Showing papers on "Cyclopropane published in 2004"

Strain energy of small ring hydrocarbons. Influence of C-h bond dissociation energies.

Abstract: Ab initio calculations at the G2, G3, and CBS-Q levels of theory have been applied to the question of the origin of ring strain in a series of unsaturated hydrocarbons. In addition to the angular ring strain germane to all three-membered ring hydrocarbons, a general trend is in evidence that suggests that the increased ring strain (SE) of unsaturated small ring alkenes may be attributed in part to their relatively weak allylic C-H bonds. The high strain energy of cyclopropene (54.1 kcal/ mol) is attributed largely to angular strain. The anomalously low SE of cyclobutene relative to cyclobutane (DeltaSE = 4 kcal/mol) is a consequence of normal C-H bond dissociation energies for cyclobutane (100.6 kcal/mol) and very strong vinyl C-H bonds (111.9 kcal/mol) and a relatively strong pi-bond energy (63.5 kcal/mol) for cyclobutene. The greater SE of methylenecyclopropane (39.5 kcal/ mol), relative to methylcyclopropane (29.8 kcal/mol), can be attributed to the strong ring C-H bonds of methylcyclopropane (110.5 kcal/mol) and relatively weak allylic C-H bonds (99.3 kcal/mol) of methylenecyclopropane. The increased SE of 1-methylcyclopropene relative to isomeric methylenecyclopropane is ascribed to its weak ring C-H bonds and to angular strain. The relative thermodynamic stability of a series of small ring alkenes is determined by a measure of their hydrogenation enthalpies. Independent confirmation of the SEs of a series of substituted cyclopropenes is provided by their dimerization/combination with cyclopropane to form a six-membered ring reference compound.

Catalytic regioselectivity control in ring-opening cycloisomerization of methylene- or alkylidenecyclopropyl ketones.

Abstract: 2-Methylene- or alkylidenecyclopropanyl ketones were easily prepared by the regioselective cyclopropanation of allenes or the reaction of methylene-/alkylidenecyclopropanyllithium with N,N-dimethyl carboxylic acid amides. Due to the presence of the exo-cyclic CC bond and the strained cyclopropane, their highly selective ring-opening cycloisomerization using PdCl2(CH3CN)2, NaI (or PdCl2(CH3CN)2 + NaI), and Pd(PPh3)4 as catalysts provided five different products, i.e., 4H-pyrans, 2,3,4-trisubstituted furans (or 4,5-disubstituted-3-alkylidene-2,3-dihydrofurans), and 2,3,4,5-tetrasubtituted furans (or 2,4,5-trisubstituted-3-alkylidene-2,3-dihydrofurans) in good yields, respectively, depending on the nature of the catalyst and reaction conditions. The less-substituted CC bonds in these products can be highly selectively hydrogenated or hydroborated to afford new heterocyclic products stereoselectively. These three types of different reactions may proceed through a highly regioselective cleavage of a carbon−car...

Magnesium Iodide Promoted Reactions of Nitrones with Cyclopropanes: A Synthesis of Tetrahydro-1,2-oxazines

Abstract: Anhydrous magnesium iodide (MgI2) is shown to be an effective promoter of the “homo 3+2” dipolar cycloaddition of nitrones with 1,1-cyclopropane diesters. In almost all cases the products tetrahydro-1,2-oxazines are formed in excellent yields. The reactions are highly diastereoselective for a cis relationship between the substitutents at the 3- and 6-positions on the tetrahydrooxazine ring. As an alternative to using a preformed nitrone, the reaction may be performed in a 3-component sense by combining an aldehyde, an hydroxylamine, and the cyclopropane in the presence of catalytic MgI2.

