Nuclear Overhauser Difference Research Articles

Organic-inorganic supramolecular solid catalyst boosts organic reactions in water.

Coordination polymers and metal-organic frameworks are appealing as synthetic hosts for mediating chemical reactions. Here we report the preparation of a mesoscopic metal-organic structure based on single-layer assembly of aluminium chains and organic alkylaryl spacers. The material markedly accelerates condensation reactions in water in the absence of acid or base catalyst, as well as organocatalytic Michael-type reactions that also show superior enantioselectivity when comparing with the host-free transformation. The mesoscopic phase of the solid allows for easy diffusion of products and the catalytic solid is recycled and reused. Saturation transfer difference and two-dimensional 1H nuclear Overhauser effect NOESY NMR spectroscopy show that non-covalent interactions are operative in these host–guest systems that account for substrate activation. The mesoscopic character of the host, its hydrophobicity and chemical stability in water, launch this material as a highly attractive supramolecular catalyst to facilitate (asymmetric) transformations under more environmentally friendly conditions.

Stabilization of a Supersaturated Solution of Mefenamic Acid from a Solid Dispersion with EUDRAGIT® EPO

The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT(®) EPO (EPO) was investigated. The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions. Dissolution tests in acetate buffer (pH 5.5) revealed that solid dispersion showed > 200-fold higher concentration of MFA. Supersaturated solution was stable over 1month and exhibited improved oral bioavailability of MFA in rats, with a 7.8-fold higher area under the plasma concentration-versus-time curve. Solid-state (1)H spin-lattice relaxation time (T(1)) measurement showed that MFA was almost monomolecularly dispersed in the EPO polymer matrix. Intermolecular interaction between MFA and EPO was indicated by solid-state infrared and (13)C-T(1) measurements. Solution-state (1)H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. (1)H-T(1) and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them. The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.

Observation of intermolecular interactions in large protein complexes by 2D-double difference nuclear Overhauser enhancement spectroscopy: application to the 44 kDa interferon-receptor complex.

NMR detection of intermolecular interactions between protons in large protein complexes is very challenging because it is difficult to distinguish between weak NOEs from intermolecular interactions and the much larger number of strong intramolecular NOEs. This challenging task is exacerbated by the decrease in signal-to-noise ratio in the often used isotope-edited and isotope-filtered experiments as a result of enhanced T(2) relaxation. Here, we calculate a double difference spectrum that shows exclusively intermolecular NOEs and manifests the good signal-to-noise ratio in 2D homonuclear NOESY spectra even for large proteins. The method is straightforward and results in a complete picture of all intermolecular interactions involving non exchangeable protons. Ninety-seven such (1)H-(1)H NOEs were assigned for the 44 KDa interferon-α2/IFNAR2 complex and used for docking these two proteins. The symmetry of the difference spectrum, its superb resolution, and unprecedented signal-to-noise ratio in this large protein/receptor complex suggest that this method is generally applicable to study large biopolymeric complexes.

Tigloylshikonin, a New Minor Shikonin Derivative, from the Roots and the Commercial Root Extract of Lithospermum erythrorhizon

Tigloylshikonin, a new shikonin derivative esterified with tiglic acid ((E)-2-methylbut-2-enoic acid), was isolated as a minor pigment from a food colorant "Shikon color," a commercial root extract from Lithospermum erythrorhizon SIEBOLD et ZUCCARINI. The structure of tigloylshikonin was elucidated using (1)H, (13)C, the difference nuclear Overhauser effect (NOE), and 2D NMR techniques. Its stereochemistry was determined by chiral-phase HPLC analysis. Tigloylshikonin was also found in the roots of L. erythrorhizon, which indicated that this new shikonin derivative is a typical component of naphthoquinone pigments in the roots of L. erythrorhizon.

