Cyclopropane Formation Research Articles

Gas Phase Pyrolysis Reaction of 1-pyrazoline: A Theoretical Kinetic Study

We report kinetic and mechanistic studies of nitrogen elimination from 1-pyrazoline and its deuterated derivatives. This study was carried out for the gas phase employing 6-311 + G(d,p) basis sets with B3LYP, MPW1PW91 and PBEPBE methods. This reaction may proceed through two different mechanisms, molecular and radical. The molecular mechanism advances via two different paths and corresponding intermediates. There are either a four-centred cyclic or a six-centred cyclic intermediate as transition states in the molecular mechanism. The calculated kinetic parameters and isotope effects for the molecular mechanism are consistent with experimental results for cyclopropane formation. However, from the kinetic isotope effects point of view, the fit is better for the radical mechanism for propene formation. Considering activation energies, theoretical calculations suggest that the radical mechanism is the less suitable. The B3LYP method results are in a better agreement with the experimental results when considering only computational data.

An Efficient and Safe Method for the Multigram Synthesis of trans-2-(Trifluoromethyl)cyclopropylamine

trans-2-(Trifluoromethyl)cyclopropylamine was prepared on a multigram scale from readily accessible 4,4,4-trifluorobut-2-enoic acid in five steps. The key step was a high-yielding cyclopropane ring formation from 4,4,4-trifluorobut-2-enoic acid methoxymethyl amide under Corey-Chaykovsky reaction conditions.

Asymmetric oxidative Lewis base catalysis—unifying iminium and enamine organocatalysis with oxidations

Enantioselective oxidative domino reactions of allylic alcohols to functionalized aldehydes have been developed. The one pot domino oxidation-iminium activation represents a convenient strategy for the enantioselective addition of malonates to allylic alcohols and the asymmetric formation of formyl cyclopropanes.

Synthesis and some transformations of 2- and 2,2′-substituted bis(ethylenedioxy)biphenyls containing cyclopropane fragments

3,4: 3′,4′-Bis(ethylenedioxy)biphenyl undergoes bromination, nitration, and cyclopropylcarbonylation only at the 2-position. Analogous reactions with 2-substituted bis(ethylenedioxy)biphenyls occur regioselectively at the 2′-position. The reactions of 2-cyclopropylcarbonyl- and 2,2′-bis(cyclopropylcarbonyl)bis(ethylenedioxy)biphenyls with complex metal hydrides afforded the corresponding arylcyclopropylcarbinols which tended to undergo intramolecular alkylation of the aromatic ring with conservation of the cyclopropane fragment (monosubstituted derivatives) and formation of cyclopropyl-containing cyclic ethers (disubstituted ethylenedioxybiphenyls). The reduction of the nitro group in 2′-cyclopropylcarbonyl-2-nitro-4,5: 4′,5′-bis(ethylenedioxy)biphenyl was accompanied by intramolecular cyclization involving spatially close functional groups, the cyclopropane fragment remaining intact.

Insights from the sea: Structural biology of marine polyketide synthases

The world's oceans are a rich source of natural products with extremely interesting chemistry. Biosynthetic pathways have been worked out for a few, and the story is being enriched with crystal structures of interesting pathway enzymes. By far, the greatest number of structural insights from marine biosynthetic pathways has originated with studies of curacin A, a poster child for interesting marine chemistry with its cyclopropane and thiazoline rings, internal cis double bond, and terminal alkene. Using the curacin A pathway as a model, structural details are now available for a novel loading enzyme with remarkable dual decarboxylase and acetyltransferase activities, an Fe(2+)/α-ketoglutarate-dependent halogenase that dictates substrate binding order through conformational changes, a decarboxylase that establishes regiochemistry for cyclopropane formation, and a thioesterase with specificity for β-sulfated substrates that lead to terminal alkene offloading. The four curacin A pathway dehydratases reveal an intrinsic flexibility that may accommodate bulky or stiff polyketide intermediates. In the salinosporamide A pathway, active site volume determines the halide specificity of a halogenase that catalyzes for the synthesis of a halogenated building block. Structures of a number of putative polyketide cyclases may help in understanding reaction mechanisms and substrate specificities although their substrates are presently unknown.