An Expedient and Practical Method for the Synthesis of a Diverse Series of Cyclopropane α-Amino Acids and Amines

Abstract: A practical synthesis for the preparation of a diverse series of cyclopropane alpha-amino acids is described. Nitrocyclopropane carboxylates can be readily prepared through treatment of alpha-nitroesters and iodobenzene diacetate or alpha-nitro-alpha-diazoesters with a Rh(II) catalyst and an olefin. Reduction of the nitro group using zinc/HCl in i-PrOH affords substituted cyclopropane alpha-amino esters in modest to high yields (54-99%). A "one-pot" procedure involving sequential cyclopropanation and reduction is described. The method can also be applied to the preparation of arylcyclopropyl amines (three examples).

Synthesis and Application of Chiral Cyclopropane-Based Ligands in Palladium-Catalyzed Allylic Alkylation

Abstract: A series of chiral, cyclopropane-based phosphorus/sulfur ligands have been synthesized and evaluated in the palladium-catalyzed allylic alkylation of 1,3-diphenylpropenyl acetate with dimethyl malonate. Variation of the ligand substituents at phosphorus, sulfur, and the carbon backbone revealed 24d to have the optimal configuration for this reaction, giving the product in high yield and with good enantioselectivity (93%). A model for the observed enantioselectivity is discussed within the context of existing models, using X-ray crystallographic data, solution-phase NMR studies, and the absolute stereochemistry of the products. Selected ligands were also evaluated in the palladium-catalyzed intermolecular Heck reaction and the rhodium-catalyzed hydrogenation of a dehydroamino acid.

Theoretical Insights into the Role of a Counterion in Copper‐Catalyzed Enantioselective Cyclopropanation Reactions

Abstract: The effect of a coordinating counteranion on the mechanism of Cu(I)-catalyzed cyclopropanation has been investigated extensively for a medium-sized reaction model by means of theoretical calculations at the B3LYP/6-31G(d) level. The main mechanistic features are similar to those found for the cationic (without a counteranion) mechanism, the rate-limiting step being nitrogen extrusion from a catalyst-diazoester complex to generate a copper-carbene intermediate. The cyclopropanation step takes place through a direct carbene insertion of the metal-carbene species to yield a catalyst-product complex, which can finally regenerate the starting complex. However, the presence of the counteranion has a noticeable influence on the calculated geometries of all the intermediates and transition structures. Furthermore, the existence of a preequilibrium with a dimeric form of the catalyst, together with a higher activation barrier in the insertion step, explains the lower yield of cyclopropane products observed experimentally in the presence of chloride counterion. The stereochemical predictions of a more realistic model (made by considering a chiral bis(oxazoline)-copper(i) catalyst) have been rationalized in terms of the lack of significant steric repulsions, and the model shows good agreement with the low enantioselectivities observed experimentally for these kinds of catalytic systems.

Isotope and elemental effects indicate a rate-limiting methyl transfer as the initial step in the reaction catalyzed by Escherichia coli cyclopropane fatty acid synthase.

Abstract: Cyclopropane fatty acid (CFA) synthases catalyze the formation of cyclopropane rings on unsaturated fatty acids (UFAs) that are natural components of membrane phospholipids. The methylene carbon of the cyclopropane ring derives from the activated methyl group of S-adenosyl-L-methionine (AdoMet), affording S-adenosyl-L-homocysteine (AdoHcys) and a proton as the remaining products. This reaction is unique among AdoMet-dependent enzymes, because the olefin of the UFA substrate is isolated and unactivated toward nucleophilic or electrophilic addition, raising the question as to the timing and mechanism of proton loss from the activated methyl group of AdoMet. Two distinct reaction schemes have been proposed for this transformation; however, neither was based on detailed in vitro mechanistic analysis of the enzyme. In the preceding paper [Iwig, D. F. and Booker, S. J. (2004) Biochemistry 43, http://dx.doi.org/10.1021/bi048693+], we described the synthesis of two analogues of AdoMet, Se-adenosyl-L-selenomethionine (SeAdoMet) and Te-adenosyl-L-telluromethionine (TeAdoMet), and their intrinsic reactivity toward polar chemistry in which AdoMet is known to be involved. We found that the electrophilicity of AdoMet and its onium congeners followed the series SeAdoMet > AdoMet > TeAdoMet, while the acidity of the carbons adjacent to the relevant heteroatom followed the series AdoMet > SeAdoMet > TeAdoMet. When each of these compounds was used as the methylene donor in the CFA synthase reaction, the kinetic parameters of the reaction, k(cat) and k(cat) K(M)(-1), followed the series SeAdoMet > AdoMet > TeAdoMet, suggesting that the reaction takes place via methyl transfer followed by proton loss, rather than by processes that are initiated by proton abstraction from AdoMet. Use of S-adenosyl-L-[methyl-d(3)]methionine as the methylene donor resulted in an inverse isotope effect of 0.87 +/- 0.083, supporting this conclusion and also indicating that the methyl transfer takes place via a tight s(N)2 transition state.

