5-Spirocyclopropane Isoxazolidines as Versatile Intermediates in Organic Synthesis

The review outlines the various different azaheterocycles available from 5-spirocyclopropane isoxazolidines. These compounds can be regarded as versatile direct precursors of tetrahydro-, dihydropyridone and azetidinone derivatives. The current scope and limitations, and the selectivity aspects of the different processes are discussed therein.     

Measurements of climatic parameters and ground-level ozone at Terra Nova Bay in Antarctica

Summary The results of local meteorology, solar radiation and ground-level ozone measurements taken in Antarctica during the second Italian expedition (December 86–February 87) at Terra Nova Bay are presented. During the summer months the site of the Italian base camp is characterized by a thin strip of deglaciated ground, along which the temperature measurements close to the ground and up to 6 m high show a strongly superdiabatic profile. This irregular trend of the temperature in the surface layer is mainly due to the notable incoming amounts of radiation and to the extreme transparency of the atmosphere. This is also shown by the low values of the ratio between total radiation and diffuse radiation. The ground is thus subjected to intense heating, especially in the warmer hours of the day, while the surface layer of the atmosphere will be characterized by strong upward heat fluxes and by turbulent convective movements. Vertical-temperature-profile measurements show an almost forced persistence in the superdiabatic trend, which tends towards isothermic values only as a resultof rapid variations in the direction and intensity of the wind, connected to the downward flux of cold air masses, shown also by the simultaneous increases in ground-level ozone concentrations which would support the presence of dry-deposition processes in the lower layer. However, the complex local orography and the horizontal discontinuity (sea, deglaciated coast, snow-covered surfaces) do not permit a correct application of profile flux relations, normally used in studies on groundlevel dry-deposition. Paper presented at the IV Congresso del Gruppo Nazionale per la Fisica dell'Atmosfera e dell'Oceano, June 22–24, 1987, Rome.     

Solid-state interactions and drug release of teicoplanin in binary combinations with peracetylated α-, β-, and γ-cyclodextrins

Triacetyl α-cyclodextrin, triacetyl β-cyclodextrin and triacetyl γ-cyclodextrin were tested as possible hydrophobic carriers to prolong the release of hydrophilic teicoplanin (TCP). Physical–chemical characterization of individual components, drug-carrier physical mixtures at 0.5, 0.67 and 0.75 mass fraction of carrier, and the respective interaction products by kneading or evaporative crystallization under microwave irradiation was carried out using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In vitro drug release in pH 7.4 phosphate buffer at 37 °C was determined by intrinsic dissolution rate (IDR) measurements on non disintegrating compressed discs. Solid-state interactions of TCP with triacetyl α-cyclodextrin by evaporative crystallization and kneading and with triacetyl β-cyclodextrin by evaporative crystallization (probably resulting in carrier amorphization) were demonstrated. The role of carrier hydrophobicity, carrier mass fraction and preparation method of solid drug-carrier combinations on solid-state drug-carrier interactions and slowing down of TCP release was assessed. Modulation of drug release can be achieved using TCP-triacetyl γ-cyclodextrin combinations at 0.5 mass fraction of carrier.     

Circular‐Dichroism Studies on Artemisinin and Epiartemisinin and Their β‐Cyclodextrin Complexes in Solution

The circular dichroism (CD) spectra of the powerful antimalarian active principle artemisinin (ART; 1 ) from Artemisia annua, and of epiartemisinin (EPI, 2), its C(7) epimer, were studied in solution in the presence and absence of β‐cyclodextrin (β‐cd). A significant inversion of sign in the region of the second electronic transition was detected. The rotational strengths were successfully calculated within the time‐dependent density functional theory (DFT), which enabled us to establish a correlation between the molecular recognition and the biological acitivities of the two isomers.     

Understanding the role of stereoelectronic effects in determining collagen stability. 2. A quantum mechanical/molecular mechanical study of (Proline-Proline-Glycine)(n) polypeptides

The importance of vicinal and long-range interresidue effects in determining the stability of the collagen triple helix has been investigated by quantum mechanical (QM) and molecular mechanical (MM) computations on suitable model polypeptides, taking into account solvent effects by the polarizable continuum model (PCM). At the QM level, the PII conformation corresponds to an energy minimum for pentapeptide analogues incorporating the sequence Gly-Pro-Pro-Gly, irrespective of the down or up puckering of the pyrrolidine ring. However, our computations indicate that the alternation of down and up prolines characterizing collagen and collagen-like peptides is not due to an intrinsic preference of the Pro-Pro-Gly sequence. This result is confirmed by MM computations of longer polypeptides. Next, MM computations on model triple helices show that a better packing is obtained for specific values of backbone dihedrals, which, in turn, favor the alternation of down and up prolines along each chain.     