New way to substitute tetracyanocyclopropanes: one-pot cascade assembling of carbonyls and malononitrile by the only bromine direct action.

The new type of the chemical cascade reaction was found: formation of cyclopropanes from carbonyl compounds and CH acid by the only bromine direct action. The action of aqueous bromine on the carbonyl compounds and malononitrile in EtOH-H2O solutions in the presence of NaOAc results in the formation of 3-substituted 1,1,2,2-tetracyanocyclopropanes in 48–93% yields. The latter are well-known precursors for the different bicyclic heterosystems, among them those containing cyclopropane ring and those possessing different types of pharmacological activity.

ChemInform Abstract: Radical Cyclization Reactions. Cyclopropane Ring Formation by 3-exo-Cyclization of 5-Phenylthio-3-pentenyl Radicals.

ChemInform Abstract: Radical Cyclization Reactions. Cyclopropane Ring Formation by 3-exo-Cyclization of 5-Phenylthio-3-pentenyl Radicals.

ChemInform Abstract: Synthesis of Cycloprop(c)indol-5-ones from 4-Diazo-3-(N-(2-propenyl) amido)cyclohexadien-1-ones. Exploration of Copper(I) and Copper(II) Complexes as Catalysts.

The cyclization of 4-diazo-3-[N-(2-propenyl)amido]cyclohexadienones to cycloprop[c]indol-5-ones under the influence of copper(I) and copper(II) compounds has been investigated. Catalysis is observed with copper(I) triflate, the carbon monoxide complexe of copper(I) triflate, and the carbon monoxide complexes of trifluoropentanedionato- and hexafluoropentanedionatocopper(I). The best results, essentially quantitative conversion, are achieved with a catalyst solution containing trifluoropentanedionatocopper(I) carbonyl and 1 equiv of n-butalymine. No significant enantioselectivity is observed with a chiral salicyliminatocopper(II), [(trifluoroacetyl)camphorato]copper(I) carbonyl, or a trifluoropentanedionatocopper(I) carbonyl solution containing (S)-α-naphthylethylamine. A mechanistic interpretation involving reductive dediazonization, exo-trig radical cyclization, and cyclopropane formation by the resulting intermediate is proposed

Conformational switch triggered by α-ketoglutarate in a halogenase of curacin A biosynthesis

The CurA halogenase (Hal) catalyzes a cryptic chlorination leading to cyclopropane ring formation in the synthesis of the natural product curacin A. Hal belongs to a family of enzymes that use Fe(2+), O(2) and alpha-ketoglutarate (alphaKG) to perform a variety of halogenation reactions in natural product biosynthesis. Crystal structures of the enzyme in five ligand states reveal strikingly different open and closed conformations dependent on alphaKG binding. The open form represents ligand-free enzyme, preventing substrate from entering the active site until both alphaKG and chloride are bound, while the closed form represents the holoenzyme with alphaKG and chloride coordinated to iron. Candidate amino acid residues involved in substrate recognition were identified by site-directed mutagenesis. These new structures provide direct evidence of a conformational switch driven by alphaKG leading to chlorination of an early pathway intermediate.