Substituted 1,3,5-Triazaadamantanes: Biocompatible and Degradable Building Blocks

Substituted 1,3,5-Triazaadamantanes: Biocompatible and Degradable Building Blocks

Aplicação de análise de componentes principais para verificação de atribuições de sinais nos espetros de RMN ¹H: o caso dos 3-aril (1,2,4)-oxadiazol-5-carboidrazida benzilidenos

The 1H NMR data set of a series of 3-aryl (1,2,4)-oxadiazol-5-carbohydrazide benzylidene derivatives synthesized in our group was analyzed using the chemometric technique of principal component analysis (PCA). Using the original 1H NMR data PCA allowed identifying some misassignments of the proton aromatic chemical shifts. As a consequence of this multivariate analysis, nuclear Overhauser difference experiments were performed to investigate the ambiguity of other assignments of the ortho and meta aromatic hydrogens for the compound with the bromine substituent. The effect of the 1,2,4-oxadiazol group as an electron acceptor, mainly for the hydrogens 12,13, has been highlighted.

Synthesis of delta(E)Phe-containing tripeptide via photoisomerization and its conformation in solution.

A new synthetic route to (E)-beta-phenyl-alpha,beta-dehydroalanine (delta(E)Phe)-containing peptide was presented via photochemical isomerization of the corresponding (Z)-beta-phenyl-alpha,beta-dehydroalanine (delta(Z)Phe)-containing peptide. By applying this method to Boc-Ala-delta(Z)Phe-Val-OMe (Z-I: Boc, t-butoxycarbonyl; OMe, methoxy), Boc-Ala-delta(E)Phe-Val-OMe (E-I) was obtained. The identification of peptide E-I was evidenced by 1H-nmr, 13C-nmr, and uv absorption spectroscopy, elemental analysis, and hydrogenation. The conformation of peptide E-I in CDCl3 was investigated by 1H-nmr spectroscopy (solvent dependence of NH chemical shift and difference nuclear Overhauser effect). Interestingly, peptide E-I differed from peptide Z-I in the hydrogen-bonding mode. Namely, for peptide Z-I, only Val NH participates in intramolecular hydrogen bonding, which leads to a type II beta-turn conformation supported by hydrogen bonding between CO(Boc) and NH(Val). On the other hand, for peptide E-I, two NHs, delta(E)Phe NH and Val NH, participate in intramolecular hydrogen bonding. In both peptides, a remarkable NOE (approximately 11-13%) was observed for Ala C(alpha) H-deltaPhe NH pair. Based on the nmr data and conformational energy calculation, it should be concluded that peptide E-I takes two consecutive gamma-turn conformations supported by hydrogen bonding between CO(Boc) and NH(delta(E)Phe), and between CO(Ala) and NH(Val) as its plausible conformation.

Solvent Dependence on the Preference of Helical Screw Sense: Effect of l-Leu Residue Second from N-Terminal on Screw Sense in Achiral Peptide

To clarify which helical screw sense is preferred when one l-residue is introduced into the second position from N-terminal of an achiral helical segment, we prepared Boc-Aib-l-Leu-(Aib-ΔZPhe)2-Aib-OMe (1: Boc = t-butoxycarbonyl; Aib = α-aminoisobutyric acid; ΔZPhe = Z-dehydrophenylalanine; OMe = methoxy). Here the segment -(Aib-ΔZPhe)2-Aib-OMe was used as an achiral backbone composed of two “enantiomeric” (left-/right-handed) helices. Peptide 1 was found to form a 310-type helical conformation in chloroform, from FT IR (the position of amide I band) and 1H NMR (difference nuclear Overhauser effect and solvent accessibility of NH resonances) measurements. Interestingly, CD patterns of peptide 1 changed with types of solvents: i.e., exciton couplets around 280 nm with a negative peak at longer wavelengths in chloroform and with a positive peak at longer wavelengths in methanol or in tetrahydrofuran. Consequently, the helical segment prefers a right-handed screw sense in chloroform and a left-handed one i...

