Hammett Correlation in the Accelerated Formation of 2,3-Diphenylquinoxalines in Nebulizer Microdroplets.

The accelerated formation of 2,3-diphenylquinoxalines in microdroplets generated in a nebulizer has been investigated by competition experiments in which equimolar quantities of 1,2-phenylenediamine, C6H4(NH2)2, and a 4-substituted homologue, XC6H3(NH2)2 [X = F, Cl, Br, CH3, CH3O, CO2CH3, CF3, CN or NO2], or a 4,5-disubstituted homologue, X2C6H2(NH2)2 [X = F, Cl, Br, or CH3], compete to condense with benzil, (C6H5CO)2. Electron-donating substituents (X = CH3 and CH3O) accelerate the reaction; in contrast, electron-attracting substituents (X = F, Cl, Br and particularly CO2CH3, CN, CF3 and NO2) retard it. A structure-reactivity relationship in the form of a Hammett correlation has been found by analyzing the ratio of 2,3-diphenylquinoxaline and the corresponding substituted-2,3-diphenylquinoxaline, giving a ρ value of -0.96, thus confirming that the electron density in the aromatic ring of the phenylenediamine component is reduced in the rate-limiting step in this accelerated condensation. This correlation shows that the phenylenediamine acts as a nucleophile in the reaction.

The mechanism of alkene elimination from protonated toluenesulphonamides generated by electrospray ionisation.

The positive ion electrospray mass spectra of a range of sulphonamides of general structure CH3C6H4SO2NHR1 [R1 = CnH2n+1 (n = 1-7), CnH2n-1 (n = 3, 4), C6H5, C6H5CH2 and C6H5CH(CH3)] and CH3C6H4SO2NR1R2 [R1, R2 = CnH2n+1 (n = 1-8)] are reported and discussed. The protonated sulphonamides derived from saturated primary and secondary aliphatic amines generally fragment to only a limited extent unless energised by collision. Two general fragmentations are observed: firstly, elimination of an alkene, CnH2n, obtained by hydrogen abstraction from one of the CnH2n+1 alkyl groups on nitrogen; secondly, cleavage to form CH3C6H4SO2+. The mechanism by which an alkene is lost has been probed by studying the variation of the intensity of the [M + H - CnH2n]+ signal with the structure of the alkyl substituent(s) on nitrogen and by monitoring the competition between the loss of different alkenes from protonated unsymmetrical sulphonamides in which two different alkyl groups are attached to nitrogen. This fragmentation is favoured by branching of the alkyl group at the carbon atom directly attached to nitrogen, thus suggesting that it involves a mechanism in which the stability of the cation obtained by stretching the bond connecting the nitrogen atom to the alkyl group is critical. This interpretation also explains the competition between alkene elimination and cleavage to form CH3C6H4SO2+ (and, in some cases, cleavage to form C6H5CH2+ or [C6H5CHCH3]+).

Application of positive mode atmospheric chemical ionisation to distinguish epimeric oleanolic and ursolic acids.

A new and more reliable method is reported for distinguishing the equatorial and axial epimers of oleanolic and ursolic acids and related triterpenoids based primarily on the relative abundance of the [M+H](+) and [M+-H(2)O](+) signals in their positive mode atmospheric pressure chemical ionisation mass spectra. The rate of elimination of water, which is the principal primary fragmentation of protonated oleanolic and ursolic acids, depends systematically on the stereochemistry of the hydroxyl group in the 3 position. For the b-epimer, in which the 3-hydroxyl substituent is in an equatorial position,[M+-H(2)O](+) is the base peak. In contrast, for the α-epimer, where the 3-hydroxyl group is axial, [M + H](+) is the base peak. This trend, which is general for a range of derivatives of oleanolic and ursolic acids, including the corresponding methyl esters, allows epimeric triterpenoids in these series to be securely differentiated. Confirmatory information is available from the collision-induced dissociation of the [M+-H(2)O](+) primary fragment ions, which follow different pathways for the species derived from axial and equatorial epimers of oleanolic and ursolic acids. These two pieces of independent spectral information permit the stereochemistry of epimeric oleanolic and ursolic acids (and selected derivatives) to be assigned with confidence without relying either on chromatographic retention times or referring to the spectra or other properties of authentic samples of these triterpenoids.

Novel formation of [2M-H](+) species in positive electrospray mass spectra of indoles.

