Trans Cyclopropane Research Articles

Experimental and Computational Studies for the Synthesis of Functionalized Cyclopropanes from 2-Substituted Allylic Derivatives with Ethyl Diazoacetate.

The catalytic asymmetric synthesis of highly functionalized cyclopropanes from 2-substituted allylic derivatives is reported. Using ethyl diazo acetate, the reaction, catalyzed by a chiral ruthenium complex (Ru(II)-Pheox), furnished the corresponding easily separable cis and trans cyclopropanes in moderate to high yields (32-97 %) and excellent ee (86-99 %). This approach significantly extends the portfolio of accessible enantioenriched cyclopropanes from an underexplored class of olefins. DFT calculations suggest that an outer-sphere mechanism is operative in this system.

Rapid and Modular Access to Vinyl Cyclopropanes Enabled by Air‐stable Palladium(I) Dimer Catalysis

AbstractWhile vinyl cyclopropanes are valuable functional groups in drugs or natural products as well as established precursors to trigger a rich variety of synthetic transformations, their reactive nature can make their installation via direct catalytic approaches challenging. We herein present a modular access to (di)vinyl cyclopropanes under very mild conditions and full conservation of stereochemistry, allowing access to thecisortranscyclopropane‐ as well asEorZvinyl‐stereochemical relationships. Our protocol relies on air‐stable dinuclear PdIcatalysis, which enables rapid (<30 min) and selective access to a diverse range of vinyl cyclopropane motifs at room temperature, even on gram scale.

Rapid and Modular Access to Vinyl Cyclopropanes Enabled by Air-stable Palladium(I) Dimer Catalysis.

While vinyl cyclopropanes are valuable functional groups in drugs or natural products as well as established precursors to trigger a rich variety of synthetic transformations, their reactive nature can make their installation via direct catalytic approaches challenging. We herein present a modular access to (di)vinyl cyclopropanes under very mild conditions and full conservation of stereochemistry, allowing access to the cis or trans cyclopropane- as well as E or Z vinyl-stereochemical relationships. Our protocol relies on air-stable dinuclear PdI catalysis, which enables rapid (<30 min) and selective access to a diverse range of vinyl cyclopropane motifs at room temperature, even on gram scale.

Novel trans iodo(2-(N-alkylsulfamoyl)phenyl)bis(-triphenylphosphine palladium) complexes: Synthesis, mass spectrometry, X-ray structural description, steric map, near infrared analyses and catalytic activities evaluation

2-iodo-N-ethylbenzenesulfonamide and 2-iodo-N-isopropylbenzenesulfonamide are used to prepare two novel palladium(II) complexes (4 and 5) by oxidative addition starting from Pd(PPh3)4. The desired complexes are fully characterized by 1H, 13C, 31P NMR and near infrared spectroscopy. Electron spray ionization mass spectrometry analyses showed identical fragmentation process of the complexes starting by the iodine cleavage. The molecular structures of the complexes 4 and 5 are confirmed by X-ray diffraction analysis. The crystal packing of these complexes are stabilized by the presence of hydrogen bonds established between oxygen and hydrogen atoms of the sulfonamide groups. In addition, Hirshfeld surface mapped over dnorm, Shape index and molecular electrostatic potential were used to describe the short interactions and electron reach domains. The analyses of molecular fingerprints reveal similar percentage of H···H (∼67%), H···C/C···H (∼23%), H···I/I···H (∼5%) and H···O/O···H (∼4.5%) contacts in 4 and 5. The valuation of the percentage of buried volume (%VBur) of these ligands shows that the N-ethyl- and N-isopropylbenzenesulfonamide substituents took around 30% share of the palladium coordination sphere. Finally, the catalytic activities of these new palladium complexes are evaluated in cyclopropanation of styrene and in atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA). The results showed that trans cyclopropane was obtained as major product independently to the tested catalyst. In polymerization reaction, the catalysts show moderate activity and did not induce a controlled polymerization of MMA.