Coordination properties of 6-deoxy-6-[1-(2-amino) ethylamino]-β-cyclodextrin and the ability of its copper(II) complex to recognize and separate amino acid enantiomeric pairs

The functionalized cyclodextrin 6-deoxy-6-[1-(2-amino)ethylamino]--cyclodextrin was synthesized, and an NMR, EPR, pH-metric, and calorimetric investigation was carried out in aqueous solution in order to ascertain its behaviour towards protonation and copper(II) complex formation. The thermodynamic parameters of the ternary complex formation with alanine, phenylalanine and tryptophan enantiomeric pairs were also determined (25° C andI=0.1 mol dm^–3). No thermodynamic enantioselectivity was observed in these systems, while a chiral, though poor, discrimination was observed in LEC: c.d. spectra also show enantiomeric stereoselectivity. The results of the present investigation, compared with previously reported results, suggest the occurence of acis-complex trans-complex equilibrium in such systems.     

Modeling of overloaded gradient elution of nociceptin/orphanin FQ in reversed-phase liquid chromatography

The Reversed-phase (RP) gradient elution chromatography of nociceptin/orphanin FQ (N/OFQ), a neuropeptide with many biological effects, has been modeled under linear and non-linear conditions. In order to do this, the chromatographic behavior has been studied under both linear and nonliner conditions under isocratic mode at different mobile phase compositions--ranging from 16 to 19% (v/v) acetonitrile (ACN) in aqueous trifluoracetic acid (TFA) 0.1% (v/v)-on a C-8 column. Although the range of mobile phase compositions investigated was quite narrow, the retention factor of this relatively small polypeptide (N/OFQ is a heptadecapeptide) has been found to change by more than 400%. In these conditions, gradient operation resulted thus to be the optimum approach for non-linear elution. As the available amount of N/OFQ was extremely reduced (only a few milligrams), the adsorption isotherms of the peptide, at the different mobile phase compositions examined, have been measured through the so-called inverse method (IM) on a 5 cm long column. The adsorption data at different mobile phase compositions have been fitted to several models of adsorption. The dependence of the isotherm parameters on the mobile phase composition was modeled by using the linear solvent strength (LSS) model and a generalized Langmuir isotherm that includes the mobile phase composition dependence. The overloaded gradient separation of N/OFQ has been modeled by numerically solving the equilibrium-dispersive (ED) model of chromatography under a selected gradient elution mode, on the basis of the previously determined generalized Langmuir isotherm. The agreement between theoretical calculations and experimental overloaded band profiles appeared reasonably accurate.     

New taxane derivatives: synthesis of baccatin[14,1-d]furan-2-one nucleus and its condensation with the norstatine side chain

New taxanes 15 and 18, containing the unsaturated and saturated baccatin[14,1-d]furan-2-one nucleus, respectively, were prepared starting from the readily available 13-oxo-7-Tes-baccatin III (3). Sequential formation of the enolate of 3 and reaction with ethyl glyoxylate gave the 13-oxo-7-Tes-baccatin[14,1-d]-3,4-dehydrofuran-2-one 4. The reduction of 4 can result in the formation of a mixture of compounds corresponding to 13-hydroxy alcohol 5 and 13-enol derivative 6. Both 5 and 6 were transformed into 13-oxo-7-Tes-baccatin[14,1-d]furan-2-one 8 by treatment with a base. Further reduction of 8 gave 13-hydroxy compound 9. Esterification of 6 and 9 with N,O-protected norstatine 12, followed by deprotection, gave the new promising anticancer taxanes 15 and 18, respectively.     

Selective synthesis of 14β-amino taxanes

The base induced deprotonation of H-14 of 7-triethylsilyl- (7-TES-) and 7-tert-butoxycarbonyl- (7-BOC-) protected 13-oxo-baccatins gave the corresponding enolates, which were selectively aminated with electrophilic nitrogen donors, such as azodicarboxylates and tosyl azide. In particular, tosyl azide gave the corresponding 7-BOC- and 7-TES-13-oxo-14β-azido-baccatin III. Alternatively, the last compound was prepared via NaN₃ induced azidation of the 13-silyl enol ether of 7-TES-13-oxo-baccatin III under oxidative (cerium ammonium nitrate) conditions. The 13-silyl enol ether was obtained in a multistep process by DBU induced silylation of 7-TES-13-oxo-baccatin III. The 7-TES-13-oxo-14β-azido-baccatin III was used as a key intermediate for the synthesis of a new family of antitumour taxanes containing amino based functional groups at the C-14 position, such as: 14β-azido, 14β-amino, 14β-amino 1, 14-carbamate, 14β-amino 1, 14-thiocarbamate, and 14β-amino N-tert-butoxycarbonyl-1,14-carbamate.     

Thermal behavior of Cu(II)-, Cd(II)-, and Hg(II)-exchanged montmorillonite complexedwith cysteine

The thermal behavior of montmorillonite and organically modified montmorillonite, both treated with heavy metal cations [Cu(II), Cd(II) and Hg(II)], was characterized via thermal analyses (TG, DTG and DTA) combined with evolved species gas mass spectrometry (MS-EGA), and X-ray diffraction at in situ controlled temperature (HTXRD). The reactions involving Cu(II)- and Cd(II)-montmorillonite samples are mostly related to H₂O and OH loss, unlike Hg(II)-montmorillonite, where effects associated to Hg(II) loss are also present. Finally reactions related to dehydration, dehydroxylation and to organic matter decomposition can be observed in montmorillonite samples treated with cysteine.