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A solid DMSO salvate of a compound of fornula (I) is described, which is a useful intemediate far preparing the broad spectrum antibiotics Ceftobiprole and Ceftobiprole Medocaril.

Experimentally determined barriers to O-acyl group topomerization in mixed anhydrides composed of β-disubstituted carboxylic acids and cyclic thiohydroxamic acid N-hydroxy-4-methylthiazole-2(3H)-thione were located in the range of ΔG‡320=68±8 kJ mol−1 (DNMR). According to modeling studies, the underlying exchange process is proposed to occur via rotation about the N,O bond for torsional movement of the O-acyl group past the heterocyclic 4-methyl substituent. The energetically lowest pathway for passing the O-acyl entity by the thione sulfur, is predicted to occur via sequential rocking about the C sp 2 ,O single bond in combination with an interlaced twist about the N,O axis.

An efficient evaluation procedure for the chemical screening and on-line structural elucidation of dimeric naphthylisoquinoline alkaloids has been developed. The method is based on the lead tetraacetate oxidation of the central binaphthalene core of the alkaloids. UV spectra of the extracts after addition of the oxidant show, in the presence of naphthylisoquinoline dimers, the appearance of a characteristic long-wavelength absorption indicative of dinaphthoquinones. The efficiency and relevance of the method has been demonstrated in the discovery of a constitutionally and configurationally new dimeric naphthylisoquinoline alkaloid, named ancistrogriffithine A (4), from the previously uninvestigated Asian liana Ancistrocladus griffithii. After verification of this screening result by LC−ESI-MS/MS, the constitution and the relative configuration of the compound were elucidated on line, by LC−NMR and LC−CD on the extract. Using an LC−NMR-WET-ROESY experiment, it was possible for the first time to determine the relative axial configuration of a natural biaryl compound on line, by observing long-range ROE interactions. Finally, an oxidative degradation right on the extract delivered the absolute configuration of 4, without isolation of the alkaloid. Ancistrogriffithine A is the as yet only dimeric naphthylisoquinoline from an Asian Ancistrocladaceae plant.

Two inhibitors of membrane-type matrix metalloproteinase (MT1-MMP) were isolated from a marine sponge Cribrochalina sp. Their structures were elucidated as unusual phosphorylated sterol sulfates by spectroscopic and chemical methods. One of the sterol sulfates was found to be identical to haplosamate A, whose structure was previously proposed to be a steroidal sulfamate ester, which led to structure revisions of both haplosamates A and B. The absolute stereochemistry of haplosamate A was determined by chemical transformation and the modified Mosher's method. The sterol sulfates inhibited MT1-MMP with IC50 values of 150 and 160 μg/mL, respectively. © 2001 Elsevier Science Ltd.

X-ray crystallographic structures of two polymorphs (α- and β-forms) of 1,5-dimethylsemibullvalene-2,6-dicarbonitrile, in which the molecules undergo rapid, nondegenerate Cope rearrangement, have been obtained over the temperature range 20−295 K. CP-MAS carbon-13 NMR spectra of the β-form have been observed over the temperature range 140−340 K. A generalized treatment for the perturbation of degeneracy has been developed and it is shown that the results of the X-ray and NMR methods are in excellent agreement. The thermodynamic parameters, ΔHP and ΔSP, for the perturbation of degeneracy in the β-form are reported. A possible explanation for the difference in the magnitudes of the perturbation of degeneracy in the two crystalline forms is suggested. It is noted that for equilibrating systems, for which the barriers for interconversion are of the order of 1−10 kJ mol-1, the transition between rapid and extremely slow equilibration occurs over a very narrow range at cryogenic temperatures, thus precluding dir...

