Electronic and Steric Structure of Thermal Isomerization Products of 1-Methyltricyclo[4.1.0.02,7]heptane Radical Cation

Distributions of the positive charge and unpaired electron in stable conformers of the thermal isomerization products of 1-methyltricyclo[4.1.0.02,7]heptane radical cation, having bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[3.2.0]hept-6-ene, and 1,3-cycloheptadiene skeletons, were estimated by the PM3 semiempirical method.     

Synthesis and Chemistry of Bicyclo[4.1.0]hept-1,6-ene

Bicyclo[4.1.0]hept-1,6-ene has been generated by elimination of 1-chloro-2-(trimethysilyl)bicyclo[4.1.0]heptane in the gas phase over solid fluoride at 25 degrees C. The cyclopropene dimerizes by a rapid ene reaction forming two diastereomeric cyclopropenes. In tetrahydrofuran or chloroform the ene dimers couple to form a single crystalline triene tetramer, whereas a mixture of tricyclohexane tetramers is formed when the neat dimers are allowed to warm to room temperature. Oxidation by dimethyldioxirane or dioxygen gives carbonyl products. Quantum mechanical calculations yielded an increase in strain of approximately 17 kcal/mol over that for 1,2-dimethylcyclopropene. The potential enegy barrier to flexing (folding) along the fused double bond of bicyclo[4.1.0]hept-1,6-ene is only approximately 1 kcal/mol at the highest level of theory investigated.     

Dihalocarbene insertion reactions into C-H bonds of compounds containing small rings: mechanisms and regio- and stereoselectivities

Novel insertion reactions of dichloro- and dibromocarbene into carbon-hydrogen bonds adjacent to cyclopropane rings are reported. It is found that the predominant isomers formed in the reactions with bicyclo[4.1.0]heptane result from insertion into the endo carbon-hydrogen bonds alpha to the three-membered ring. In the reactions of bicyclo[3.1.0]hexane, however, the exo dihalocarbene insertion products are formed as the major isomers. In some compounds cyclopropane rings "activate" adjacent carbon-hydrogen bonds, whereas other systems containing three-membered rings do not. Moreover, the influence of various substituents (methyl, geminal dimethyl, phenyl, methoxy, and ethoxy) attached to bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane in dihalocarbene reactions has been studied. The findings can be explained by the concept of maximum orbital overlaps of Walsh orbitals of the cyclopropane rings and the alpha carbon-hydrogen bonds. In stark contrast, selective insertion into the tertiary carbon-hydrogen bonds of the cyclobutane ring in bicyclo[4.2.0]octane is observed.     

Tandem catalytic carbene addition/bicyclization of enynes. One-step synthesis of fluorinated bicyclic amino esters by ruthenium catalysis

The reaction of diazo compounds with enynes, containing a fluorinated amino acid moiety, in the presence of the precatalyst Cp(Cl)Ru(COD) leads to fluorinated alkenyl bicyclo[3.1.0]hexane and [4.1.0]heptane amino acid derivatives. It is remarkable that the catalyst, in situ generated from ruthenium complex and diazo compound, completely inhibits the ring closing metathesis of enyne to the profit of tandem alkenylation/cyclopropanation with high stereoselectivity. The study shows that the Cp(Cl)Ru moiety in ruthenacyclobutane favors reductive elimination versus expected alkene metathesis. [reaction: see text]     

PtCl2-mediated cycloisomerization of unsaturated propargylic carboxylates

The PtCl₂-mediated cycloisomerization of unsaturated propargylic carboxylates yields differently functionalized bicyclo[4.1.0]heptane enol esters from moderate to good yield, in a very diastereoselective manner. We have prepared and submitted to PtCl₂-catalyzed cycloisomerization a series of differently substituted hept-1-en-6-ynes with different O-acyl (acetyl, trichloroacetyl, 3,4,5-trimethoxybenzoyl, etc.) protecting groups at propargylic positions, investigating also the effect of the geometry at the double bond, as well as the effect of the number of substituents at the alkene moiety. As a result, we have found that the O-acetyl migrating group is the best one in terms of simplicity and chemical yields. In this reaction we have isolated mixtures of compounds formed by minor 1-acetoxy-allenes and major bicyclo[4.1.0]heptane derivatives. Major products are the result of a sequential process involving steps of cycloisomerization plus cyclopropanation, followed by acyl migration. The basic methanolysis (K₂CO₃, MeOH) of these intermediates gave mixtures of cis and trans-caran-2-ones. This two-step protocol (cycloisomerization plus basic methanolysis) for the syntheses of α,β-unsaturated cyclopropyl ketones constitutes a synthetic alternative to the usual unfriendly, intramolecular cyclopropanation of unsaturated α-diazocarbonyl derivatives. The formation of these bicyclo[4.1.0]heptane derivatives is a simple, but efficient entry into the skeleton of the ‘carane’ family of natural products.     

