An alternative to the use of delta-lactam urethanes in the "ring switch" approach to higher homologues of AMPA-type glutamate antagonists

In an alternative strategy to the use of delta-lactam urethanes for the preparation of homologues of AMPA-type glutamate antagonists, we have used 5-exomethylene derivatives of pyroglutamate esters. The homochiral pyrazole amino acid derivatives 18 and 19 have been prepared in this way. Although this synthesis yields products with a glycine residue separated from a heterocyclic ring by two carbon atoms, the substitution of the heterocyclic ring is different from that in compounds prepared from delta-lactam urethanes. The branched chain compounds 32 and 33 have also been prepared in this way but the second chiral centre is epimerised during the synthesis. An interesting reaction, giving the pyridone 27 from the imino ether 24 and tert-butyl acetoacetate, is also reported.     

Investigation of a route to ibotenic acid analogues via a reduced pyroglutamate template

Two alternative "ring switch" based syntheses have been shown to give access to the reduced protected homochiral analogues, 27, 28 and 36, of the CNS active compound ibotenic acid.     

Homochiral metal-organic frameworks for heterogeneous asymmetric catalysis

Homochiral crystallizations of two enantiomeric metal-organic frameworks (MOFs) Ce-MDIP1 and Ce-MDIP2 were achieved by using L- or D-BCIP as chiral inductions, respectively, where the chiralities were characterized by solid state CD spectra. Ce-MDIPs exhibit excellent catalytic activity and high enantioselectivity for the asymmetric cyanosilylation of aromatic aldehydes; the homochiral Cd-TBT MOF having L-PYI as a chiral adduct exhibits stereochemical catalysis toward the Aldol reactions.     

A homochiral porous metal-organic framework for highly enantioselective heterogeneous asymmetric catalysis

A homochiral porous noninterpenetrating metal-organic framework (MOF), 1, was constructed by linking infinite 1D [Cd(mu-Cl)2]n zigzag chains with axially chiral bipyridine bridging ligands containing orthogonal secondary functional groups. The secondary chiral dihydroxy groups accessible via the large open channels in 1 were utilized to generate a heterogeneous asymmetric catalyst for the addition of diethyzinc to aromatic aldehydes to afford chiral secondary alcohols at up to 93% enantiomeric excess (ee). Control experiments with dendritic aromatic aldehydes of different sizes indicate that the heterogeneous asymmetric catalyst derived from 1 is both highly active and enantioselective as a result of the creation of readily accessible, uniform active catalyst sites inside the porous MOF.     

Efficient desymmetrization of "pseudo"-C2-symmetric substrates: illustration in the synthesis of a disubstituted butenolide from arabitol

A short synthesis of the homochiral disubstituted butenolide 1 is described in four steps from arabitol. The key steps are the selective kinetic protection of arabitol and the cyclization of 11 to form the butenolide ring. This last transformation represents a rare example of a fully stereoselective cyclitive desymmetrization process of a "pseudo"-C2-symmetric substrate.     

Dynamic chiral flipping within strongly chemisorbed molecular monolayers at surfaces

Unexpected local chiral switching events are shown to occur within strongly chemisorbed homochiral domains, in which a pair of surface-bonded molecules dynamically switches their chiral configuration for a short period of time.     

Switching of chirality from racemic to homochiral state in new liquid crystalline monomers with bent-core molecules

The synthesis and physical properties of bent-shaped molecules with ester linkages and methoxy substitution on a non-central ring are presented. Terminal chains of most mesogens contain a group with double bond, which promotes polymerization. In all the compounds studied a B₂ phase just below the isotropic phase has been found. Polarization current profiles indicate that this phase is antiferroelectric, and dielectric spectroscopy data with a pronounced high frequency mode support this fact. For several compound chirality switching from racemic to the homochiral state was seen after application of a low frequency a.c. field. Another phase, which could be assigned to the B₇ family, appears below the B₂ phase on cooling.     