Kinetic study of stereoselective synthesis of highly functionalized cyclopropane catalyzed by triphenylarsine

A DFT method was used to enlighten the reaction mechanism between dimethylacetylendicarboxylate (DMAD) and acetylacetone (ACAC) in the presence of triphenylarsine (TPA) as an efficient catalyst. Different paths of mechanism and transition states with possible intermediates were proposed and evaluated thermodynamically and kinetically. The results showed that the reaction starts with a nucleophilic attack by the TPA on the DMAD, and then it was followed by other four steps. For all of the intermediates, Z conformer was more favorable than E conformer, and also the trans configuration of the product was more favorable than of cis configuration. Enol form of ACAC was more preferred than keto form in step4, but keto form was favorable for the other steps. For this reason, the reaction mechanism couldn’t proceed through the enol-form, and the mechanism regarding keto-form of ACAC was the right mechanism. There were two possibilities for the proton-transferring step4 which lead to different products. Trans di (methoxycarbonyl)-3,3-diacetylcyclopropane product 3, which was the result of 1, 3 non-linear proton-transfer arrangement and (Z)-Alkene dimethyl 2-(pentane-2,4-dione) fumarate (product 4) which was produced by 1, 2 non-linear proton-transferring arrangement. Thermodynamic parameters exhibited that Z-Alkene is more stable than cyclopropane product, but cyclopropane product was more preferred kinetically (Ea trans cyclopropane = 44.75 kcal mol−1, Ea Alkene = 66.75 kcal mol−1).

Diastereoselective Radical-Type Cyclopropanation of Electron-Deficient Alkenes Mediated by the Highly Active Cobalt(II) Tetramethyltetraaza[14]annulene Catalyst.

A new protocol for the catalytic synthesis of cyclopropanes using electron‐deficient alkenes is presented, which is catalysed by a series of affordable, easy to synthesise and highly active substituted cobalt(II) tetraaza[14]annulenes. These catalysts are compatible with the use of sodium tosylhydrazone salts as precursors to diazo compounds in one‐pot catalytic transformations to afford the desired cyclopropanes in almost quantitative yields. The reaction takes advantage of the metalloradical character of the Co complexes to activate the diazo compounds. The reaction is practical and fast, and proceeds from readily available starting materials. It does not require the slow addition of diazo reagents or tosylhydrazone salts or heating and tolerates many solvents, which include protic ones such as MeOH. The CoII complexes derived from the tetramethyltetraaza[14]annulene ligand are easier to prepare than cobalt(II) porphyrins and present a similar catalytic carbene radical reactivity but are more active. The reaction proceeds at 20 °C in a matter of minutes and even at −78 °C in a few hours. The catalytic system is robust and can operate with either the alkene or the diazo reagent as the limiting reagent, which inhibits the dimerisation of diazo compounds totally. The protocol has been applied to synthesise a variety of substituted cyclopropanes. High yields and selectivities were achieved for various substrates with an intrinsic preference for trans cyclopropanes.

Stereocontrolled asymmetric synthesis of syn-E-1,4-diol-2-enes using allyl boronates and its application in the total synthesis of solandelactone F

The solandelactones A-H comprise a novel class of oxygenated fatty acids bearing an eight-membered lactone, trans cyclopropane, and a 2-ene-1,4-diol subunit. The relative stereochemistry of the 1,4-diol subunit is anti in solandelactones A, C, E & G, and syn in solandelactones B, D, F & H. Having prepared one member of the solandelactones bearing anti stereochemistry (solandelactone E), we have targeted the syn series and developed methodology for the synthesis of enantioenriched syn-2-ene-1,4-diols. The methodology comprises asymmetric deprotonation of an alkyl 2,4,6-triisopropylbenzoate using sBuLi/sparteine, followed by addition of the α-lithiobenzoate to β-silyl vinyl boronic acid ethylene glycol ester. The boron-ate complex generated undergoes a 1,2-metallate rearrangement furnishing an intermediate allyl boronic ester which is trapped by an aldehyde in the presence of MgBr(2) to furnish anti-β-hydroxy E-allylsilanes in good yields, high diastereoselectivity and high enantioselectivity. These sensitive products were oxidized using mCPBA to the corresponding epoxides and subsequently treated with acid to furnish syn-E-2-ene-1,4-diols (~4:1 d.r.). Application of the methodology to appropriately functionalized aldehyde and ω-alkenyl 2,4,6-triisopropylbenzoate coupling partners, led to a short, highly selective route to solandelactone F (bearing a syn-E-2-ene-1,4-diol).