Stereochemistry of cyclopropane formation involving group IV organometallic complexes.

Abstract: The reaction of (Z)-HDCCHCH(OCH3)C6H5 (1) with Cp2Zr(D)Cl followed by BF3·OEt2 gave phenylcyclopropanes 3a and 3b, both having cis deuterium. This stereochemical outcome requires inversion of configuration at the carbon bound to zirconium and is consistent with a “W-shaped” transition state structure for cyclopropane formation. In a Kulinkovich hydroxycyclopropanation, trans-3-deutero-1-methyl-cis-2-phenyl-1-cyclopropanol (5) was formed stereospecifically from Ti(O-i-Pr)4, ethyl acetate, EtMgBr, and trans-β-deuterostyrene. This stereochemistry requires retention of configuration at the carbon bound to titanium and is consistent with frontside attack of the carbon−titanium bond on a carbonyl group coordinated to titanium. In a de Meijere cyclopropylamine synthesis, a 3:1 mixture of N,N-dimethyl-N-(trans-3-deutero-trans-2-phenylcyclopropyl)amine (6a) and N,N-dimethyl-N-(cis-3-deutero-cis-2-phenylcyclopropyl)amine (6b) was formed from Ti(O-i-Pr)4, DMF, Grignard reagents, and trans-β-deuterostyrene. This ster...

Highly regio- and stereoselective synthesis of polysubstituted cyclopropane compounds via the Pd(0)-catalyzed coupling-cyclization reaction of 2-(2',3'-allenyl)malonates with organic halides

Abstract: A new method for highly regio- and stereoselective synthesis of polysubstituted cyclopropane compounds via the Pd(0)-catalyzed coupling-cyclization reaction of 2-(2',3'-allenyl)malonates with organic halides is described. In these reactions, the starting materials are easily available and the operation is convenient. The ratios of trans-isomer/cis-vinylic cyclopropanes are up to 98:2.

Alkylation of carboxylic acid derivatives with dialkoxytitanacyclopropane reagents

Abstract: Methods for the generation of dialkoxytitanacyclopropanes (dialkoxytitanium olefin complexes) are surveyed. Alkylation of carboxylic acid derivatives with these reagents giving rise to β-titanio ketones and related species, which are spontaneously transformed into the corresponding cyclopropane compounds or react with external electrophiles, are considered.

Synthesis of high enantiomeric purity gem-dihalocyclopropane derivatives from biotransformations of nitriles and amides

Abstract: Enantioselective biotransformations of geminally dihalogenated cyclopropanecarbonitriles and amides are described. Both the reaction rate and enantioselectivity of the nitrile hydratase and amidase involved in Rhodococcus sp. AJ270 microbial cells are strongly governed by the nature of gem -disubstituents on the cyclopropane ring; the amidase generally exhibits steric dependence on the substituents while both the steric and electronic factors of the substituents may affect the action of the nitrile hydratase. The match of steric bulkiness of the substituents at 2- with that at 3-positions on the cyclopropane ring benefits the efficient and highly enantioselective reaction. Coupled with facile chemical transformations, biocatalytic transformations of nitrile and amide supply an effective synthesis of optically active 2,2-disubstitued-3-phenylcyclopropanecarboxylic acid and amide in both enantiomeric forms.