Configurationally unstable biaryl lactones of type (M)-1 ⇌ (P)-1 and ring-opened 2-acyl-2‘-hydroxy biaryl compounds of type (M)-4 ⇌ (P)-4 are versatile precursors for the atroposelective preparation of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched material for smaller interconversion rates. For the lactones, the free activation energies ΔG⧧298 increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe (t1/2 ≈ ms) < Me (t1/2 ≈ s) < Et < i-Pr (t1/2 ≈ min) < t-Bu (t1/2 ≈ d). The formally ring-opened 2-acyl-2‘-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configurationally less stable) intermediates, have a significantly slower atropisomerization rate as a result of the high loss in acti...

Oxidation with barium manganate of the enol of tetraacetylethane (10) affords tetraacetylethylene (7a) in good yield. Treatment of the 1,3-diketones 15a and b with iodosobenzene in the presence of boron trifluoride does not result in oxidative coupling yielding 10 and diacetyldibenzoylethane 17, respectively, as has been reported by Moriarty et al. Instead the known difluoroborylenolates 16 are formed. Oxidative coupling of the sodium enolate of 15b with iodine affords the meso-tetraketone meso-17 and diacetyldibenzoylethylene (E)-7b besides small amounts of rac-17 and the bisenol 19. In the presence of 1,4-diazabicyclo[2.2.2]octane, meso-17 and 19 tautomerise yielding identical equilibrium mixtures of meso-17, rac-17, and 19 (26:29:45). Dehydrogenation with 5,6-dichloro-2,3-dicyanobenzoquinone of meso-17 yields (E)-7b and an isomer (77:23) which was assigned structure (Z)-7b on the basis of spectroscopic evidence. – Tetraacetylethylene (7a) reacts with 1,2-dimethylenecyclohexane to afford two different [4+2]cycloadducts, viz. the spirocyclic dihydropyran 25 (30 %) and the tetraacetyloctalin 27. Whereas the latter is stable, the former isomerises to the latter on heating. Formation of both [4+2]cycloadducts and the isomerisation 25 27 are interpreted by invoking the zwitterion 26 as common intermediate. Monoolefines that cannot generate stable carbenium ions don't give [4+2]cycloadducts with 7a. In contrast, α-methylstyrene yields the oxa Diels–Alder product 30. The structures of (E)-7b, 19, 25, and 27 are established by X-ray diffraction analyses.

The deuterium-labelled 2,4,6,8-substituted barbaralanes [D5]-1a and b, and the two model barbaralanes 15 und 19 for the estimation of 13C chemical shifts in the slow-exchange limit are synthesised from bicyclo[3.3.1]nona-3,7-diene-2,6-dione (5). – The extension of Saunders′ isotopic perturbation method bridges the gap between the limiting cases “perturbation of shift equivalence in delocalised systems” and “perturbation of degeneracy” by considering the simultaneous presence of delocalised species of higher symmetry and skewed equilibria between localised molecules that are degenerate in the absence of the isotopic perturbation. An equation (Equation 7) is derived for such multi-component systems which describes the temperature dependence of the relative isotopic splittings in 13C spectra with three parameters, viz. the isotopic perturbation parameters ΔHP and ΔSP of the skewed equilibria and the enthalpy difference ΔH0 between the delocalised and localised species. – Relative isotopic splittings ΔδP/Δδ are calculated from estimated chemical shifts in the slow-exchange limit (Δδ) and isotopic splittings (ΔδP) of signals in variable-temperature 151-MHz 13C NMR spectra recorded for solutions of [D5]-1a and b in [D8]toluene and N,N′-dimethylpropylene urea. The results obtained from [D5]-1a in both solvents and from [D5]-1b in the former are compatible with either a skewed equilibrium between localised valence tautomers alone or the simultaneous presence of localised and small amounts of delocalised valence tautomers. In striking contrast, the small isotopic splittings themselves and their small temperature dependence, observed for solutions of [D5]-1b in N,N′-dimethylpropylene urea, demonstrate that one half of the solvated compound exists in the delocalised state [D5]-1b*, which is more stable by 2 kJ mol–1 than the equilibrating localised species [D5]-1b ⇌ [D5]-1b′.