‘Carbene Radicals’ in CoII(por)-Catalyzed Olefin Cyclopropanation

The mechanism of cobalt(II)-porphyrin-mediated cyclopropanation of olefins with diazoesters was studied. The first step--reaction of cobalt(II)-porphyrin with ethyl diazoacetate (EDA)--was examined using EPR and ESI-MS techniques. EDA reacts with cobalt(II)-porphyrin to form a 1:1 Co(por)(CHCOOEt) adduct that exists as two isomers: the 'bridging carbene' C' in which the 'carbene' is bound to the metal and the pyrrolic nitrogen of the porphyrin that has a d(7) configuration on the metal, and the 'terminal carbene' C in which the 'carbene' behaves as a redox noninnocent ligand having a d(6) cobalt center and the unpaired electron residing on the 'carbene' carbon atom. The subsequent reactivities of the thus formed 'cobalt carbene radical' with propene, styrene, and methyl acrylate were studied using DFT calculations. The calculations suggest that the formation of the carbene is the rate-limiting step for the unfunctionalized Co(II)(por) and that the cyclopropane ring formation proceeds via a stepwise radical process: Radical addition of the 'carbene radical' C to the C=C double bonds of the olefins results in formation of the gamma-alkyl radical intermediates D. Species D then easily collapse in almost barrierless ring-closure reactions (TS3) to form the cyclopropanes. This radical mechanism readily explains the high activity of Co(II)(por) species in the cyclopropanation of electron-deficient olefins such as methyl acrylate.

Organocatalyzed Cyclopropanation of α‐Substituted α,β‐Unsaturated Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral Quaternary Center

An enantioselective cyclopropanation of alpha-substituted alpha,beta-unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/alpha-alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the alpha-position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and alpha,beta-unsaturated aldehydes previously reported by other groups. Very good yields (up to 81%) and enantioselectivities (up to 97% ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures.

ChemInform Abstract: Cyclopropane Ring Formation by an SmI2-Mediated Cyclization of δ-Halo-α,β-Unsaturated Esters.

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.

Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N, N′-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons–Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald–Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The p K a of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74±0.05, which is 1.3 p K a units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules.

One-pot cascade assembling of 3-substituted tetracyanocyclopropanes from alkylidenemalononitriles and malononitrile by the only bromine direct action

The new cascade reaction was found: the formation of cyclopropanes from alkylidenemalononitriles and malononitrile by the only bromine direct action; the action of aqueous bromine on the equal amounts of alkylidenemalononitriles and malononitrile in EtOH–H 2 O solutions results in the formation of 3-substituted 1,1,2,2-tetracyanocyclopropanes in 55–98% yields.

ChemInform Abstract: Selective Formation of Spiro Dihydrofurans and Cyclopropanes Through Unexpected Reaction of Aldehydes with 1,3‐Dicarbonyl Compounds.

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.

Organylthio(silyl)carbenes

AbstractThe title carbenes 5 can be generated either from diazo compounds 9 by copper‐catalyzed catalysis or from chloro(organylthio)methylsilanes 12 by base‐induced α‐elimination. This is confirmed by [2+1] cycloadditions with alkenes to give the cyclopropanes 4a–d and 14. Product 4a is identical with the product obtained from carbanion 1c, phenyloxirane, and styrene, for which a carbene intermediate 5a had been invoked. On heating in the presence of copper triflate, cyclopropane 4a undergoes ring enlargement to the thiochroman 11. With (Z)‐ or (E)‐alkenes 20, carbene 5a gives stereospecific cyclopropane formation, although maleate turns out not to be a suitable indicator for a stereospecific cycloaddition. The suggested singlet character of 5 is confirmed by DFT calculations (B3LYP/cc‐pVTZ). The structures of cyclopropanes 4a and 23, as well as those of thiochroman 11 and carbene dimer 15, were confirmed by single‐crystal X‐ray investigations.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Metamorphic enzyme assembly in polyketide diversification

