Synthesis and characterization of tetraoctyloxy substituted naphthalenophanedienes

Tetraoctyloxy-substituted naphthalenophanedienes were synthesized from tetraoctyloxy-substituted dithia[3.3]naphthalenophanes via sequential benzyne Stevens rearrangement, oxidation, and pyrolysis reactions. Surprisingly, only the pseudo-geminal isomer of tetraoctyloxy-substituted dithia[3.3]naphthalenophane was obtained after cyclization of the corresponding starting materials. The structures of the pseudo-geminal isomers of tetraoctyloxy-substituted dithia[3.3]naphthalenophane and tetraoctyloxy-substituted naphthalenophanediene were fully determined by nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and X-ray crystallography. The pseudo-geminal and pseudo-meta diastereomers of tetraoctyloxy-substituted naphthalenophanedienes were isolated by multiple fractional recrystallization from hexane at 5 °C. The solid state structure of the pseudo-geminal isomer of tetraoctyloxy-substituted naphthalenophanediene revealed strongly distorted naphthyl rings with high levels of ring strain.     

Synthesis of 1‐azabicyclic systems by double cyclization

5‐Cyano‐1‐azabicyclo[3.3.0]octane ( 1 ) was prepared in one step from 1,7‐dichloro‐4‐heptanone ( 4 ) under mild conditions. The application of this method for the preparation of 5‐cyano‐4,6‐dimethyl‐1‐azabicy‐clo[3.3.0]octane ( 11 ) gave two diastereomers in equilibrium. The NMR measurements of 11 and its reduced compound 15 showed that the major isomer is the cis‐exo form, and the minor isomer is the trans form. Molecular orbital calculations indicated that the cis‐exo form is more stable than the trans form, in agreement with the experimental results. Furthermore, 6‐cyano‐1‐azabicyclo[4.3.0]nonane ( 17 ) and 1‐azabicy‐clo[4.4.0]decane ( 19 ), both including a six‐membered ring, were prepared from appropriate haloketones by using this double cyclization method.     

Deuterium kinetic isotope effects and mechanism of the thermal isomerization of bicyclo[4.2.0]oct-7-ene to 1,3-cyclooctadiene

The thermal conversion of cis-bicyclo[4.2.0]oct-7-ene to cis,cis-1,3-cyclooctadiene might involve a direct disrotatory ring opening, or it might possibly take place by way of cis,trans-1,3-cyclooctadiene. This cis,trans-diene might possibly form the more stable cis,cis isomer through a [1,5] hydrogen shift or a trans-to-cis isomerization about the trans double bond. Deuterium kinetic isotope effect determinations for the isomerizations of 2,2,5,5-d(4)-bicyclo[4.2.0]oct-7-ene and 7,8-d(2)-bicyclo[4.2.0]oct-7-ene rule out these two alternatives because the observed effects are much smaller than would be anticipated for these mechanisms: k(H)/k(D)(d(4)) at 250 degrees C is 1.17 (1.04 per D), and k(H)/k(D)(d(2)) at 238 degrees C is 1.20 (1.10 per D). The direct disrotatory ring opening route remains the preferred mechanism.     

Photoreactivity of 2-pyridones with furan, benzene, and naphthalene. Inter- and intramolecular photocycloadditions

Pyridones, well-known for their ability to photodimerize, have been found to undergo [4 + 4] photocycloaddition with furan and naphthalene but not with benzene. In some cases these reactions can be highly regio- and stereospecific. Intramolecular reaction with furan produces both cis and trans [4 + 4] products. The cycloaddition with naphthalene can occur both inter- and intramolecularly. The intermolecular reaction yields primarily the cis isomer, whereas the trans isomer is the major product from the intramolecular reaction. A mixture of 4-methoxy-2-pyridone and 2-methoxynaphthalene that could form up to eight regio- and stereoisomers forms largely one [4 + 4] product.     