Solution NMR Conformational Analysis of the Potent Equilibrative Sensitive (ES) Nucleoside Transporter Inhibitor, S 6-(4-Nitrobenzyl)mercaptopurine Riboside (NBMPR)

High resolution NMR analysis involving one-dimensional (1-D) 1H and nuclear Overhauser (NOE) difference spectroscopy was applied to solutions of NBMPR in DMSO-d 6. Coupling constants were obtained at different temperatures between 285 and 353 K, and used to analyze the rotamer preferences about the C-4′-C-5′ bond. The results revealed a rotamer distribution about the χ tortion angle that favors the high-anti range, a preponderance of the γ+ rotamer (at ∼64 %) with respect to the γ torsion angle, and a higher population of the south (S) conformer, which was favored by as little as the 4 % to as much as 31 % over the north (N) conformer as calculated by the program PSEUROT 6.2. The high-anti glycosidic torsion orientation appears to be the major conformational difference between the solution structure of NBMPR determined in this study and the structure previously observed in the solid state.

Synthesis, Structure, and Conformational Analysis of Novel Co- and P-Chiral Cobalt Amidophosphonate Complexes

Reaction of (SC)-(η5-Cp)CoI2(PPh2NHC*H(Me)Ph) with 1 equiv of dimethyl (diethylamino)phosphonite in benzene at ambient temperature affords diastereomeric, P-chiral methyl (diethylamido)phosphonate Arbuzov products (η5-Cp)CoI(PPh2NHC*H(Me)Ph)(P(O)(NEt2)(OMe)) (3) with 88% diastereomeric excess for Co→P chiral induction, as well as the phosphorus−nitrogen bond cleavage products (η5-Cp)CoI(PPh2NHCH(Me)Ph)(P(O)(OMe)2) (4). RCoSPSC diastereomer 3-2 was characterized by single crystal X-ray diffraction. The absolute configuration of all four possible diastereomers was assigned on the basis of crystallographic results and circular dichroism spectra. The molecular structure of 3-2 shows PO···HN intramolecular hydrogen bonding which establishes a “chaise longue” conformation with pseudoequatorial η5-Cp and pseudoaxial iodide. Proton nuclear Overhauser difference (NOED) spectra are consistent with retention of the solid-state conformation in solution. A model based on 1,3-diaxial steric interactions in the transition state leading to dealkylation is proposed to account for the observed Co→P chiral induction. Evidence supporting a hydrolysis mechanism for the formation of 4 is presented.

Alpha 1-adrenoceptor reagents. Synthesis of some 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido and 5,6,11,11b-tetrahydro-1H-imidazo[1',5':1,2]pyrido[3,4-b]indole-1,3(2H) -diones.

Several 2-substituted 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido (1) and 5,6,11,11b-tetrahydro-1H-imidazo [1',5':1,2]pyrido[3,4-b]indole,3(2H)-diones (2) were synthesized and studied by 2D-NMR spectroscopy and difference nuclear Overhauser effect experiments. All the compounds were evaluated for in vitro alpha(1) adrenoceptor affinity by radioligand receptor binding assays. The most active derivative in displacement of [3H]prazosin from rat cortical membranes was 1b (K(i) = 219 nM). At 1 microM concentration, compounds 1 and 2 had no effect on the benzodiazepine or 5-HT(1A) receptor. The biological activity profile of 1b makes it a possible lead compound for the design of new selective alpha1 adrenoceptor ligands.

Effect of nucleoside modifications on the structure and thermal stability of Escherichia coli valinetRNA

Transfer RNA transcribed in vitro lacks the base modifications found in native tRNA. To understand the effect of base modifications on the structure of tRNA, the downfield region of the 1H NMR spectrum of in vitro transcribed E coli tRNA Val in aqueous phosphate buffer in the presence of excess Mg 2+ was investigated. The resonances of all imino protons involved in hydrogen bonds in the helical stem regions and in tertiary interactions were assigned using two-dimensional nuclear Overhauser enhancement spectroscopy (NOESY) and one-dimensional difference nuclear Overhauser effect (NOE) methods. In addition, some aromatic C2 and C8 proton resonances as well as one amino proton resonance were assigned. The chemical shifts of the assigned resonances of unmodified E coli tRNA Val were compared with those of the native tRNA molecule under similar solution conditions. The similarity of the NMR data for unmodified and modified tRNA indicates that the in vitro transcribed tRNA has nearly the same solution structure as the native molecule in the presence of excess Mg 2+. The only significant differences were the chemical shifts of resonances corresponding to protons in (or interacting with) bases, indicating the possibility of local structural perturbations. The thermal stability of E coli modified and unmodified tRNA Val in the presence of Mg 2+ was also investigated by analyzing the temperature dependence of the imino proton spectra. Several tertiary interactions involving modified nucleosides in native E coli tRNA Val are less stable in the absence of base modifications.