Copper Bis(oxazoline) Encapsulated in Zeolites and Its Application as Heterogeneous Catalysts for the Cyclopropanation of Styrene

A copper C2-symmetric bis(oxazoline), CuBox, was introduced in two forms of commercial Y zeolite: a sodium form (NaY) and an ultrastable form (NaUSY). CuBox was introduced by first partially exchanging the sodium cations of both zeolites for copper and then by refluxing the obtained materials with a solution of bis(oxazoline) (Box). Two different loadings were prepared for each form of zeolite. The materials were characterized by copper ICP-AES, elemental analysis, XPS, FTIR, TG, and nitrogen adsorption isotherms at −196 °C. Evidence for Box ligand location in the supercages of NaY and NaUSY zeolites and its coordination to the exchanged copper(II) was obtained by the several techniques used. The materials were all active in the cyclopropanation of styrene with ethyldiazoacetate at room temperature and diastereoselective toward trans cyclopropanes. Although the materials containing Box showed low enantioselectivities, their catalytic activities were higher than the parent copper exchanged zeolites, and did not decrease with reuse, at least during three consecutive cycles.

Metal-organic framework based on copper(I) sulfate and 4,4 ′-bipyridine catalyzes the cyclopropanation of styrene

The hydrothermal synthesis of a new metal-organic framework (MOF) formulated as Cu 2(4,4′-bpy) 2SO 4·6(H 2O), [abbreviation: (1); bpy or 4,4′-bpy=4,4′-bipyridine; SO 4 2−=sulfate group] has been reported. The structure of this MOF consists of Cu + nodes connected via 4,4′-bpy to form infinite chains, with two neighboring chains further bridged on the nodes by SO 4 2−, resulting in a 1-D double chain network. Guest water molecules reside in between the chains and are hydrogen-bonded to the O and S atoms from the nearest sulfate groups, leading to the formation of a 3-D supramolecular framework. This MOF is good heterogeneous catalyst for the cyclopropanation of styrene, with high trans cyclopropane diastereoselectivity and was recycled and reused for three consecutive cycles without a significant loss of catalytic activity.

Asymmetric Total Synthesis of Solandelactone E: Stereocontrolled Synthesis of the 2‐ene‐1,4‐diol Core through a Lithiation–Borylation–Allylation Sequence

The solandelactones comprise a novel class of oxygenated fatty acids that contain an eight-membered lactone linked to a trans cyclopropane, and were first isolated by Shin and coworkers in 1996 from the hydroid Solanderia secunda. These compounds belong to a wider group of marine oxylipins that contain the linked lactone and cyclopropane unit, including halicholactone and the constanolactones. Initial assignment of structure and absolute stereochemistry was based primarily on NMR studies, which led to two sets of compounds depending on their configuration at C11: R configuration for A, C, E, and G; S configuration for B, D, F, and H. However, the experimental data for synthetic solandelactone “F”, which had been synthesized by Martin and coworkers, matched the data for solandelactone E, thus indicating that the two sets of compounds had been incorrectly assigned. Further syntheses by White et al. as well as Pietruszka and Rieche confirmed that the configuration at C11 in all of the solandelactones A–H should be depicted as in Scheme 1.