The Brönsted-Lewis superacid HSO3F-SbF5 or "magic acid" is re-investigated by modern 19F NMR methods over a wide concentration range. The system is found to be considerably more complex than had been assumed previously. A total of 13 different anions are identified of which only five have previously been identified in magic acid. With increasing SbF5 contents the concentration of monomeric anions like [SbF6]-, [SbF5(SO3F)]-, cis- and trans-[SbF4(SO3F)2]-, and mer-[SbF3(SO3F)3]- gradually decreases. Except for [Sb2F11]-, which is present in very small concentrations only, the formation of oligomers involves exclusively μ-fluorosulfato bridges. In addition to donor (SO3F)- and acceptor (SbF5) complex formation to give [SbF5(SO3F)]- and possibly ligand redistribution, the solvolysis of SbF5 or SbF4(SO3F) in HSO3F appears to be the principal formation reaction for polyfluorosulfatofluoroantimonate(V) anions. In glass (NMR tubes) the solvolysis product HF is converted to the oxonium ion [H3O]+, which has previously been identified by 1H NMR and structurally characterized as [H3O][Sb2F11] by us.Key words: magic acid, conjugate superacid, fluorosulfuric acid, 19F NMR spectra.

Whereas 1,5-dimethylsemibullvalene (1b) equilibrates with 1,5-dimethylcyclooctatetraene (2b), the semibullvalene-2,6-dicarbonitriles 13 rearrange irreversibly to afford mixtures of the isomeric cyclooctatetraene-1,5-dicarbonitriles 14 and 15. Arrhenius and Eyring parameters of these thermal isomerisation reactions have been determined for the gas phase (1b 2b) and [D6]benzene solutions (1b 2b, 13 14 + 15). Furthermore, the activation parameters of the known rearrangement of octamethylcyclooctatetraene (3) to octamethylsemibullvalene (4) have been determined. – The data for these compounds, together with those for related compounds previously reported in the literature, show that substituents not only influence the relative stabilities of the semibullvalene and cyclooctatetraene systems but also the height of the energy barrier for their interconversion. Those substituents that lower the barrier toward the degenerate Cope rearrangement of semibullvalenes simultaneously accelerate their rearrangement to cyclooctatetraenes thus limiting the thermal stability of the former.

The activation parameters [ΔG# (200 K), ΔH#, and ΔS#] for the degenerate Cope rearrangements of barbaralane (1a) and several semibullvalenes (3a, 7a, 8a), and for those of a number of their 3,7- and 2,6-disubstituted derivatives, have been determined by variable-temperature carbon-13 NMR spectroscopy at 126 and 151 MHz. the disubstituted compounds studied include the barbaralanes 1c, d, e, h, j, k, and 2e, h, j, and the semibullvalenes 3d, e, h, 4e, h, i, l, m, and 5h–8h. Careful attention has been given to the measurement of temperatures. The data for these compound, together with those for related compounds previously reported in the literature, show that conjugating subsituents (e. g. aryl, CH, CO2R) in the 2,6 positions lower the barriers of the degenerate Cope rearrangement, whereas substituents that are electron-withdrawing through the inductive effect (e. g. Cl, CF3, SO2Ar) retard the reaction. Substituents in the 3,7-positons have little effect or are rate-retarding. The presence of 1,5-tri- and tetramethylene bridges in semibullvalenes accelerates the rearrangements, the effect being larger in the case of the former.

The first synthesis of the macrocyclic natural product xestodecalactone A, a metabolite of a sponge-derived fungus, is described. By the use of methyl 5-hydroxyhexanoate in its R- or S-configured form, or as its racemate as the precursors, both enantiomers of xestodecalactone A as well as the racemic compound were obtained. Comparison of these synthetic products with the natural product by circular dichroism (CD) spectroscopy and by HPLC on a chiral phase revealed the natural product to have the (R)-configuration.