Structural analysis of pseudomonas 1 -aminocyclopropane-1 -carboxylate deaminase complexes: insight into the mechansim of a unique pyridoxal-5-phosphate dependent cyclopropane ring-opening reaction

Abstract: 1-Aminocyclopropane-1-carboxylate (ACC) deaminase is a pyridoxal 5'-phosphate (PLP) dependent enzyme catalyzing the opening of the cyclopropane ring of ACC to give alpha-ketobutyric acid and ammonia as the products. This ring cleavage reaction is unusual because the substrate, ACC, contains no abstractable alpha-proton and the carboxyl group is retained in the product. How the reaction is initiated to generate an alpha-carbanionic intermediate, which is the common entry for most PLP-dependent reactions, is not obvious. To gain insight into this unusual ring-opening reaction, we have solved the crystal structures of ACC deaminase from Pseudomonas sp. ACP in complex with substrate ACC, an inhibitor, 1-aminocyclopropane-1-phosphonate (ACP), the product alpha-ketobutyrate, and two d-amino acids. Several notable observations of these structural studies include the following: (1) a typically elusive gem-diamine intermediate is trapped in the enzyme complex with ACC or ACP; (2) Tyr294 is in close proximity (3.0 A) to the pro-S methylene carbon of ACC in the gem-diamine complexes, implicating a direct role of this residue in the ring-opening reaction; (3) Tyr294 may also be responsible for the abstraction of the alpha-proton from d-amino acids, a prelude to the subsequent deamination reaction; (4) the steric hindrance precludes accessibility of active site functional groups to the l-amino acid substrates and may account for the stereospecificity of this enzyme toward d-amino acids. These structural data provide evidence favoring a mechanism in which the ring cleavage is induced by a nucleophilic attack at the pro-S beta-methylene carbon of ACC, with Tyr294 as the nucleophile. However, these observations are also consistent with an alternative mechanistic possibility in which the ring opening is acid-catalyzed and may be facilitated by charge relay through PLP, where Tyr294 functions as a general acid. The results of mutagenesis studies corroborated the assigned critical role for Tyr294 in the catalysis.

Cyclopropane compounds and pharmaceutical use thereof

Abstract: The present invention provides a compound having aggrecanase inhibitory activity and MMP-13 inhibitory activity, and useful as a therapeutic agent for osteoarthritis, rheumatoid arthritis and the like, more specifically, a cyclopropane compound of formula (1): wherein R1 is - (CH2) m-X- (CH2)n-A1 etc, wherein m and n are the same or different and each is 0 to 6, X is a single bond, etc and A1 is a substituted C3-14 hydrocarbon ring group, etc; R2 and R3 are the same or different and each is a hydrogen atom, -(CH2)p-X1-(CH2)q-A2, etc, wherein p and q are the same or different and each is 0 to 6, X1 is a single bond, etc and A2 is an optionally substituted C3-14 hydrocarbon ring group, etc; R4 is -C02R9, etc, wherein R9 is a hydrogen atom, etc; and R20 and R21 are the same or different and each is a hydrogen atom, - (CH2)m12-X12- (CH2)m12-R30, etc, wherein m12 and m12 are the same or different and each is 0 to 6, X12 is a single bond, etc and R30 is a hydrogen atom, etc; or a prodrug thereof or a pharmaceutically acceptable salt thereof

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

Abstract: 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.