RATIONALE: When subjected to positive ion electrospray ionisation (ESI+) mass spectrometry (MS), indoles with a 3-alkyl substituent show a propensity to form novel [2M-H](+) 'covalently bound dimers'. This process, which appears to be initiated in the nebuliser of the instrument, is mechanistically interesting, analytically useful and potentially significant in organic synthesis. METHODS: A selection of 2- and 3-substituted indoles have been synthesised and analysed by ESI-MS. The formation of the 'homo' and 'hetero' dimers of these compounds has been investigated using ESI+ mode. The mechanism of formation of the observed 'dimeric' species has been probed by synthesising authentic samples of the dimeric compounds. RESULTS: 'Dimeric' species corresponding to [2M-H](+) have been observed for all 3-substituted indoles studied, but not for indoles substituted in just the 2-position. By infusing equimolar mixtures of labelled and unlabelled indoles through the instrument, the expected approximately statistical mixture of homo- and heterodimeric species has been observed. Further experiments have established that this novel dimerisation occurs in the droplets formed in the nebuliser of the instrument. CONCLUSIONS: It has been shown that 3-substituted indoles form [2M-H](+) dimers in high abundance in the spray obtained from the nebiliser of an ESI+ instrument. The mechanism for the dimerisation does not involve the known 2M dimeric species that is readily formed in the solution-phase chemistry of indoles.

The anticancer/cytotoxic effect of a novel gallic acid derivative in non-small cell lung carcinoma A549 cells and peripheral blood mononuclear cells from healthy individuals and lung cancer patients.

Gallic acid (GA) is a naturally occurring polyphenol with a strong antioxidant capacity. GA stimulates the apoptosis of cancer cells, thereby suppressing cancer cell invasion. However, the low oral permeability of GA limits its therapeutic use. In order to enhance the antioxidant capacity and oral permeability of GA, a series of compounds analogous to GA were synthesized: 4-methoxybenzenesulfonamide (MBS), 3,4-dimethoxybenzenesulfonamide (DMBS) and 3,4,5-trimethoxybenzenesulfonamide (TMBS). In the new compounds, hydroxyl groups were replaced with various numbers of methoxy groups (stronger electron-donating groups), to increase hydrophobicity and oral permeability compared to GA. In addition, the carboxylic group was replaced with a sulfonyl group (a stronger electron-withdrawing group), to increase the molecular polarity and antioxidative activities of the compounds. The cell counting kit-8 (CCK-8) assay was used to detect the effect of GA, MBS, DMBS, and TMBS on cell proliferation and apoptosis in peripheral blood mononuclear cells (PBMCs) from healthy individuals and non-small cell lung carcinoma A549 cells. Additionally, the comet assay was used to assess the genotoxicity of these compounds in PBMCs from healthy individuals, lung cancer patients, and A549 cells. Compared to untreated cells, TMBS reduced DNA damage more effectively than GA in PBMCs from lung cancer patients and healthy donors. Furthermore, in comparison to GA, TMBS was more cytotoxic in A549 cells. Moreover, TMBS was not cytotoxic in healthy PBMCs, suggesting that TMBS demonstrates therapeutic potential in cancer.

Hammett correlation in competition experiments in dissociation of ionised substituted benzophenones and dibenzylideneacetones.

A convenient method of applying competition experiments to devise a Hammett correlation in the dissociation by α-cleavage of 17 ionised 3- and 4-substituted benzophenones, YC6H4COC6H5 [Y=F, Cl, Br, CH3, CH3O, NH2, CF3, OH, NO2, CN and N(CH3)2] is reported and discussed. The results given by this approach, which rely on the relative abundance of [M-C6H5]+ and [M-C6H4Y]+ ions in the electron ionisation spectra of the substituted benzophenones, are compared with those obtained by previous methods. Various refinements of the method are considered, including reducing the ionising electron energy, making allowance for the relative abundance of ions such as C6H5+ and C6H4Y+, which may be formed to some extent by secondary fragmentation, and using substituent constants other than the standard σ constants. The reaction constant, ρ, of 1.08, which is in good agreement with that deduced previously, is consistent with a considerable reduction in electron density (corresponding to an increase in positive charge) at the carbon of the carbonyl group during fragmentation. This method has been successfully extended to the corresponding cleavage of 12 ionised substituted dibenzylideneacetones, YC6H4CH=CHCOCH=CHC6H5 (Y=F, Cl, CH3, OCH3, CF3, and NO2), which may fragment to form either a substituted cinnamoyl cation, [YC6H4CH=CHCO]+, or the cinnamoyl cation, [C6H5CH=CHCO]+. The derived ρ value of 0.76 indicates that the substituent, Y, influences the stability of the cinnamoyl cation somewhat less strongly than it does the analogous benzoyl cation.

Proximity Effects in Mass Spectra of Benzanilides.

The analytical value of peaks arising by a proximity effect in the electron ionization mass spectra of benzanilides has been established by examining the spectra of numerous examples of general structure XC6H4NHCOC6H4Y. Significant [M-X]+ signals are observed only when X = Cl, Br, I or CH3O in the 2-position. The presence of strong [M-X]+ signals, but negligibly weak [M-Y]+ peaks, even when the C-Y bond would be expected to break more readily than the C-X bond, indicates that these diagnostically useful signals do not arise by simple cleavage. Similarly, the presence of an appreciable [M-Cl]+ signal, but no [M-Br]+ signal, in the spectra of representative examples of 4-Br-2ClC6H3NHCOC6H4Y, reveals that loss of a substituent from the 2-position occurs much more rapidly than fission of a weaker bond to a substituent in the 4-position. These trends are interpreted in terms of cyclization of the ionized 2-substituted benzanilide, followed by elimination of the substituent originally in the 2-position, to form a protonated 2-arylbenzoxazole.