Ein neuer Zugang zu Bicyclo[4.1.0]heptan-Derivaten

A New Approach to Bicyclo[4.1.0]heptane Derivatives The reaction of the dienone 1 with ethyl α-bromoacetate does not furnish the expected glycidic acid ester 2 but leads to the bicyclo[4.1.0]heptenone derivative 3 . The structure of this new compound has been proved by means of spectroscopic methods (1R, ¹H-NMR, ¹³C-NMR, MS). The elucidation of the configuration at C(7) could be realized by measuring a NOE effect. Other α-alkylated α-bromoacetates react with 1 in the same manner.     

三乙醇胺催化合成7,7—二氯双环[4,1,0]庚烷

报道了三乙醇胺催化二氯卡宾与环己烯的加成反应，考察了催化剂用量、氯仿用量、氢氧化钠浓度，反应时间、反应温度对产品７，７－二氯双环「４，１，０」庚烷收率的影响，在优化条件下，产品收率可达９０．０％     

A potent bicyclic inhibitor of a family 27 alpha-galactosidase

Two isomeric bicyclo[4.1.0]heptane analogues of the glycosidase inhibitor galacto-validamine, (1R*,2S,3S,4S,5S,6S*)-5-amino-1-(hydroxymethyl)bicyclo[4.1.0]heptane-2,3,4-triol, have been synthesized in 13 steps from 2,3,4,6-tetra-O-benzyl-D-galactose. The inhibitory activities of the two conformationally restricted amines, and their corresponding acetamides, were measured against commercial alpha-galactosidase enzymes from coffee bean and E. coli. The activity of the glycosyl hydrolase family GH27 enzyme (coffee bean) was competitively inhibited by the 1R,6S-amine (7), a binding interaction that was characterized by a K(i) value of 0.541 microM. The GH36 E. coli alpha-galactosidase exhibited a much weaker binding interaction with the 1R,6S-amine (IC(50)= 80 microM). The diastereomeric 1S,6R-amine (9) bound weakly to both galactosidases, (coffee bean, IC(50)= 286 microM) and (E. coli, IC(50)= 2.46 mM).     

Reaction of vinylidenecyclopropanes with aromatic imines in the presence of Lewis acids

1-Methyl-2-(2-methylpropenylidene)-1-phenylcyclopropane, 7-(2-methylpropenylidene)bicyclo[4.1.0]heptane, and (Z)-9-(2-methylpropenylidene)bicyclo[6.1.0]non-4-ene react with N-benzylideneanilines in the presence of boron trifluoride-ether complex to give pyrrolidine derivatives. Reactions of 1-methyl-1-phenyl-2-diphenylvinylidenecyclopropane with N-benzylideneanilines in the presence of BF₃·Et₂O, Yb(OTf)₃, or Sc(OTf)₃ lead to the formation of substituted 1,2,3,4-tetrahydroquinolines. 7-Diphenylvinylidenebicyclo[4.1.0]heptane in the presence of BF₃·Et₂O undergoes isomerization into 5-phenyl-8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalene.     

Transformations of halocyclopropanes—VII : Reactions of 7,7-dichlorobicyclo[4.1.0] heptane with carbanions

The reactions of 7,7-dichlorobicyclo[4.1.0] heptane 1 were carried out with C-H acids in the presence of t- BuOK in DMSO. The respective syn-7-chlorobicyclo[4.1.0] heptane derivatives 3 were the major products of the reactions with diethyl malonate and ethyl cyanoacetate. The dehydrochlorinated material α-bicyclo[4.1.0] hepten-5-yl-α-phenylpropionitrile 5c, was obtained in good yield in the reaction with α-phenylpropionitrile.     

The Interaction of Walsh-Orbitols in Diademane and Related Hydrocarbons

To obtain further information concerning the interaction between Walsh-orbitols of ‘conjugated’ cyclopropane rings, the photoelectron spectra of the following compounds have been recorded: bicyclo[4.1.0]heptane 1 , cis- and trans-tricyclo[5.1.0^{3, 5}]octane 2, 3 , diademane 4 , trans-pentacyclo[3.3.2.0^{2, 9}.0^{4, 10}, 0^{6, 8}]decan 5 and bicyclo[4.1.0]heptene-2 6 . The first bands in the PE.-spectra of these compounds have been assigned on the basis of a ZDO HMO-approximation. For 2 and 4 the value for resonance integral between linked 2p atomic orbitals of two adjacent eclipsed cyclopropane rings is found to be ?1.73 eV.     