NMR Studies of Cyclodextrin Inclusion Complex with Ethyl Hexanoate in Ethanol Solution

The formation of a βCD inclusion complex for aliphatic ethyl ester, with ethyl hexanoate as a guest molecule was investigated. Proton T1 measurements by the IR method and 1D difference nuclear Overhauser enhancement experiments showed that ethyl hexanoate exists with the groups (H-2 and H-3) around the ester bond nearer to the narrower βCD cavity and the other protons are proximal to the H(CD)-3 and H(CD)-5 protons within the cavity with a folded structure. The complexation of βCD was greatly affected by the addition of ethanol. With increasing ethanol concentration, a marked increase in volatility of ethyl hexanoate from the βCD solution was observed; the volatility in 30% ethanol was about 3 times larger than in 0% one. On the basis of the observed NOE and T1 values, the lowering of the abilitys of βCD complexation in ethanol solution is assumed to be caused by the situation shift of guest molecule toward the narrower side or outside of the cavity.

NMR spectral assignment of lactone pheromone components emitted by Caribbean and Mexican fruit flies

By utilizing one- and two-dimensional nuclear magnetic resonance techniques, the complete assignments of the proton and carbon spectra of the lactones anastrephin, epianastrephin, and suspensolide have been accomplished. These compounds are pheromone components for both the Caribbean and Mexican fruit flies. The relative stereochemistries of anastrephin and epianastrephin were demonstrated by nuclear Overhauser difference spectroscopy. With complete spectral assignments now available, biosynthesis of these molecules may be studied by feeding specific isotopically labeled nutrients to flies and subsequently analyzing the volatiles produced for the presence and position of the labelling isotope.

New Eudesmanolide Sesquiterpenes from a Philippines Collection of Wedelia prostata

Two known, but previously uncharacterized, ent-kaurenic acid derivatives, 1 and 2, and four new sesquiterpenes of the eudesmanolide type, 3-6, have been isolated from Wedelia prostata. The structures were eludidated by a range of 1D and 2D high field nmr techniques, and the stereochemistry of the new eudesmanolides was defined from a combination of coupling constant analyses and nuclear Overhauser difference spectra

Revised Structures of Flavidulols, Constituents of Lactarius flavidulus IMAI, and the Structure of Flavidulol D.

The structure 1a proposed for flavidulol A, which was isolated from the mushroom Lactarius flavidulus IMAI, was revised to 1b based upon comparison with a synthetic specimen, as well as a difference nuclear Overhauser effect (NOE) experiment. As a consequence, the structures of flavidulols B (2a) and C (3a) were also revised to 2b and 3b, respectively. Flavidulol D (4) was newly isolated from the same mushroom, and its structure was elucidated as flavidulol A stearate on the basis of spectroscopic data.

Syntheses and Absolute Configurations of Optically Pure 4-Isopropyl-N-tosyl-1,3-oxazolidines

(2S,4S)-4-Isopropyl-N-tosyl-1,3-oxazolidines (3a-e) having methyl, cyclohexyl, phenyl, o-bromophenyl, or o-formylphenyl group at the 2-position of the ring were synthesized, and these products were confirmed to consist of one isomer by 1 H-nmr spectral analyses in spite of a newly created asymmetric center at the 2-position. The absolute configurations of 3a-e were determined by difference nuclear Overhauser effect studies