Highly branched poly(N-isopropyl acrylamide) functionalized with an inducer molecule suppresses quorum sensing in Chromobacterium violaceum.

Bacterial quorum sensing has been implicated in a number of pathogenic bacterial processes, such as biofilm formation, making it a crucial target for developing materials with a novel antibiotic mode of action. This paper describes poly(N-isopropyl acrylamide) that has been covalently linked, at multiple chain ends, to homoserine lactone to give a highly branched polymer functionalized with a key messenger molecule implicated in QS. This novel functional material has shown promising anti-QS activity in a Chromobacterium violaceum assay.

Synthesis of an advanced intermediate for (+)-pillaromycinone. Staunton-Weinreb annulation revisited.

Condensation of an orsellinate anion with a 2-cyclohexenone (Staunton-Weinreb annulation) afforded a linear tetracycle which was converted to a protected derivative of 12a-epipillaromycinone. Methodology for introducing a 12a-hydroxyl substituent into the tetracycle with correct (R) configuration is described.

Total synthesis of solandelactones E and F, homoeicosanoids from the hydroid Solanderia secunda.

Asymmetric total syntheses of solandelactones E and F confirmed that hydroxyl configuration at C11 in these oxylipins had been misassigned and that the stereochemistry at this center should be reversed. Key steps in the synthesis involved a Nagao asymmetric acetate aldol reaction, a directed Simmons-Smith cyclopropanation, a Holmes-Claisen rearrangement to establish the unsaturated octalactone, and a Nozaki-Hiyama-Kishi coupling to connect two major fragments at C11-C12.

Ring closing metathesis in the synthesis of biologically interesting peptidomimetics, sugars and alkaloids.

Olefin metathesis has rapidly established itself as an essential tool in the synthetic chemist's armoury. The ease of operation and functional group tolerance that is obtained with the modern generation of catalysts makes the use of metathesis an extremely attractive option when preparing medicinally interesting molecules. This article will outline some of the ways in which chemists from both industry and academia have been utilising and developing metathesis in the search for novel biological probes and drug leads.

Revisiting the Maitland-Japp reaction. Concise construction of highly functionalised tetrahydropyran-4-ones.

Application of modern synthetic methods to the Maitland-Japp reaction has provided a one pot, one step procedure for the efficient construction of highly substituted tetrahydropyran-4-ones.

Diastereoselective synthesis of highly substituted tetrahydropyran-4-ones.

[reaction: see text] Aldol reactions of beta-ketoesters with aldehydes followed by a tandem Knoevenagel condensation, with a further equivalent of aldehyde, and intramolecular Michael addition produces single diastereomers of highly substituted tetrahydropyran-4-ones.

Total synthesis of solandelactones A, B, E, and F exploiting a tandem Petasis-Claisen lactonization strategy.

Solandelactones A, B, E, and F were synthesized using Nozaki-Hiyama-Kishi coupling of iododiene 13 with aldehydes 14 and 99 obtained by oxidation of alcohols 92 and 94. Key steps in the synthesis of 92 and 94 were (i) a Nagao asymmetric acetate aldol reaction of aldehyde 77 with thionothiazolidine 78 to set in place an alcohol that becomes the (7 S) lactone center of solandelactones, (ii) a Simmons-Smith cyclopropanation of 80 directed by this alcohol, and (iii) Petasis methylenation of cyclic carbonate 90 in tandem with a Claisen rearrangement that generates the octenalactone portion of solandelactones. Synthesis of solandelactones A, B, E, and F confirmed their gross structure and absolute configuration at C7, 8, 10, and 14 but showed that alcohol configuration at C11 must be reversed in pairs, A/B and E/F, from the previous assignment made to these hydroid metabolites. Thus, solandelactones A and B are correctly represented by 2 and 1, respectively, whereas solandelactones E and F are 6 and 5. A biogenesis of solandelactones is proposed for these C 22 oxylipins that parallels a hypothesis put forward previously to explain the origin of C 20 cyclopropane-containing algal products.

The one-pot, multi-component construction of highly substituted tetrahydropyran-4-ones using the Maitland-Japp reaction.

A one-pot, multi-component reaction for the synthesis of highly substituted tetrahydropyran-4-ones, based on the long forgotten Maitland-Japp reaction has been realised. Two different aldehydes and a derivative of a beta-ketoester can be condensed regioselectively in the presence of a Lewis acid to form tetrahydropyran-4-ones in excellent yields. The diastereoselectively of the reaction was found to be dependant upon the nature of the Lewis acid and the temperature at which the reaction was carried out. This procedure was also extended to the formation of tetrahydropyran-4-ones in greater than 95% enantiomeric excess.