Convenient synthesis of novel 5‐substituted 3‐methylisoxazole‐4‐sulfonamides

A number of novel sulfonamide derivatives of 5‐substituted‐3‐methylisoxazole were synthesized and characterized, starting from 3,5‐dimethylisoxazole. Key steps include the generation of 3,5‐dimethylisoxazole‐4‐sulfonamides followed by their reactions with N‐(dimethoxymethyl)‐N,N‐dimethylamine or various aromatic and heteroaromatic aldehydes. As a result, a series of novel aryl/heteroaryl‐ and aminovinylsubstituted derivatives of the isoxazole heterocycle were obtained. The scope and limitations of the developed approach are discussed.     

Dipicolylglycyl-phenylalanine zinc(II): a metallopeptide with a built-in conformational switch and its homochiral helical coordination polymer

The peptide-zinc complex [(Dpg-Phe)Zn]2+ (Dpg = N,N-dipicolylglycine; Phe = phenylalanine) reversibly forms a homochiral P-helical coordination polymer upon switching the pH from mildly basic to mildly acidic.     

Ion/molecule reactions of the protonated serine octamer

The protonated homochiral octamer of serine exchanges all 33 of its labile hydrogens with CH(3)OD and undergoes ligand switching reactions with amines in a quadrupole ion trap mass spectrometer.     

Sc3+-catalyzed aldol-type additions of N-benzoylcyclopropanecarboxamides via iodide-mediated ring-opening: stereoselective synthesis of gamma-lactams

A new catalytic aldol-type addition of cyclopropanecarboximides to aldehydes via iodide-mediated ring-opening is presented. The reaction was found to be catalyzed at 0 degrees C using either a Sc(OTf)3/NaI system or ScI3. Stereoselective formation of alpha,alpha-disubstituted enolates occurred in situ. gamma-Lactams bearing alpha-carbonyl quaternary stereocenters were obtained in 97-57% yield and dr = 90:10-80:20 after ring closure.     

Morphing Hydrogel Patterns by Thermo‐Reversible Fluorescence Switching

Stimuli responsive surfaces that show reversible fluorescence switching behavior in response to temperature changes were fabricated. Oligo(ethylene glycol) methacrylate thermoresponsive polymers with amine end‐groups were prepared by atom transfer radical polymerization (ATRP). The polymers were patterned on silicon surfaces by electron beam (e‐beam) lithography, followed by conjugation of self‐quenching fluorophores. Fluorophore conjugated hydrogel thin films were bright when the gels were swollen; upon temperature‐induced collapse of the gels, self‐quenching of the fluorophores led to significant attenuation of fluorescence. Importantly, the fluorescence was regained when the temperature was cooled. The fluorescence switching behavior of the hydrogels for up to ten cycles was investigated and the swelling‐collapse was verified by atomic force microscopy. Morphing surfaces that change shape several times upon increase in temperature were obtained by patterning multiple stimuli responsive polymers.

     

Azetidinic amino acids: stereocontrolled synthesis and pharmacological characterization as ligands for glutamate receptors and transporters

A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have been synthesized in a diastereo- and enantiomerically pure form from beta-amino alcohols through a straightforward five step sequence. The key step of this synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine ring upon an intramolecular Michael addition. This reaction was proven to be reversible and to lead to a thermodynamic distribution of two diastereoisomers that were easily separated and converted in two steps into azetidinic amino acids. Azetidines 35-44 were characterized in binding studies on native ionotropic Glu receptors and in functional assays at cloned metabotropic receptors mGluR1, 2 and 4, representing group I, II and III mGlu receptors, respectively. Furthermore, azetidine analogues 35, 36, and 40 were also characterized as potential ligands at the glutamate transporter subtypes EAAT1-3 in the FLIPR Membrane Potential (FMP) assay. The (2R)-azetidines 35, 37, 39, 41 and 43 were inactive in iGlu, mGlu and EAAT assays, whereas a marked change in the pharmacological profile at the iGlu receptors was observed when a methyl group was introduced in the C-4 position, compound 36 versus t-CAA. At EAAT1-3, compound 35 was inactive, whereas azetidines 36 and 40 were both identified as inhibitors and showed selectivity for the EAAT2 subtype.     