Effect of support properties on the performance of silica-supported bis(oxazoline)–copper chiral complexes

Mesoporous silica materials with different textural properties have been prepared by sol–gel synthesis under mild acidic conditions, and used as supports for chiral IndaBox ligand. After complexation with copper, these solids are catalysts for cyclopropanation reactions. Enantioselectivities in the range of 52–57% e.e. for cis cyclopropanes and 42–48% e.e. for trans cyclopropanes are obtained without any effect of the textural properties. However, these properties show an important effect on the activity and mainly on the recyclability of the catalyst. In contrast with the expected effect, solids with very large pores but low surface area lead to a significant deactivation upon recovery, whereas solids with highly developed surface area lead to the best overall results.

Redundant Function ofcmaA2andmmaA2inMycobacterium tuberculosis cisCyclopropanation of Oxygenated Mycolates

The Mycobacterium tuberculosis cell envelope contains a wide variety of lipids and glycolipids, including mycolic acids, long-chain branched fatty acids that are decorated by cyclopropane rings. Genetic analysis of the mycolate methyltransferase family has been a powerful approach to assign functions to each of these enzymes but has failed to reveal the origin of cis cyclopropanation of the oxygenated mycolates. Here we examine potential redundancy between mycolic acid methyltransferases by generating and analyzing M. tuberculosis strains lacking mmaA2 and cmaA2, mmaA2 and cmaA1, or mmaA1 alone. M. tuberculosis lacking both cmaA2 and mmaA2 cannot cis cyclopropanate methoxymycolates or ketomycolates, phenotypes not shared by the mmaA2 and cmaA2 single mutants. In contrast, a combined loss of cmaA1 and mmaA2 had no effect on mycolic acid modification compared to results with a loss of mmaA2 alone. Deletion of mmaA1 from M. tuberculosis abolishes trans cyclopropanation without accumulation of trans-unsaturated oxygenated mycolates, placing MmaA1 in the biosynthetic pathway for trans-cyclopropanated oxygenated mycolates before CmaA2. These results define new functions for the mycolic acid methyltransferases of M. tuberculosis and indicate a substantial redundancy of function for MmaA2 and CmaA2, the latter of which can function as both a cis and trans cyclopropane synthase for the oxygenated mycolates.

Energetic, geometric and magnetic analysis of all- syn, trans cyclic cyclopropanes

Structural, energetic and magnetic properties of a series of cyclic cyclopropanes have been investigated on the DFT (B3LYP/6-31G(d)) level. The cyclization of these oligomeric all- syn, trans cyclopropanes, designated [ N]rondelanes, should be possible on energetic grounds, since no substantial destabilization energies were calculated for the larger homologues. However, the high strain for the smaller rondelanes might prevent their successful synthesis. Thermochemical reactions, structural data, and NICS values were investigated in order to test for homoaromatic stabilization. The careful choice of a homoisodesmic reaction revealed weak aromatic stabilization energies for [3] and [7]rondelane, 2.3 kcal/mol and 2.2 kcal/mol, respectively. However, we could not observe a pattern according to the Hückel rule and the stabilization energies are small compared to the stabilization of cyclopropane due to σ-aromaticity. Calculated structural data indicate homoconjugation for the smaller homologues. [3]Rondelane showed a NICS value of −2.54 indicating a weak neutral homoaromaticity.

Density Functional Theory Investigations on Sulfur Ylide Promoted Cyclopropanation Reactions: Insights on Mechanism and Diastereoselection Issues

The mechanism and diastereoselectivity of synthetically useful sulfur ylide promoted cyclopropanation reactions have been studied using the density functional theory method. Addition of different substituted ylides (Me2S+CH-R) to enone ((E)-pent-3-en-2-one, MeHC=CH-COMe) has been investigated. The nature of the substituent on the ylidic carbon brings about subtle changes in the reaction profile. The stabilized (R=COMe) and semistabilized (R=Ph) ylides follow a cisoid addition mode, leading to 1,2-trans and 1,2-cis cyclopropanes, respectively, via syn and anti betaine intermediates. The simplest and highly reactive model ylide (R=H) prefers a transoid addition mode. Diastereoselectivity is controlled by the barrier for cisoid-transoid rotation in the case of stabilized ylides, whereas the initial electrophilic addition is found to be the diastereoselectivity-determining step for semistabilized ylides. High selectivity toward trans cyclopropanes with stabilized ylides are predicted on the basis of the relative activation energies of diastereomeric torsional transition states. The energy differences between these transition states could be rationalized with the help of weak intramolecular as well as other stereoelectronic interactions.