Natural product chemical diversity is fuelled by the emergence and ongoing evolution of biosynthetic pathways in secondary metabolism. However, co-evolution of enzymes for metabolic diversification is not well understood, especially at the biochemical level. Here, two parallel assemblies with an extraordinarily high sequence identity from Lyngbya majuscula form a beta-branched cyclopropane in the curacin A pathway (Cur), and a vinyl chloride group in the jamaicamide pathway (Jam). The components include a halogenase, a 3-hydroxy-3-methylglutaryl enzyme cassette for polyketide beta-branching, and an enoyl reductase domain. The halogenase from CurA, and the dehydratases (ECH(1)s), decarboxylases (ECH(2)s) and enoyl reductase domains from both Cur and Jam, were assessed biochemically to determine the mechanisms of cyclopropane and vinyl chloride formation. Unexpectedly, the polyketide beta-branching pathway was modified by introduction of a gamma-chlorination step on (S)-3-hydroxy-3-methylglutaryl mediated by Cur halogenase, a non-haem Fe(ii), alpha-ketoglutarate-dependent enzyme. In a divergent scheme, Cur ECH(2) was found to catalyse formation of the alpha,beta enoyl thioester, whereas Jam ECH(2) formed a vinyl chloride moiety by selectively generating the corresponding beta,gamma enoyl thioester of the 3-methyl-4-chloroglutaconyl decarboxylation product. Finally, the enoyl reductase domain of CurF specifically catalysed an unprecedented cyclopropanation on the chlorinated product of Cur ECH(2) instead of the canonical alpha,beta C = C saturation reaction. Thus, the combination of chlorination and polyketide beta-branching, coupled with mechanistic diversification of ECH(2) and enoyl reductase, leads to the formation of cyclopropane and vinyl chloride moieties. These results reveal a parallel interplay of evolutionary events in multienzyme systems leading to functional group diversity in secondary metabolites.

A new type of cascade reaction: direct conversion of carbonyl compounds and malononitrile into substituted tetracyanocyclopropanes

A new type of chemical cascade reaction was found: the direct formation of cyclopropanes from carbonyl compounds and C–H acid. The action of free halogen or active halogen containing compounds on a mixture of 1 equiv of carbonyl compound and 2 equiv of malononitrile in a basic alcohol solution results in the formation of substituted 1,1,2,2-tetracyanocyclopropanes in 15–80% yield. The latter are well-known precursors for the different bicyclic heterosystems, among them compounds containing a cyclopropane ring and possessing different types of pharmacological activity. Thus, the new, simple and efficient ‘one-pot’ way to substituted tetracyanocyclopropanes in 50–80% yield was found directly from such simple and reasonable starting compounds as aldehydes, or some cyclic ketones, or substituted cyclohexanones and malononitrile.

TfNH2 as Achiral Hydrogen-Bond Donor Additive to Enhance the Selectivity of a Transition Metal Catalyzed Reaction. Highly Enantio- and Diastereoselective Rhodium-Catalyzed Cyclopropanation of Alkenes Using α-Cyano Diazoacetamide

A highly stereoselective (up to 98% ee and 99:1 dr) Rh(II)-catalyzed formation of nitrile-substituted cyclopropanes is described. Alpha-cyano diazoacetamide reagents react with a variety of mono- and disubstituted olefins in good yields and excellent enantio- and diastereocontrol. Less reactive substrates, such as aliphatic olefins, also undergo the reaction. This new methodology features the unprecedented use of an achiral hydrogen-bond donor additive to enhance the selectivity and exploits the powerful trans-directing ability of amides solving the diastereocontrol issue of the formation of substituted 1-cyanocyclopropane-1-carboxy derivatives.

Selective Formation of Spiro Dihydrofurans and Cyclopropanes Through Unexpected Reaction of Aldehydes with 1,3-Dicarbonyl Compounds

An efficient methodology for the oxidative addition reaction of various aldehydes with 5,5-dimethylcyclohexane-1,3-dione and 1,3-indandione to selectively afford spiro dihydrofuran and cyclopropane derivatives, promoted by molecular iodine and dimethylaminopyridine under mechanical milling conditions, has been demonstrated. The products were obtained in good to excellent yields. A possible mechanism of this unusual reaction process is proposed.