Enantioselective synthesis of the papulacandin ring system: conversion of the mannose diastereoisomer into a glucose stereoisomer

[structure] An enantioselective synthesis of three diastereoisomers of the C-arylglycoside tricyclic spiroketal nucleus of the papulacandins has been achieved, in which the initial asymmetry was introduced via a Sharpless dihydroxylation of substituted 5-aryl-2-vinylfurans. A selective oxidation-reduction sequence converted the mannose isomer into the glucose isomer. This sequence can conveniently produce both the papulacandin ring system along with its enantiomer and diastereomers in only 10-14 steps from 3,5-dimethoxybenzyl alcohol in 5-8% overall yield.     

Light-driven molecular hinge: a new molecular machine showing a light-intensity-dependent photoresponse that utilizes the trans-cis isomerization of azobenzene

[reaction: see text] A new class of molecular machine exhibits a hingelike motion upon photoirradiation. The motion (close and open) can be operated by alternate irradiation with UV and visible light. The trans/trans and cis/cis isomers are thermally stable at 40 degrees C, and the photochemical closure reaction (from trans/trans to cis/cis isomer) is dependent on the intensity of the light used because of the short-lived intermediate (trans/cis isomer).     

Triplet photochemistry of medium ring trienes

The photochemistry of the triplets of 10- and 11-membered ring 1,3,5-trienes has been studied. At ?70° cis,trans,cis-cyclodeca-1,3,5-triene goes only to the cis,cis,cis-isomer. At 25°, this latter compound is converted into cis-bicyclo[4.4.0]deca-2,4-diene via the thermally labile trans,cis,trans-cyclodeca-1,3,5-triene. At ?70° cis,trans,cis-cycloundeca-1,3,5-triene is converted to the cis,cis,cis-isomer. At 25°, this primary ptotochemical product undergoes a thermal 1,7-sigmatropic hydrogen migration to yield the trans,cis,cis, isomer. This latter triene upon sensitized irradiation yields cis-bicyclo[5.4.0]undeca-8,10-diene and trans-bicyclo[7.2.0]undeca-2,10-diene. The ratio of these latter two products changes with the temperature of the sensitized reaction. The possible mechanisims of these transformations are discussed.     

Triptycene-derived oxacalixarenes as new wheels for the synthesis of [2]rotaxanes: acid-base- and metal-ion-switchable complexation processes

A pair of triptycene-derived oxacalixarenes, 1a and 1b, containing two naphthyridine subunits have been synthesized by a convenient one-pot approach. Macrocycles 1a and 1b are diastereomers, with 1a being a cis isomer with a boat-like 1,3-alternate conformation and 1b being a trans isomer with a curved boat-like conformation in the solid state. Both 1a and 1b have fixed conformations in solution at room temperature, as revealed by variable-temperature (1)H NMR spectroscopy experiments. It was found that oxacalixarenes 1a and 1b could both form 1:1 [2]pseudorotaxane-type complexes with paraquat derivatives with different functional groups in solution and in the solid state, which resulted in the further synthesis of a pair of novel isomeric [2]rotaxanes. Moreover, the controlled dethreading and rethreading processes of the [2]pseudorotaxanes were also easily achieved by acid-base stimuli or Hg(2+) association/dissociation.     

Product ion studies of diastereomeric benzo[ghi]fluoranthene tetraols by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and post-source decay

The product ion formation characteristics of the four diastereomeric tetrahydroxy benzo[ghi]fluoranthene compounds formed by hydrolysis of the syn and anti diastereomers of trans-3,4-dihydroxy-5,5a-epoxy-3,4,5,5a-tetrahydrobenzo[ghi]fluoranthene are studied using matrix-assisted laser desorption/ionization and post-source decay (PSD) to determine a correlation between the fragmentation characteristics of these tetraols and the structures of the diol-epoxide diastereomers from which they are hydrolyzed. The tetraols formed by the trans ring opening of the diol epoxides during hydrolysis yield product ion spectra specific for the syn and anti configurations of their precursor diol epoxides. All four diastereomeric tetraols form product ions by the losses of one and/or two water molecules in varying proportions when lithium-cationized molecule ions (m/z 301) are selected for PSD product ion analysis. The differences in the PSD spectra of these four Li+-cationized molecules are rationalized in terms of a water loss mechanism that involves the 1,2 elimination of a hydrogen atom and hydroxyl group that are cis with respect to each other on adjacent carbons.     