Location of functional groups in mycobacterial meromycolate chains; the recognition of new structural principles in mycolic acids.

Mycobacterial alpha-, methoxy- and keto-mycolic acid methyl esters were separated by argentation chromatography into mycolates with no double bond, with one trans double bond or with one cis double bond. Meromycolic acids were prepared from each methyl mycolate fraction by pyrolysis, followed by silver oxide oxidation, and analysed by high-energy collision-induced dissociation/fast atom bombardment MS to reveal the exact locations of the functional groups within the meromycolate chain. The locations of cis and trans double bonds, cis and trans cyclopropane rings, methoxy and keto groups, and methyl branches within the meromycolate chain were determined from their characteristic fragment ion profiles, and the structures of the meromycolic acids, including those with three functional groups extracted from Mycobacterium tuberculosis H37Ra, Mycobacterium bovis BCG and Mycobacterium microti, were established. Meromycolic acids with one cis double bond were structurally closely related to those with one cis cyclopropane ring, whereas the meromycolic acids with one trans cyclopropane ring were closely related to the corresponding meromycolic acids with one cis cyclopropane ring. A close relationship between methoxy- and keto-meromycolic acids was also implied. The relationship between the meromycolic acids with a trans double bond and the other meromycolic acids was not clearly revealed, and they did not appear to be immediate substrates for trans cyclopropanation.

Stereochemical considerations on the stereoselective cyclopropanation reactions of 3-aryl-2-phosphonoacrylates induced by the (–)-8-phenylmenthylIn this paper, menthyl refers to the menthan-3-yl radical. group as a chiral auxiliary

The cyclopropanation of (−)-8-phenylmenthyl (E)-3-aryl-2-phosphonoacrylates E-3a–d with dimethyloxosulfonium methylide and diazomethane affords the corresponding trans cyclopropane derivatives as the major diastereomers with high diastereoselectivity. On the other hand, the cyclopropanation of (−)-8-phenylmenthyl (Z)-3-aryl-2-phosphonoacrylates Z-3a–d and (−)-menthyl derivative 4 gives mixtures of cis and trans cyclopropane derivatives with low diastereoselectivity. The high diastereoselectivity in the cyclopropanation of (E)-acrylates E-3a–d can be rationalized by considering the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety in the s-cis conformer. The low selectivity in the cyclopropanation of (Z)-acrylates (Z-3a–d and 4) can be attributed to a low-lying conformer with the acrylate moiety twisted out of conjugation.

Stereoselective cyclopropanation of 3-aryl-2-phosphonoacrylates induced by the (−)-8-phenylmenthyl group as a chiral auxiliary

The cyclopropanation of (−)-8-phenylmenthyl ( E)-3-aryl-2-phosphonoacrylates with dimethyloxosulfonium methylide and diazomethane afforded the corresponding trans cyclopropane derivatives with high diastereoselectivity as the major diastereomer. The high selectivity is understandable in terms of the π–π interaction between the phenyl ring of the chiral auxiliary and the acrylate moiety.