Nuclear magnetic resonance studies of cyclodextrin complexes of linoleic acid and arachidonic acid

Structures of a- and /3-cyclodextrin complexes of linoleic and arachidonic acids were investigated by detailed 1H spin-lattice relaxation time (7'1) measurements and one-dimensional difference nuclear Overhauser enhancement (NOE) studies. On the basis of the observed NOE proximities and 2'1 values, it is concluded that the carboxyl arms of both linoleic and arachidonic acids are present within the cyclodextrin cavity with double bonds partly exposed or buried. While the double bond at 9-10 in linoleic acid is buried, the one at 12-13 is exposed, the molecule from position 11 being present in an inclined position, with the methyl end pointing away from the cavity laterally. The double bond in arachidonic acid at position 5-6 is buried; the other at 8-9 lies exposed. While the carboxyl arm is present within the cavity, the methyl arm lies parallel to the carboxyl arm outside the cavity.

Antinociceptive (aminoalkyl)indoles

The (aminoalkyl)indole (AAI) derivative pravadoline (1a) inhibited prostaglandin (PG) synthesis in mouse brain microsomes in vitro and ex vivo and exhibited antinociceptive activity in several rodent assays. In vitro structure-activity relationship studies of this new class of PG synthesis inhibitors revealed a correspondence in three respects to those reported for the arylacetic acids: (1) "alpha-methylation" caused an increase in PG inhibitory potency, (2) the (R)-alpha-methyl isomer was more active than the S isomer, (3) the hypothesized aroyl group conformation of the 2-methyl derivatives corresponded to the proposed and reported "active" conformations of the aroyl and related aromatic acetic acid derivatives. The 1H NMR chemical shift of the C-4 hydrogen of pravadoline in comparison to the deshielding seen with 50, which lacks a substituent at C-2, suggested that the carbonyl group of pravadoline is located near C-2 but is located near C-4 in 50. Associated with this conformational change of the carbonyl group of 1a is a diminution of PG synthetase inhibitory activity. The results of UV and difference nuclear Overhauser studies of the two compounds were consistent with these conformational assignments. The low eudismic ratios of the alpha-methyl derivatives and the observation that the side chain may be extended by three methylene groups without significant loss of PG inhibitory potency suggests that this class of inhibitors bound less strongly and less selectively to the active site of PG synthetase than do the arylacetic acids. Two AAIs, 1a and 30, were found to be metabolized to the corresponding acetic acid derivatives, both of which inhibited PG synthesis. An exception to the observation that the antinociceptive activity of the AAIs was associated with PG synthetase inhibitory activity was the 1-naphthoyl derivative 67 since neither it nor its acetic acid metabolite 74 inhibited PG synthesis. Yet 67 was antinociceptive in four different rodent assays. This naphthoyl derivative, like opioids, also inhibited electrically stimulated contractions in the mouse vas deferens (MVD) preparation. Unlike opioids, however, the inhibition was not antagonized by naloxone. A subseries of AAIs was identified, of which 67 was prototypic. These compounds lacked PG synthetase inhibitory activity, but their inhibitory potency in MVD preparations correlated roughly with their antinociceptive potency in vivo. Pravadoline was also inhibitory in the MVD. Its antinociceptive activity, therefore, may be a consequence of both its PG synthetase inhibitory potency and another antinociceptive mechanism, the latter associated with its inhibitory potency in the MVD.(ABSTRACT TRUNCATED AT 400 WORDS)

Reaction of pyridine derivatives with butyl glycidyl ether as a model system for glycidyl ether modified agarose: structural assignment by selective inept spectra

The reaction of 2-thio-pyridine N-oxide, 2-amino-, 2-hydroxy, 2-thio-, and 4-thiopyridine with butyl glycidyl ether was investigated as a model system for the functionalization of 2,3-epoxypropyl activated agarose. Unambiguous structural assignment of the products was provided by selective INEPT and nuclear Overhauser difference spectra. All reactions were shown to give only one of the possible regioisomers. Further conclusions regarding the structure of the agarose derivatives were drawn from IR spectra.