Enol-to-keto tautomerism of peptide groups

Density functional based simulations, performed on polyglycine containing an enol peptide group [-C(OH)N-] which is a structural isomer of a keto form [-CONH-], show that in the enol-to-keto tautomeric reaction, the enol peptide group is less stable than the keto form, and that the enol-to-keto tautomerism is characterized by a cis/trans isomerization of the C-N peptide bond. The rate-limiting step in the cis/trans isomerization is a hydrogen migration from O to N atoms in the peptide group with a transition state consisting of a four-membered ring in the cis configuration. An analysis of the cis/trans isomerization pathway shows that the mechanisms for the cis/trans isomerization are essentially different between the enol and keto forms.     

1H and13C NMR spectra,stereoisomerism, and conformational states of 3-phenyl-5-isopropoxytetrahydro-2-furanones

The¹H and¹³C NMR spectra of the diastereomers of 3-phenyl-5-isopropoxytetrahydro-2-furanone were obtained. The stereoisomerism and preferred conformational states of these diastereomers were established by means of the spectroscopic criteria found for 3,4-disubstituted sulfolanes and 1,1,3,4-tetrasubstituted silacyclopentanes. It is shown that for the cis isomer the equilibrium is shifted to favor pseudoequatorial conformers, whereas for the trans isomer it shifted to favor ae conformers with a preferred pseudoequatorial orientation of phenyl substituent.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 593–597, May, 1988.     

1.1](3,3')-azobenzenophane: novel crystal structure and cis-trans isomerization of distorted azobenzene

[formula: see text] [1.1](3,3')-Azobenzenophane, in which two azobenzenes are cyclically connected by -CH2- chains at the meta positions, has been synthesized. The crystal structures of all isomers have been revealed. This is the first report on the crystal structure of the cis isomer of macrocyclic azobenzenes. The trans,trans isomer was slightly distorted, the trans,cis isomer highly deformed, and the cis,cis isomer unstrained. The thermal stability of cis isomers in solutions are deducible from the crystal structures.     

Synthesis of bisbicyclo[1.1.1]pentyldiazene. The smallest bridgehead diazene

Bisbicyclo[1.1.1]pentyldiazene, the smallest bicyclic azo compound, has been synthesized from the precursor [1.1.1]propellane via synthesis of N,N'-bis(bicyclo[1.1.1]pentyl)sulfamide and azoxybicyclo[1.1.1]pentane. The UV absorption of this diazene at 382 nm indicates that the compound is the trans isomer. Conversion to the cis isomer by irradiation was not possible because of attainment of a photostationary state. However, on the basis of the photochemical studies, the absorption of the cis-[1.1.1] isomer is estimated to be 384 nm.     

Synthesis and biological evaluation of a phosphonate analog of the natural acetyl cholinesterase inhibitor cyclophostin

Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than the cis isomer against AChE from two sources.     

Chemical control on the coordination mode of benzaldehyde semicarbazone ligands. synthesis, structure, and redox properties of ruthenium complexes

