Structural Investigations of 13-O-Demethyl-FK506 and Its Isomers Generated by in vitro Metabolism of FK506 Using Human-Liver Microsomes

FK506 is currently under investigation as immunosuppressant after organ transplantation and in immune diseases. The structure of a demethylated metabolite 1 of FK506 isolated after in vitro metabolism by human-liver microsomes was established using two-dimensional homo- and heteronuclear NMR experiments. The demethylation position was found to be at O? C(13) using HMBC spectra. In contrast to FK506, 7 different isomers could be differentiated in COSY, HMBC, and HMQC spectra. The intensity of their signals was 50:18:11:9:6:6 (one isomer could not be quantified). This isomerization may be explained by epimerization at C(10) or alternative formations of the hemiketal ring between C(10) and C(13) or C(9) and C(13), in addition to cis/trans-isomerism about the amide bond (see Scheme). The structural variation is possible by participation of the OH group at C(13) formed after demethylation and could be derived from HMBC spectra. Chemical exchange evidenced by ROESY spectra proved the rotational isomerism. NMR investigation of the structure of 13-O-demethyl-FK 506 ( 1 ) revealed at least seven isomers.     

Solid-supported nitroso hetero-Diels-Alder reactions. 3. Acid-mediated transformation of cycloadducts by scission of the oxazine C-O bonds

Polymer-supported dihydro[1,2]oxazine derivatives were prepared by acyl- and arylnitroso hetero-Diels-Alder reactions and exposed to strong (trifluoroacetic) acid during cleavage from resin-bound linkers. Cycloadducts prepared from cyclic dienes containing electron-donating substituents at the C6 oxazine carbon promoted formation of carbocations by cleavage of the C-O bond. The carbocations were quenched by nucleophilic reagents including triethylsilane, water, and alcohols and provided access to novel derivatives of N-alkyl hydroxamates. Products were submitted to biological assays, and the results are reported.     

Isotopically resolved {ie30-01} electronic spectrum of Ag3 and calculation of its Jahn-Teller effects

Ag₃ was produced by pulsed-nozzle laser vaporisation and jet-cooled in a Ne supersonic expansion. Onecolor resonant two-photon ionisation (R2PI) spectra of the {ie30-02} transition of Ag₃ were separately measured for all four isotopic combinations. Long vibrational progressions are observed, involving clearly resolved bands at low energy, merging into a dense but resolvable spectrum up to 1000 cm¹ above the origin. Both the ground {ie30-03} and excited {ie30-04} states of Ag3 are susceptible to Jahn-Teller distortion along the degenerate e′ bending coordinate. The Jahn-Teller analysis includes both linear and quadratic terms, simultaneously with the spin-orbit coupling. Following extensive parameter fitting, the absorption spectrum is calculated, and bands assigned. The spin-orbit splitting is quenched below the localization energy, but becomes observable ≈ 300 cm^-1 above the origin.     

Thermal degradation observed with different injection techniques: Quantitative estimation by the use of thermolabile carbamate pesticides

An experiment has been designed to study the thermal degradation of thermolabile compounds caused by various injection techniques. The four carbamate pesticides aminocarb, bendiocarb, carbaryl, and dioxacarb decompose thermally into methylisocyanate and the corresponding phenol. The carbamets and the phenols arising from them were separated on a 25 m SE-54 fused silica column; all compounds exhibited sharp peak shape indicating that the degradation observed took place completely within the injector. When cold on-column injection was employed no thermal degradation was observed whereas with hot splitless injection at 220°C decomposition of the carbamates was almost complete. PTV injection was found to produce intermediate results. When packed with glass wool and operated with glass wool and operated with starting temperatures lower than the boiling point of the solvent, decomposition was found to be almost complete. Applying isothermal conditions at 140°C (30°C above the boiling point of toluene) aminocarb and bendiocarb underwent only slight decomposition while carbaryl and dioxacarb were about half degraded. Results from PTV injection with an empty insert resembled those obtained using cold on-column injection and in this mode the application of temperatures up to 200°C resulted in no visible degradation. This can be explained by the short residence time of the sample in the injector.     

Poly(hydroxyalkanoates): A Fifth Class of Physiologically Important Organic Biopolymers?

Along with polyisoprenoids, polypeptides, polysaccharides, and polynucleotides, Nature contains a further group of biopolymers, the poly(hydroxyalkanoates). The commonest member of this group, poly[(R)-3-hydroxybutyrate] P(3-HB), had been identified by Lemoigne as early as the 1920s, as a storage substance in the microorganism Bacillus megaterium made up of more than 12000 (3-HB) units. However, the widespread distribution and significance of these biopolymers has only become clear recently. The work of Reusch, in particular, has shown that low molecular weight P(3-HB) (100–200 3-HB units) occurs in the cell membranes of prokaryotic and eukaryotic organisms. The function of P(3-HB) in the latter sources is largely unknown; it has been proposed that a complex of P(3-HB) and calcium polyphosphate acts as an ion channel through the membrane. Indeed, it has even been speculated that P(3-HB) plays a role in transport of DNA through the cell wall. In the present article, the following subjects will be discussed: metabolism of P(3-HB) and analogous polyesters in the synthesis and degradation of storage materials; P(3-HB) as a starting material for chiral synthetic building blocks; synthesis of cyclic oligomers (oligolides) of up to ten 3-HB units, and their crystal structure; high molecular weight bio-copolymers of hydroxybutyrate and hydroxyvalerate (BIOPOL) as biologically degradable plastics; nonbiological production of polyhydroxyalkanoates from 3-hydroxy carboxylic acids and the corresponding β-lactones; specific synthesis of linear oligomers with a narrow molecular weight distribution, consisting of about 100 (R)-3-hydroxybutyrate units, by using an exponential coupling procedure; structure of the polyesters, and a comparison with other polymers; the experimental results which led to the postulation of a P(3-HB) ion channel through the cell wall; modeling of P(3-HB) helices of various diameters, by using the parameters obtained from the crystal structures of oligolides; formation of a crown ester complex and ion transport experiments with the triolide of 3-HB. The article describes one example of the contributions that synthetic organic chemists can make to important biological problems in an interdisciplinary framework.     