Conformation of bicyclo[n.1.0] derivatives: Part 2. Norcarane and cyclohexene epoxide

The conformation al geometries and the possible interconversion paths for bicyclo[4.1.0] heptane (norcarane) and cyclohexene epoxide have been studied by both quantum mechanical and molecular mechanics calculations. The half-chair conformation is the most stable in the two compounds even if conformational equilibria with other forms cannot be excluded. Theoretical results are compared with the experimental data of molecular geometry, heat of formation, rotational constants, dipole moment, molar Kerr constant and proton coupling constants. The results obtained by the force-field method are satisfactory and consequently the extension of the method to derivatives of this kind seems possible.     

Contraction de cycle a partir de la tosyloxy-8 bicyclo[4.2.0]octanone-7 cis

Cis 8-endo tosyloxybicyclo[4.2.0]oct-3-en-7-one treated with H₄AlLi undergoes a stereospecific ring contraction to give endo 7-formyl bicyclo[4.1.0]hept-3-ene and endo 7-hydroxymethyl bicyclo[4.1.0]hept-3-ène. On the contrary, the same compound treated with MeONa in ether or methanol (conditions of the Favorski rearrangement) gives, beside solvolysis products when CH₃OH is solvent, the two epimeric esters 7-endo and 7-exo carbomethoxybicyclo[4.1.0]hept-3-ène. Several pathways are postulated for the rearrangement.     

Rotational isomerism relative to C-O bonds in stereoisomeric cyclic trans-methoxy alcohols

Conclusions The dipole moments and Kerr constants of monomethyl ethers of trans-3,4-diols of the bicyclo[4.1.0]heptane series and cyclohexane were determined. Based on the set of data from physical methods, a conclusion was drawn concerning the conformational equilibrium of the compounds and the rotational states relative to the C-O bonds.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1768–1772, August, 1988.     

Hydration of 3-methyl-3-norcarene epoxides under acid and basic catalysis conditions

Conclusions The hydration of the cis- and trans-epoxides of 3-methyl-3-norcarene under acid catalysis conditions is characterized by a retention of the bicyclo[4.1.0]heptane structure and cleavage of the tertiary C-O bond of the epoxide rings; a regiospecificity of the opening is not observed under alkaline conditions.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1636–1638, July, 1982.     

Bicyclo[3.1.0]hex-(1,5)-ene and bicyclo[4.1.0]hept-(1,6)-ene

The formation and trapping of bicyclo[3.1.0]hex-(1,5)-ene and bicyclo[4.1.0]hept-(1,6)-ene from the corresponding vicinal dibromides is described.     

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 pK_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 pK_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.     

A novel synthetic route to 6-oxabicyclo[3.1.1]heptane skeleton

6-Oxabicyclo[3.1.1]heptane skeleton is synthesized starting from bicyclo[2.2.1]heptane skeleton, in which as a key reaction, Baeyer-Villiger oxidation of the tricyclic oxetane (19) is involved.     

Rh(III)-Catalyzed Annulative Coupling of Sulfoxonium Ylides with Allyl Acetates: Generation of Bicyclo[4.1.0]heptan-2-ones

A highly efficient Rhodium(III)-catalyzed annulative coupling was developed for generating bicyclo[4.1.0] heptan-2-ones from sulfoxonium ylides and allyl acetates under mild conditions. This cascade reaction is versatile to construct cyclopropanes, and the starting materials are stable and easily obtainable.     

Carbon-13 chemical shifts of bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane derivatives

¹³C chemical shifts of more than fifty bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane derivatives (hydrocarbons, alcohols, ketones and esters) have been determined. The usefulness of ethyl derivatives for the assignment of close ¹³C chemical shifts in bicyclic methyl derivatives is shown both for the bicyclo[3.2.1]octane and bicyclo[2.2.1]heptane series. Comparison of substituent effects on α-, β-, γ- and δ-carbons in both series of compounds shows remarkable differences in steric interactions. In contrast to the rigid bicyclo[2.2.1]heptane system, both chair and boat conformations can be predominant in the bicyclo[3.2.1]octane series with the conformationally flexible 6-membered ring.