Reaction of benzaldehyde semicarbazone (HL-R, where H is a dissociable proton and R is a substituent (R = OMe, Me, H, Cl, NO(2)) at the para position of the phenyl ring) with [Ru(PPh(3))(3)Cl(2)] and [Ru(PPh(3))(2)(CO2)Cl2] has afforded complexes of different types. When HL-NO(2) and [Ru(PPh(3))(3)Cl2] react in solution at ambient temperature, trans-[Ru(PPh(3))(2)(L-NO2Cl] is obtained. Its structure determination by X-ray crystallography shows that L-NO2 is coordinated as a tridentate C,N,O-donor ligand. When reaction between HL-NO2 and [Ru(PPh(3))(3)Cl2] is carried out in refluxing ethanol, a more stable cis isomer of [Ru(PPh(3))(2)(L-NO2)Cl] is obtained. The trans isomer can be converted to the cis isomer simply by providing appropriate thermal energy. Slow reaction of HL-R with [Ru(PPh(3))(2)(CO2)Cl2] in solution at ambient temperature yields 5-[Ru(PPh(3))(2)(L-R)(CO)Cl] complexes. A structure determination of 5-[Ru(PPh(3))(2)(L-NO2)(CO)Cl] shows that the semicarbazone ligand is coordinated as a bidentate N,O-donor, forming a five-membered chelate ring. When reaction between HL-R and [Ru(PPh(3))(2)(CO2Cl2] is carried out in refluxing ethanol, the 4-[Ru(PPh(3))(2)(L-R)(CO)Cl] complexes are obtained. A structure determination of 4-[Ru(PPh(3))(2)(L-NO2)(CO)Cl] shows that a semicarbazone ligand is bound to ruthenium as a bidentate N,O-donor, forming a four-membered chelate ring. All the complexes are diamagnetic (low-spin d(6), S = 0). The trans- and cis-[Ru(PPh(3))(2)(L-NO2)Cl] complexes undergo chemical transformation in solution. The 5- and 4-[Ru(PPh(3))(2)(L-R)(CO)Cl] complexes show sharp NMR signals and intense MLCT transitions in the visible region. Cyclic voltammetry of the 5-[Ru(PPh(3))(2)(L-R)(CO)Cl] and 4-[Ru(PPh(3))(2)(L-R)(CO)Cl] complexes show the Ru(II)-Ru(III) oxidation to be within 0.66-1.07 V. This oxidation potential is found to linearly correlate with the Hammett constant of the substituent R.     

Dichlorobis(2-phenylazopyridine)ruthenium(II) complexes: characterisation, spectroscopic and structural properties of four isomers

The didentate ligand 2-phenylazopyridine (azpy) can--in theory--give rise to five different isomeric complexes of the type [Ru(azpy)2Cl2], of which three have been known since 1980. The molecular structures of the cis-dichlorobis(2-phenylazopyridine) ruthenium(II) complexes alpha-[Ru(azpy)2Cl2] and beta-[Ru(azpy)2Cl2](in which the coordinating pyridine nitrogen atoms are in mutually trans and cis positions, respectively, whilst the azo nitrogen atoms are in mutually cis positions) were unambiguously determined in the early 1980s. The third isomer, gamma-[Ru(azpy)2Cl2], has for two decades, erroneously, been assumed to be the all-trans isomer. In a recent communication we have proven that for this gamma isomer the chloride ions are indeed in a trans geometry, but the pyridine nitrogen and azo nitrogen atoms of the two azpy ligands are in mutually cis geometries. In this paper the isolation of a fourth isomer is presented, the hitherto unknown delta-[Ru(azpy)2Cl2]. The isomeric structure of delta-[Ru(azpy)2Cl2] has been determined by 1H-NMR spectroscopy and single-crystal X-ray diffraction analysis, and is the all-trans isomer. The bis(azpy)-ruthenium(II) isomers are of interest because of the pronounced cytotoxicity they exhibit against tumour cell lines and could be very useful in the search for structure-activity relationships of antitumour-active ruthenium complexes, as among the isomers there is a significant difference in activity. It is of paramount importance to have a good understanding of the structural and spectroscopic properties of these complexes, which in this paper are compared and discussed, with a particular emphasis on 1D and 2D 1H NMR spectroscopies.     

Syntheses of conformationally constricted molecules as potential NAALADase/PSMA inhibitors

Two six-membered ring targeted analogues of PSMA inhibitors (4a and 4b) were designed on the basis of a computational analysis and synthesized. (E,Z)-Diene 10 was subjected to the nitroso Diels-Alder reaction to give the 1,4-trans six-membered ring adduct, 4a. The cis isomer 4b was derived from similar nitroso cycloaddition reactions with the corresponding (E,E)-diene and separately from cyclohexadiene. The IC(50) values of 4a and 4b in a NAALADase assay were found to be 0.9 and 0.1 microM, respectively. [reaction: see text]     

Energetics of oxaspirocycle prototypes: 1,7-dioxaspiro[5.5]undecane and 1,7,9-trioxadispiro[5.1.5.3]hexadecane

