structures of Two Triazole Derivatives: 4-Cyclopropyl-4,5-dihydro-1H-1,2,3-triazole and Methyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate

AbstractThe molecule in 4-cyclopropyl-4,5-dihydro-1H-1,2,3-triazole (I) is disposed about a mirror plane with the triazole ring lying in the plane and being orthogonal to the cyclopropyl ring. Considerable delocalization of π-electron density within the triazole ring is indicated by the pattern of bond distances in (I). The molecule of methyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate (II) adopts a curved shape with the dihedral angle formed between the triazole and benzene rings being 63.23(8)°. By contrast to (I), localization of π-electron density within the triazole ring in (II) is indicated. Both (I), via N-H···N hydrogen bonding, and (II), via C-H···O and C-H···N interactions, associate in the solid state to form supramolecular chains. In (I), the chain is a zigzag with a flat topology, whereas in (II) the linear chain has a curved topology. Compound (I) crystallizes in the orthorhombic space group Pnma with a = 5.6470(2) A, b = 7.3359(4) A, c = 13.4404(7) A, and Z = 4. Compound (II) crystallizes in the monoclinic space group P2 1 /c with a = 12.1314(5) A, b = 5.5951(2) A, c = 16.4339(7) A, β = 111.269(2)°, and Z = 4.Graphical AbstractSupramolecular chains mediated by N-H···N hydrogen bonding (illustrated) or C-H···O and C-H···N interactions are found in the title structures, respectively.[IMAGE]

Formation of a Cyclopropyl Epoxide via a Leukotriene A Synthase-related Pathway in an Anaerobic Reaction of Soybean Lipoxygenase-1 with 15S-Hydroperoxyeicosatetraenoic Acid: EVIDENCE THAT OXYGEN ACCESS IS A DETERMINANT OF SECONDARY REACTIONS WITH FATTY ACID HYDROPEROXIDES

The further conversion of an arachidonic acid hydroperoxide to a leukotriene A (LTA) type epoxide by specific lipoxygenase (LOX) enzymes constitutes a key step in inflammatory mediator biosynthesis. Whereas mammalian 5-LOX transforms its primary product (5S-hydroperoxyeicosatetraenoic acid; 5S-HPETE) almost exclusively to LTA(4), the model enzyme, soybean LOX-1, normally produces no detectable leukotrienes and instead further oxygenates its primary product 15S-HPETE to 5,15- and 8,15-dihydroperoxides. Mammalian 15-LOX-1 displays both types of activity. We reasoned that availability of molecular oxygen within the LOX active site favors oxygenation, whereas lack of O(2) promotes LTA epoxide synthesis. To test this, we reacted 15S-HPETE with soybean LOX-1 under anaerobic conditions and identified the products by high pressure liquid chromatography, UV, mass spectrometry, and NMR. Among the products, we identified a pair of 8,15-dihydroxy diastereomers with all-trans-conjugated trienes that incorporated (18)O from H(2)(18)O at C-8, indicative of the formation of 14,15-LTA(4). A pair of 5,15-dihydroxy diastereomers containing two trans,trans-conjugated dienes (6E,8E,11E,13E) and that incorporated (18)O from H(2)(18)O at C-5 was deduced to arise from hydrolysis of a novel epoxide containing a cyclopropyl ring, 14,15-epoxy-[9,10,11-cyclopropyl]-eicosa-5Z,7E,13E-trienoic acid. Also identified was the delta-lactone of the 5,15-diol, a derivative that exhibited no (18)O incorporation due to its formation by intramolecular reaction of the carboxyl anion with the proposed epoxide intermediate. Our results support a model in which access to molecular oxygen within the active site directs the outcome from competing pathways in the secondary reactions of lipoxygenases.

Gold-Catalyzed Benzannulation of 3-Alkoxy-1,5-enynes: Access to Functionalized Benzenes

A cationic Au(I) complex catalyzed benzannulation of 3-alkoxy-1,5-enynes bridged by a cyclopropyl ring with a variety of nucleophiles is described. The reaction occurs selectively through a 6-endo-dig pathway to provide tri- and tetrasubstituted benzenes efficiently under mild reaction conditions.

Mechanistic Insights in Gold-Stabilized Nonclassical Carbocations: Gold-Catalyzed Rearrangement of 3-Cyclopropyl Propargylic Acetates

The reaction of 3-cyclopropyl propargylic carboxylates with Au(I) and Au(III) catalysts affords selectively 5-(E)-alkylidenecyclopentenyl acetates via [3,3]-sigmatropic rearrangement of the carboxylic moiety followed by cyclopropyl ring opening and cyclization. DFT calculations have been performed, supporting a two-step no-intermediate mechanism along the cyclization coordinate. The stereoselective formation of the exocyclic alkenes is kinetically controlled in the first of these events. Although stereospecific in nature through a gold-stabilized nonclassical carbocation, the chirality transfer in these cyclopentannulations is not complete. Computational and experimental evidence is provided for a Au-promoted cyclopropyl ring opening/epimerization/ring closure in both cis- and trans-cyclopropyl settings, which competes with the cyclization event, thus eroding the stereochemical information transfer. When tertiary acetates were used, products of both 1,2- and 1,3-acyloxy migration processes could be isolated, supporting the competitive coexistence of these two pathways along the reaction profile, as suggested also by DFT calculations.