Simultaneous determination of cefoxitin,cefuroxime, cephalexin and cephaloridine in plasma using HPLC and a column-switching technique

Summary A new high performance liquid chromatographic method was developed using a column-switching technique for the simultaneous determination of cephalexin, cefuroxime, cefoxitin and cephaloridine in plasma. The plasma samples were injected onto a precolumn packed with Corasil RP C₁₈ (37–50 m) after simple dilution with an internal standard solution in 0.01 M acetate buffer (pH 3.5). Polar plasma components were washed out using 0.01 M acetate buffer (pH 3.5). After valve switching, the concentrated drugs were desorbed in back-flush mode and separated on a Partisil ODS-3 column using acetonitrile in 0.02 M acetate buffer (pH 4.3) (1585, v/v) as the mobile phase. The method showed excellent precision with good sensitivity and speed with a detection limit of 0.5 g/ml. The total analysis time per sample was less than 25 min, and the mean coefficients of variation for intra- and inter-assay were both less than 4.9 %.This method has been successfully applied to plasma from rats after subcutaneous injection of cefuroxime.     

An optimized RGD-decorated micellar drug delivery system for albendazole for the treatment of ovarian cancer: from RAFT polymer synthesis to cellular uptake

Block copolymers were prepared via RAFT polymerization with P(PEGMEMA) as the hydrophilic block to form micelles for the controlled delivery of ABZ. The group contribution method was used to estimate the partial solubility parameters for ABZ and various polymers as potential core‐forming block to achieve optimum compatibility. Different ratios between MMA and LMA, a non‐compatible monomer, were prepared. Cytotoxicity tests revealed a high toxicity of the ABZ‐loaded micelle resulting in 80% cell deaths at a micelle concentration of 10 µg · mL^?1. Cellular uptake of micelles has been studied using fluorescently labeled micelles, showing that a large fraction of micelles is readily taken up by OVCAR‐3 cells. RGD‐conjugated micelles were prepared and showed an increased cellular uptake.

     

Synthesis and structural characterization of homochiral homo-oligomers of parent cis- and trans-furanoid-β-amino acids

The synthesis of homochiral homo-oligomers of cis- and trans-3-aminotetrahydrofuran-2-carboxylic acids (parent cis- and trans-furanoid-β-amino acids, referred to as "cis-/trans-FAA") has been carried out to understand their secondary structures and their dependence on the ring heteroatom. The oligomers of two diastereomers have been shown to have a distinct left-handed helicity. The cis-FAA homo-oligomers show a 14-helix structure, in contrast to the homo-oligomers of cis-ACPC, which adopt a sheet like structure. The trans-FAA homo-oligomers were found to adopt a 12-helix structure, the same trend found in trans-ACPC homo-oligomers. With the help of ab initio calculations, the structural features of cis-ACPC and cis-FAA hexamers were compared. We believe that the more compact packing of the cis-FAA hexapeptide should be due to a more favorable interaction between the ring and the backbone amide hydrogen.     

New homochiral ketoalcohols from aldol reactions of (+)-isomenthone and reversal of diastereoselectivity

Aldol reaction of (+)-isomenthone lithium enolate with aryl and alkyl aldehydes proceeds with complete diastereocontrol at the -carbon (C6), but the stereochemical outcome at the secondary alcohol stereocentre (established by X-ray crystal structure determinations) can be unexpectedly reversed by changing reaction quenching temperature. This provides a route to a range of new homochiral ketoalcohols.     