The relative gas-phase energetics of several low-lying isomers of 1,7-dioxaspiro[5.5]undecane and 1,7,9-trioxadispiro[5.1.5.3]hexadecane have been calculated with second-order Mller-Plesset perturbation theory and basis sets as large as aug-cc-pVQZ. Relative energies in THF, dichloromethane, acetone, and DMSO have been estimated with corrections from polarized continuum model calculations at the B3LYP/6-311+G(d) level. In the most stable conformation of 1,7-dioxaspiro[5.5]undecane, both rings adopt chair conformations, and both oxygens are axially disposed (2A). It is more than 2 kcal mol(-1) more stable than all the other conformers. In agreement with previous work, the "twist-boat" trans isomer (3A) is the most stable isomer of 1,7,9-trioxadispiro[5.1.5.3]hexadecane. However, in contrast to this earlier study, an "all-chair" conformation (3B) is found to be the most stable cis isomer of 1,7,9-trioxadispiro[5.1.5.3]hexadecane (E approximately 0.5 kcal mol(-1) in acetone and DMSO). Gauge-independent atomic orbital computations at the B3LYP/6-311+G(d) level indicate that this is the only cis isomer with (13)C NMR chemical shifts that are qualitatively consistent with the experimental spectra.     

Intramolecular [2 + 2] photocycloaddition/thermal fragmentation: formally "allowed" and "forbidden"pathways toward 5-8-5 ring systems

The thermal fragmentation of highly functionalized, linear polycyclobutanes with a cis,syn,cis-relative stereochemistry is shown to offer a rapid entry into the dicyclopenta[a,d]cyclooctenyl (5-8-5) ring system. The thermolysis of polyfused cyclobutanes with a cis,syn,cis- or a cis,anti,cis-relationship proceeds in a formally "symmetry-allowed" manner through the intermediacy of a cis,trans-cyclooctadiene. When a bridging tether used to establish the cis,syn,cis-stereochemistry in the intramolecular [2 + 2] photocyclization is present in the thermolysis step, however, the result of a formally "symmetry-forbidden" fragmentation is observed yielding cis,cis-cyclooctadiene-containing 5-8-5 products. In general, the stereochemical observations noted in these fragmentations offer new opportunities for accessing a variety of stereochemical relationships in these 5-8-5 ring systems.     

Cascade radical cyclizations of benzannulated enyne-allenes. Unusual cleavage of a benzene ring leading to twisted 1,1'-dialkyl-9,9'-bifluorenylidenes and spiro[1H-cyclobut[a]indene-1,9'-[9H]fluorenes

Treatment of the benzannulated enediynyl propargylic alcohol 16 (isomer ratio = 2:1) with thionyl chloride induced a sequence of reactions leading to the twisted 1,1'-dipropyl-9,9'-bifluorenylidene 17, the polycyclic compounds 18 and 19, and the spiro[1H-cyclobut[a]indene-1,9'-[9H]fluorene] 20 (trans/cis = 5:1). The transformation from 16 to the unexpected 17 presumably involved an initial formation of the benzannulated enyne-allene 21 followed by a C(2)-C(6) cyclization reaction and an intramolecular radical-radical coupling reaction, giving rise to the formal Diels-Alder adduct 23. Repeat of this sequence then furnished 24. Cleavage of the bond connecting the two carbons having the propyl substituent afforded 25. A subsequent rotation of the carbon-carbon bond joining the two central five-membered rings then gave the trans isomer 26. Oxidation of 26, presumably by oxygen, followed by hydrolysis then produced 17. Interestingly, the pathway leading to 17 involved an unusual cleavage of a benzene ring. The X-ray crystal structure of 17 reveals that it has a twist angle of 45.2 degrees for the carbon-carbon double bond connecting the two bifluorenylidene fragments. The spiro[1H-cyclobut[a]indene-1,9'-[9H]fluorene] 20 apparently was produced via two intramolecular [2 + 2] cycloaddition reactions of the benzannulated enyne-allene moieties, generated in situ from the benzannulated enediynyl propargylic alcohols. The twisted 1,1'-dimethyl-9,9'-bifluorenylidene 33 and the spiro[1H-cyclobut[a]indene-1,9'-[9H]fluorene] 39 (trans/cis = 3:1) were likewise produced from 32 and 38, respectively.