A theoretical study on the cyclopropane adsorption onto the copper surfaces by density functional theory and quantum chemical molecular dynamics methods

Abstract: We report a theoretical study on the cyclopropane adsorption onto Cu(1 1 1) surfaces by density functional theory (DFT) and quantum chemical molecular dynamics methods. The equilibrium geometry of the physisorbed species was obtained using both periodic and cluster models by DFT methods that employ Cambridge serial total energy package (CASTEP), DMol ab initio quantum chemistry software of Accelrys’ materials studio (DMol), and Amsterdam density functional (ADF) program. It was found that the adsorbate molecule was tilted towards the metal surface with one CC bond (upwards) parallel to the surface and that the physisorption occurred via a third carbon atom pointing (downwards) towards the surface. The electronic distribution and geometrical structure of physisorbed cyclopropane were slightly deviated from its gas phase molecule. The calculated vibrational frequencies and adsorption energies are close to experimental data, confirming the reliability of our DFT results. The adsorption process was simulated using our novel tight-binding quantum chemical molecular dynamics program, ‘Colors’. The calculation results indicated that both the adsorption and desorption processes of cyclopropane took place molecularly. The electron transfer and structural properties of equilibrium position obtained by ‘Colors’ are consistent with those by the first principles DFT methods.

Mechanism of Substitution Reaction on sp2-Carbon Center with Lithium Organocuprate

Abstract: Theory and experiments suggest that the substitution reaction of a lithium dialkylcuprate(I) with an alkenyl bromide takes place through a pi-complex (cuprio(III)cyclopropane) that directly breaks down to the alkenylated product rather than via a conventional three-centered transition state. This mechanism is consistent with the broader mechanistic picture of the organocuprate reactions and accounts for the retentive stereochemistry and the kinetic isotope effect observed in the experiments.

Most stable conformation of the cyclopropane ring attached at a carbon atom in a 1,2-dicarba-closo-dodecaborane(12) system.

Abstract: We obtained two crystal structures of electronically interesting dicarba-closo-dodecaborane(12)s (hereafter, “carboranes”) substituted with a cyclopropyl group at a caged carbon atom, i.e., C-cyclopropyl-o-carborane (4) and C-cyclopropyl-o-carboranylphenylmethanol (9), at 123 K. In these C-cyclopropyl-o-carboranes, the cyclopropyl group adopted a slightly twisted perpendicular conformation with respect to the electron-deficient carbon−carbon (C−C) bond axis in the o-carborane cage. In contrast, it has previously been shown that a phenyl group substituted at the caged carbon atom, i.e., C-phenyl-o-carborane (3), is almost parallel to this axis at both 150 and 199 K. In other words, the π system of the phenyl ring adopted an almost bisected conformation in 3. The preferred conformation of the cyclopropane ring in these C-cyclopropyl-o-carboranes was compared among the solid, the solution, and the gaseous states and was retained under the present conditions. Moreover, we found that the C−C bond length in the...

Efficient synthesis of protected cyclopropyl β-aspartylphosphates

Abstract: The in situ reaction of protected dehydroamino acids with derivatives of vinyldiazomethane leads to good to excellent yields of vinyl cyclopropanes via 3 + 2 dipolar cycloaddition followed by N2 extrusion. Chromatographic separation of the cyclopropane diastereomeric products, followed by characterisation by 1H NMR and X-ray crystallography allowed the cis and trans diastereomers to be easily identified. Oxidative cleavage of the vinyl moiety then led directly to protected cyclopropane aspartic acid derivatives in three steps from commercially available materials. These compounds were converted to protected methylenephosphonate, difluoromethylenephosphonate and phosphoramidate analogues of β-aspartyl phosphate.

Stereoselective Synthesis of Pentacarbonyl(3-oxa-2-bicyclo[3.1.0]hexylidene)- and Pentacarbonyl(cyclopropylmethoxymethylene)tungsten Compounds on the Route to Cyclopropane-γ-lactones and -carboxylates

Abstract: The diastereoselective synthesis of pentacarbonyl-3-oxa-2-bicyclo[3.1.0]hexylidene- and pentacarbonyl(cyclopropylmethoxymethylene)tungsten compounds 4 and 9 by the reaction of lithiated oxazolinylo...