Rhodium-catalyzed cyclopropanations of allylsilanes and allylstannanes: the role of the silyl/stannyl group in trans– cis stereoselection

The stereochemistry of cyclopropanation reactions between allylsilanes and allylstannanes 6 with four representative diazoalkanes in the presence of rhodium acetate has been studied. Cyclopropanations with ethyl diazoacetate show a preference for the formation of the trans cyclopropane esters 7, whereas the corresponding reactions with (trimethylsilyl)diazomethane favor the cis stereoisomers. In both cases, overall stereoselection is low, ranging from 1.3:1 to 2.4:1. The product ratios show a small dependence on the nature of the silyl or stannyl groups, with silyl substituents giving better stereoselection than stannyl, and larger ligands on the metal center leading to lower selectivity. On the other hand, rhodium-catalyzed cyclopropanations using methyl 2-diazo-4-phenyl-3-butenoate or 1-aryldiazoacetates occur with excellent stereocontrol. The stereochemical patterns found in these reactions are in accord with an open transition state model wherein the rhodium carbenoid approaches the allylmetal π-bond from an antiperiplanar orientation with respect to the allylic carbonML 3 bond. While the metal center may help stabilize developing β-cationic charge in the transition states, hyperconjugation effects appear to play a minor role, if any, in directing the stereochemical course of cyclopropanation.

Cis-Selective Asymmetric Cyclopropanation of Olefins Catalyzed by Five-Coordinate [RuCl(PNNP)]+ Complexes

The five-coordinate complex [RuCl(1a)]PF6 (3a; 1a = (S)-N,N‘-bis[2-(diphenylphosphino)benzylidene]-2,2‘-diamino-6,6‘-dimethylbiphenylene) catalyzes the cyclopropanation of styrene by decomposition of diazoesters. The cis cyclopropane derivative is formed with moderate selectivity (cis:trans ratio is 48:52), but high enantioselectivity (90−96% ee). The related species [RuCl(1b)]PF6 (3b; 1b = N,N‘-bis[2-(diphenylphosphino)benzylidene]-(1S,2S)-diaminocyclohexane) gives the cis product with selectivity up to 95% and enantioselectivity up to >99% ee. High cis selectivity is obtained also with 2,5-dimethyl-2,4-hexadiene as substrate. Complex 3a yields ethyl chrysanthemate with 94% cis selectivity and enantioselectivity up to 80% ee. The putative carbene intermediate trans-[RuCl(C(H)COOEt)(1b)]+ (11b) was prepared and characterized spectroscopically in solution. Its reaction with styrene gives the cyclopropane derivative with 98:2 cis:trans selectivity. The steric constraints in the transition states involving 11b and styrene were estimated by means of molecular modeling calculations. The relative total energies of the four diastereomeric aggregates follow the experimental enantio- and diastereoselectivity trends. The model proposed also predicts the correct absolute configuration of both cis and trans cyclopropane products.

The Mycobacterium tuberculosis cmaA2 Gene Encodes a Mycolic Acid trans-Cyclopropane Synthetase

Infection with Mycobacterium tuberculosis remains a major global health emergency. Although detailed understanding of the molecular events of M. tuberculosis pathogenesis is still limited, recent genetic analyses have implicated specific lipids of the cell envelope as important effectors in M. tuberculosis pathogenesis. We have shown that pcaA, a novel member of a family of M. tuberculosis S-adenosyl methionine (SAM)-dependent methyl transferases, is required for alpha-mycolic acid cyclopropanation and lethal chronic persistent M. tuberculosis infection. To examine the apparent redundancy between pcaA and cmaA2, another cyclopropane synthetase of M. tuberculosis thought to be involved in alpha-mycolate synthesis, we have disrupted the cmaA2 gene in virulent M. tuberculosis by specialized transduction. Inactivation of cmaA2 causes accumulation of unsaturated derivatives of both the methoxy- and ketomycolates. Analysis by proton NMR indicates that the mycolic acids of the cmaA2 mutant lack trans-cyclopropane rings but are otherwise intact with respect to cyclopropane and methyl branch content. Thus, cmaA2 is required for the synthesis of the trans cyclopropane rings of both the methoxymycolates and ketomycolates. These results define cmaA2 as a trans-cyclopropane synthetase and expand our knowledge of the substrate specificity of a large family of highly homologous mycolic acid methyl transferases recently shown to be critical to M. tuberculosis pathogenesis.