The activation parameters [ΔG# (200 K), ΔH#, and ΔS#] for the degenerate Cope rearrangements of barbaralane (1a) and several semibullvalenes (3a, 7a, 8a), and for those of a number of their 3,7- and 2,6-disubstituted derivatives, have been determined by variable-temperature carbon-13 NMR spectroscopy at 126 and 151 MHz. the disubstituted compounds studied include the barbaralanes 1c, d, e, h, j, k, and 2e, h, j, and the semibullvalenes 3d, e, h, 4e, h, i, l, m, and 5h–8h. Careful attention has been given to the measurement of temperatures. The data for these compound, together with those for related compounds previously reported in the literature, show that conjugating subsituents (e. g. aryl, CH, CO2R) in the 2,6 positions lower the barriers of the degenerate Cope rearrangement, whereas substituents that are electron-withdrawing through the inductive effect (e. g. Cl, CF3, SO2Ar) retard the reaction. Substituents in the 3,7-positons have little effect or are rate-retarding. The presence of 1,5-tri- and tetramethylene bridges in semibullvalenes accelerates the rearrangements, the effect being larger in the case of the former.

Oxidation with barium manganate of the enol of tetraacetylethane (10) affords tetraacetylethylene (7a) in good yield. Treatment of the 1,3-diketones 15a and b with iodosobenzene in the presence of boron trifluoride does not result in oxidative coupling yielding 10 and diacetyldibenzoylethane 17, respectively, as has been reported by Moriarty et al. Instead the known difluoroborylenolates 16 are formed. Oxidative coupling of the sodium enolate of 15b with iodine affords the meso-tetraketone meso-17 and diacetyldibenzoylethylene (E)-7b besides small amounts of rac-17 and the bisenol 19. In the presence of 1,4-diazabicyclo[2.2.2]octane, meso-17 and 19 tautomerise yielding identical equilibrium mixtures of meso-17, rac-17, and 19 (26:29:45). Dehydrogenation with 5,6-dichloro-2,3-dicyanobenzoquinone of meso-17 yields (E)-7b and an isomer (77:23) which was assigned structure (Z)-7b on the basis of spectroscopic evidence. – Tetraacetylethylene (7a) reacts with 1,2-dimethylenecyclohexane to afford two different [4+2]cycloadducts, viz. the spirocyclic dihydropyran 25 (30 %) and the tetraacetyloctalin 27. Whereas the latter is stable, the former isomerises to the latter on heating. Formation of both [4+2]cycloadducts and the isomerisation 25 27 are interpreted by invoking the zwitterion 26 as common intermediate. Monoolefines that cannot generate stable carbenium ions don't give [4+2]cycloadducts with 7a. In contrast, α-methylstyrene yields the oxa Diels–Alder product 30. The structures of (E)-7b, 19, 25, and 27 are established by X-ray diffraction analyses.

[reaction: see text] UV/vis spectra of thermochromic semibullvalenes 1 and barbaralanes 2, which undergo rapid degenerate Cope rearrangements, display temperature-dependent shoulders (1b, 1d, 1e) or absorption maxima (1c, 2c, 2f) at the low-energy side of their strong UV bands. These long-wavelength absorptions are ascribed to Franck-Condon transitions from delocalized structures 1(deloc) and 2(deloc). Gibbs free energy differences, DeltaG*, between delocalized and localized forms were calculated from the temperature dependence of the long-wavelength absorptions. Dipolar and polarizable solvents strongly affect and even may reverse the relative stabilities of the localized and delocalized forms of 1c, 2c, and 2f. For example, DeltaG*(2c) = 8 kJ mol(-)(1) in cyclohexane, 2 kJ mol(-)(1) in dimethylformamide, and -3 kJ mol(-)(1) in N,N'-dimethylpropylene urea (DMPU), so that (2c(deloc))(DMPU) becomes the global minimum. In contrast to the case for 2c, the intensities of the long-wavelength shoulders of the yellow semibullvalenes 1b, 1d, and 1e are only moderately influenced by solvents, and the rates of Cope rearrangements of the nonthermochromic, colorless barbaralanes 2a and 2b, determined by NMR methods, are almost solvent-invariant. In search of the solute properties that are decisive in determining the influence of solvent upon DeltaG*, electrical dipole and quadrupole moments and molecular polarizabilities have been calculated using the B3LYP/6-31G* method and solvation energies have been computed with the conductorlike polarized continuum model (CPCM). The results of these calculations indicate that the solvent effects are due to the greater polarity and polarizability of the delocalized structures relative to the localized structures.