Researches on furan compounds

This paper gives the results obtained by liquid phase catalytic hydrogenation under pressure, over ruthenium catalysts, of furan aldehydes, ketones, and carboxylic acids. It is shown that the ruthenium catalysts are highly effective for hydrogenating the furan ring, ethylenic double bonds, and the carbonyl group, though they are not selective with respect to them. At room temperature the furan ring is mostly reduced to a tetrahydrofuran one. It is confirmed that compounds containing the 1, 6-dioxaspiro [4, 4]-nonane grouping are formed by hydrogenating furfurylidene aldehydes and ketones, and -furylalkanols.For Part XXX see [15].     

Determination of heats of decomposition of some 1,3,5,7-tetraazacyclooctane and 1,3,5-triazacyclohexane derivatives using differential scanning calorimetry

Differential scanning calorimetry was used to determine the heats of decomposition of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane(HMX), 1,5-diacetyl-3,7-dinitro-1,3, 5,7-tetraazacyclooctane(DADN), 1,5-endomethylene-3,7-dinitro-1,3,5,7-tetraazacyclooctane(DPT), 1,3,5-trinitro-1,3,5-triazacyclohexane(RDX), 1,3,5-trinitroso-1,3,5-triazacyclohexane (R-salt), and 1,5-endomethylene-3,7-dinitroso-1,3,5,7-tetraazacyclooctane(DNPT). The value of the decomposition heat of unit mass of sample was found to increase inHMX, DADN andRDX with decreasing degree of filling of the reaction volume. In the R-salt and inDNPT, however, the trend of this dependence was found to be the reverse and more pronounced. No analogous dependence was found to exist forDPT under the given experimental conditions.

---

Zusammenfassung Die Bestimmung der Zersetzungswärmen von 1,3,5,7-Tetranitro-1,3,5,7-tetraazacyclooktan(HMX), 1,5-Diacetyl-3,7-dinitro-1,3,5,7-tetraazacyclooktan(DADN), 1,5-Endomethylen-3,7-dinitro-1,3,5,7-tetraazacyclooktan (DPT), 1,3,5-Trinitro-1,3,5-triazacyclohexan(RDX), 1,3,5-Trinitroso-1,3,5-triazacyclohexan (R-salz) und 1,5-Endomethylen-3,7-dinitroso-1,3,5,7-tetraazacyclooktan(DNPT) wurde mittels Differential-Abtastkalorimetrie durchgeführt. Es wurde festgestellt, daß der Wert der Zersetzungswärme der Masseneinheit der Probe beiHMX, DADN undRDX mit abnehmendem Füllungsgrad des Reaktionsvolumens zunimmt. Bei R-salz undDNPT war hingegen die Richtung der Abhängigkeit umgekehrt und stärker. Keine analoge Abhängigkeit wurde fürDPT unter den Bedingungen des obigen Versuchs gefunden.

---

Résumé On a déterminé par analyse calorimétrique différentielle les chaleurs de décomposition des composés suivants: 1,3,5,7-tétranitro-1,3,5,7-tétraazacyclooctane (HMX), 1,5-diacé tyle-3,7-dinitro-1,3,5,7-tétraazacyclooctane(DADN), 1,5-endométhylène-3,7-dinitro-1,3,5,7-tétraazacyclooctane(DPT), 1,3,5-trinitro-1,3,5-triazacyclohexane(RDX), 1,3,5-trinitroso-1,3,5-triazacyclohexane (selR) et 1,5-endométhylène-3,7-dinitroso-1,3,5,7-tétraazacyclooctane(DNPT). La valeur de la chaleur de décomposition par masse unité d'échantillon augmente dans le cas deHMX, DADN etRDX, quand le degré de remplissement du volume réactionnel diminue. On a trouvé, cependant, avec le selR et leDNPT, une dépendance inverse et plus prononcée. Aucune dépendance similaire n'a été trouvée, dans les conditions expérimentales appliquées dans le cas duDPT.

---

-5- . . , , .

---

---

The authors express their gratitude to Mr. Milan Andoga for his precise DSC measurements.