Papillamide, a Novel Fatty Acid Amide from the Red Alga Laurencia papillosa

Abstract Papillamide (1), a novel fatty acid amide that incorporates a cyclopropyl ring, was isolated from the Okinawan red alga Laurencia papillosa, which overgrows hermatypic corals. The structure of 1 was determined by spectroscopic analyses.

Synthesis and complexation of dichalcogenoethers with cyclopropyl backbones, (CH2EMe)2 (E=Se or Te)

The reaction of LiTeMe with C(CH2Br)4 in thf gives (CH2TeMe)2 irrespective of the ratio of reactants, in contrast to the reaction with LiSeMe, which gives either C(CH2SeMe)4 or (CH2SeMe)2 depending upon the reaction conditions. The synthesis and properties of [ (CH2TeMe2)2]I2, (CH2TeMeI2)2, [Mn(CO)3Cl{ (CH2EMe)2}] (E = Se or Te) and [MCl(?6-p-cymene){ (CH2EMe)2}]PF6 (M = Ru or Os) are described. X-ray crystal structures are reported for [ (CH2TeMe2)2]I2, [Mn(CO)3Cl{ (CH2TeMe)2}], [MCl(?6-p-cymene){ (CH2TeMe)2}]PF6 (M = Ru, E = Se or Te and M = Os, E = Se). The effect of the cyclopropyl ring in the ligand backbone is to open up the C–C–C angle within the chelate ring, compared with trimethylene linked analogues. Selenium–carbon bond fission occurs on attempted quaternisation of o-C6H4(CH2SeMe)2 or (CH2SeMe)2 with MeI yielding [Me3Se]I.

Abstract A36: Bracken fern carcinogen causes cancer in humans

Abstract Bracken fern (genus Pteridium) is the only plant known to cause cancer naturally in animals. In addition to the well recognised syndromes of thiamine deficiency, acute haemorrhage associated with myeloid aplasia and blindness due to retinal degeneration, it causes neoplasia of urinary bladder and in some circumstances oesophagus origin. In addition, it has been shown to cause neoplasia in a wide range of tissues in many experimental species. The major carcinogen has been shown to be ptaquiloside (PT), a norsesquiterpene glucoside that can be present in bracken in extraordinary concentrations, up to 13000 ppm. The highest concentrations were found in the crosiers and young fronds. The mutagenicity, clastogenicity, tetratogenicity and carcinogenicity of PT have been convincingly demonstrated. Under alkaline conditions the loss of the glucose give rise to the formation of a dienone intermediate which possess a highly reactive cyclopropyl ring capable of reacting with cellular macromolecules. Pt has been shown to alkylate DNA at N3 of adenines in the minor groove, preferentially in 5′-TAG and 3′-A in 5′-AA-3′ sequences. It also alkylates N7 guanines in the major groove occurring in 5′-TG sequences. It is believed that these alkylation lead to mismatch repair and subsequent mutations in particular proto-oncogene. Recently a rat model of carcinogenesis has been established using intravenously administrated PT. Some epidemiological evidence has indicated higher risk of cancer in people who consume bracken fern crosiers, people who consume milk of cows feeding on bracken and those live in bracken-infested areas. PT has been found in the milk of cows fed on bracken fern experimentally and the milk of bracken fed cows has been shown to cancer in rats. PT carcinogenesis presents an excellent model of environmental carcinogenesis. More recently it has been found that immunosuppressive effects of bracken fern (P. aquilinum) and that many of the functions that were modulated could contribute to the increased risk of cancer formation in exposed hosts. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A36.

The Photochemical C2−C6Cyclization of Enyne−Allenes: Interception of the Fulvene Diradical with a Radical Clock Ring Opening

The mechanism of the photochemical C(2)-C(6) cyclization of enyne-allenes has been studied through radical clock, intramolecular kinetic isotope effect, and laser flash photolysis (LFP) experiments as well as density functional theory (DFT) and ab initio computations. While the photochemical cyclization of enyne-allenes 1 and 2 furnished ene and Diels-Alder products without any cyclopropyl ring opening, that of 3 carrying the ultrafast diphenylcyclopropylcarbinyl radical clock afforded products derived from cyclopropyl ring opening. Laser flash photolysis (LFP) studies on enyne-allene 3 point to an allene triplet excited state (transient A) as a primarily formed short-lived (tau = 430 ns) intermediate. In addition, we have obtained evidence for the formation of a diphenylmethyl-type diradical (transient C, tau = 1.0 micros) resulting from ring opening of a diphenylcyclopropane ring. C subsequently undergoes a surprisingly slow (tau = 1.0 micros) 1,6-hydrogen shift leading to the stable 1,3-diene 6.