Femtosecond rotational Raman coherence spectroscopy of cyclohexane in a pulsed supersonic jet

We combine the technique of femtosecond degenerate four-wave mixing (fs-DFWM) with a high repetition-rate pulsed supersonic jet source to obtain the rotational coherence spectrum (RCS) of cold cyclohexane (C(6)H(12)) with high signal/noise ratio. In the jet expansion, the near-parallel flow pattern combined with rapid translational cooling effectively eliminate dephasing collisions, giving near-constant RCS signal intensities over time delays up to 5 ns. The vibrational cooling in the jet eliminates the thermally populated vibrations that complicate the RCS coherences of cyclohexane at room temperature [Brügger, G.; et al. J. Phys. Chem. A 2011, 115, 9567]. The rotational cooling reduces the high-J rotational-state population, yielding the most accurate ground-state rotational constant to date, B(0) = 4305.859(9) MHz. Based on this B(0), a reanalysis of previous room-temperature gas-cell RCS measurements of cyclohexane gives improved vibration-rotation interaction constants for the ν(32), ν(6), ν(16), and ν(24) vibrational states. Combining the experimental B(0)(C(6)H(12)) with CCSD(T) calculations yields a very accurate semiexperimental equilibrium structure of the chair isomer of cyclohexane.     

On the weakly C-H···π hydrogen bonded complexes of sevoflurane and benzene

A vibrational assignment of the anaesthetic sevoflurane, (CF(3))(2)CHOCH(2)F, is proposed and its interaction with the aromatic model compound benzene is studied using vibrational spectroscopy of supersonic jet expansions and of cryosolutions in liquid xenon. Ab initio calculations, at the MP2/cc-pVDZ and MP2/aug-cc-pVDZ levels, predict two isomers for the 1?:?1 complex, one in which the near-cis, gauche conformer of sevoflurane is hydrogen bonded through its isopropyl-hydrogen atom, the other in which the same conformer is bonded through a bifurcated hydrogen bond with the fluoromethyl hydrogen atoms. From the experiments it is shown that the two isomers are formed, however with a strong population dominance of the isopropyl-bonded species, both in the jet and liquid phase spectra. The experimental complexation enthalpy in liquid xenon, ΔH(o)(LXe), of this species equals -10.9(2) kJ mol(-1), as derived from the temperature dependent behaviour of the cryosolution spectra. Theoretical complexation enthalpies in liquid xenon were obtained by combining the complete basis set extrapolated complexation energies at the MP2/aug-cc-pVXZ (X = D,T) level with corrections derived from statistical thermodynamics and Monte Carlo Free Energy Perturbation calculations, resulting in a complexation enthalpy of -11.2(3) kJ mol(-1) for the isopropyl-bonded complex, in very good agreement with the experimental value, and of -11.4(4) kJ mol(-1), for the fluoromethyl-bonded complex. The Monte Carlo calculations show that the solvation entropy of the isopropyl-bonded species is considerably higher than that of the fluoromethyl-bonded complex, which assists in explaining its dominance in the liquid phase spectra.     

Darstellung, 11B-NMR-, Schwingungsspektren und Kristallstruktur von (PPh4)[1-(NO)B10H9]

Synthesis, ¹¹B NMR, Vibrational Spectra, and Crystal Structure of (PPh₄)[1-(NO)B₁₀H₉] By reaction of (n-Bu₄N)₂[B₁₀H₁₀] in aqueous acetonitrile with NO₂ a reaction mixture is formed from which [1-(NO)B₁₀H₉]^– has been isolated by ion exchange chromatography on diethylaminoethyl(DEAE) cellulose. The X-ray structure determination of (PPh₄)[1-(NO)B₁₀H₉] (triclinic, space group P1, a = 7.6553(11), b = 13.179(2), c = 14.122(3) Å, α = 69.853(13), β = 82.445(14), γ = 87.230(13)°, Z = 2) reveals the coordination of the NO group via N in an apical position of the B₁₀ cluster with B1–N = 1.457(5) and N–O = 1.101(4) Å. The ¹¹B NMR spectrum exhibits the characteristic feature (1 : 1 : 4 : 4) of a in 1 position substituted B₁₀ cluster with a strong downfield shift of the ipso-B atom at +6.5 ppm. The IR and Raman spectra show a strong NO stretching vibration at 2219 cm^–1.     

Kristallstruktur von Tetraphenylphosphonium-Monothiocyanatohydro-closo-Decaborat, [P(C6H5)4]2[2-(SCN)B10H9] · CH3CN

Crystal Structure of Tetraphenylphosphonium Monothiocyanatohydro-closo-Decaborate, [P(C₆H₅)₄]₂[2-(SCN)B₁₀H₉] · CH₃CN The X-ray structure determination of [P(C₆H₅)₄]₂[2-(SCN)B₁₀H₉] · CH₃CN (monoclinic, space group P2₁/n, a = 10.6040(10), b = 13.8880(9), c = 33.888(3) Å, β = 94.095(8)°, Z = 4) reveals the S coordination of the SCN substituent with a B? S distance of 1.913(6) Å and a B? S? C angle of 105.3(3)°. The SCN group is nearly linear (178.2(7)°).