Fungal isolates of Penicillium cf. montanense were obtained from the marine sponge Xestospongia exiguacollected from the Bali Sea, Indonesia. Culture filtrates of the fungi yielded three novel decalactone metabolites, xestodecalactones A, B, and C (1, 2a, and 2b), consisting of 10-membered macrolides with a fused 1,3-dihydroxybenzene ring. Online HPLC-NMR, ESI-MS/MS, and -CD spectra were acquired, and the structures of the new compounds were established and confirmed on the basis of offline NMR spectroscopic ((1)H, (13)C, COSY, ROESY, (1)H-detected direct and long-range (13)C-(1)H correlations) and mass spectrometric (EIMS) data. Quantum chemical calculations of the CD spectra proved to be difficult because of the conformational flexibility of the xestodecalactones. These compounds, of which 2a and 2b, due to the additional stereocenter at C-9, are diastereomeric compounds, are structurally related to a number of biologically active metabolites found in terrestrial fungal strains. Compound 2a was found to be active against the yeast Candida albicans.

A series of six 1,5-(ethylmethyl)semibullvalenes (1a==1a', 2==2', 3==3') and two 4(2)-substituted semibullvalenes (4==4'), each undergoing Cope equilibria between nondegenerate valence tautomers, was investigated by carbon-13 NMR spectroscopy at a range of temperatures in several different solvents. Gompper's treatment of substituent perturbation was extended, specifically accounting for the effects of the substituents on chemical shifts, to allow the determination of the thermodynamic parameters for these skewed equilibria. These new treatments were used to determine the population difference (f - f ') between the valence tautomers and the perturbation thermodynamic quantities DeltaH(P), DeltaS(P), and DeltaG(P). The slow-exchange limit was reached for the parent 1,5-(ethylmethyl)semibullvalenes 3a==3a' from which it was established that the preferred valence tautomer is 3a with the ethyl group on the cyclopropane ring. Despite considerable effort, the slow-exchange limit could not be reached in any of our other remotely substituted semibullvalenes. Provided that the ethyl group always prefers the cyclopropyl position as in 3a, the 1-ethyl-5-methylsemibullvalenes 1a, 2, and 3 are more stable by DeltaH(P) = 0.7-1.7 kJ mol(-1) than their valence tautomers 1a', 2', and 3'. In the directly substituted semibullvalenes (4 left harpoon ovet right harpoon 4'), the preferred valence tautomers 4a and 4b have the bromine atom or the nitrile group on the vinyl position (C(4)) rather than on the cyclopropane ring (C(2)) and are more stable than 4a' and 4b' by DeltaH(P) = 4.8 and 7.0 kJ mol(-1), respectively.

The first high-performance liquid chromatography-nuclear magnetic resonance (HPLC-NMR) investigation of exchangeable protons of low-molecular-mass natural products is reported. Model alkaloids or crude plant extracts were dissolved in 2H2O-1H2O-MeCN (deuterium oxide-water-acetonitrile) or 2H2O-MeCN and, after direct injection or chromatographic separation, examined in a 60-microl NMR flow probe. Exchangeable amino protons initially detected by HPLC-electrospray ionization mass spectrometry were subsequently identified and investigated by stop-flow 1H-NMR, two-dimensional (2D) total correlation spectroscopy (TOCSY), and 2D nuclear Overhauser effect spectroscopy (NOESY). These experiments extend the applicability of HPLC-NMR for the investigation and structure elucidation of natural products.