Synthesis and chromatographic resolution of conformationally constrained analogues of homotaurine

The first series of conformationally constrained analogues of homotaurine is reported. The partial constriction of the skeleton was realized through the insertion of a cyclopropyl ring, between the α,β- and β,γ-positions, thus affording, respectively, trans- and cis-2-aminomethylcyclopropane-1-sulfonic acids and trans- and cis-(2-aminocyclopropyl)methanesulfonic acids. The resolution of all four racemic mixtures was accomplished using HPLC system carrying the polysaccharide-based Chiralpak ® IB ® column as the chiral stationary phase. The coupling with an ‘Evaporative Light Scattering Detector (ELSD)’ has been particularly valuable during the chromatographic study.

ChemInform Abstract: Silylmethyl‐Substituted Cyclopropyl and Other Strained Ring Systems: Cycloaddition with Dipolarophiles

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.

Highly efficacious factor Xa inhibitors containing α-substituted phenylcycloalkyl P4 moieties

We previously disclosed a series of highly potent FXa inhibitors bearing α-substituted (CH 2NR 1R 2) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the α -substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K i), human plasma anticoagulant activity (PT EC 2×) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC 50s = 29–81 nM).

Molecular Structure of a Cyclopropyl Substituted Vinyl Cation

The experimentally determined molecular structure of vinyl cation 1 provides clear evidence for the occurrence of extended sigma-conjugation involving the cyclopropyl ring and the beta-C-Si bonds.

4,4-Dichlorotricyclo[5.4.0.03,5]undeca-7,9,11-triene

The title compound, C11H10Cl2, is a useful inter­mediate for the synthesis of 1H-cyclo­propa[b]naphthalene. Strain in the mol­ecule is evidenced by the fact that the cyclo­hexane ring is essentially planar and nearly coplanar with the benzene ring [dihedral angle 1.87 (18)°], and the cyclo­propyl ring is almost perpendicular to the cyclo­hexane ring [dihedral angle 70.99 (12)°]. The mol­ecules are loosely connected into one-dimensional chains by inter­molecular Cl⋯Cl inter­actions with a distance of 3.571 (1) Å. The centroid-to-centroid distance between stacked benzene rings is ca 5.89 Å, indicating that no π–π stacking exists in the crystal structure.

Reaction of aromatic nitroso compounds with chemical models of ‘thiamine active aldehyde’

Aromatic nitroso compounds in the presence of base and 2-(α-hydroxyalkyl)-3,4-dimethylthiazolium trifluoromethanesulfonate and related salts furnish in variable yields O- and N-acyl-aryl hydroxylamines and 3,4-dimethylthiazolium trifluoromethanesulfonate. A primary kinetic isotope effect of 4.9, obtained for the appropriate 2α-deuterated thiazolium salt, points to the C 2α–H bond cleavage as the rate determining step. Radical species detected by ESR were unambiguously identified as phenylhydronitroxide, but attempted trapping of the corresponding C–heterocyclic radicals by TEMPO was not successful, and substrates incorporating a potential cyclopropyl radical clock gave products with the cyclopropyl ring intact. Theoretical calculations revealed a large activation energy for such reaction, which thus cannot per se exclude the intervention of such radical species. Evidence for the likely operation of two concurrent mechanisms, a radical and a preponderant ionic pathway, involving the conjugate base of the thiazolium salt, as the chemical model for ‘active thiamine’, and ArNO is presented for the formation of the products of the reaction.

Synthesis of 2-amino-4H-3,1-benzoxazines and 2-amino-4H-3,1-benzothiazines by the rearrangement of o-cyclopropylphenylureas and o-cyclopropylphenylthioureas

Syntheses are reported for 2-cyclopropylphenylureas and 2-cyclopropylphenylthioureas and the behavior of these compounds was studied under conditions for the acid-catalyzed opening of the cyclopropyl ring. Upon the action of concentrated sulfuric acid or trifluoroacetic acid, these ureas and thioureas can undergo rearrangement to the corresponding 3,1-benzoxazines and 3,1-benzothiazines.

Synthesis of substituted 6-cyclopropylpurine bases and nucleosides by cross-coupling reactions or cyclopropanations

Synthesis of novel purine bases and nucleosides bearing unsubstituted or substituted cyclopropyl rings in position 6 is reported. Unsubstituted 6-cyclopropylpurines were efficiently prepared by cross-coupling reactions of 6-chloropurines with cyclopropylzinc chloride. 6-Vinylpurines underwent Cu-mediated cyclopropanations with ethyl diazoacetate to give 6-[(ethoxycarbonyl)cyclopropyl]purines that were further transformed to carboxylic acids, amides and alcohols. 6-Cyclopropylpurine ribonucleoside exerted a significant cytostatic effect while all substituted derivatives were inactive.

First Catalytic Functionalization of Unreactive Aryl C-N Bonds in Anilines

The first catalytic functionalization of unreactive aryl C-N bonds with the help of a low-valent transition metal is demonstrated in this article. Hereby, the C-N bond is activated via an oxidative addition to the Ru complex. The subsequent coupling reaction proceeds through trans­metallation between the Ru-amide complex and an organoboronic ester. Cyclopropyl rings are transferred without ring opening.