Clathrate and inclusion compounds. Part 8 [1]. An investigation of the usefulness of the spectral substraction technique in analysing the infrared spectra of clathrates

An investigation has been carried out into the usefulness of the spectral subtraction technique in analyzing the infrared spectra of the clathrates of quinol and of Dianin's compound. Due to the flexibility of the quinol host lattice, it is not advisable to use guest-free -quinol as the reference if the host lattice in the clathrate is considerably distorted, as it is in the CH₃CN clathrate. In this case it is advisable to use another clathrate as the reference provided that the spectrum of the new reference does not contain guest bands in the region of interest. The Dianin's compound host lattice is less flexible than that of quinol, and guest-free Dianin's compound can be used as the reference irrespective of the size of the guest molecule. With both clathrates the spectral subtraction technique has revealed guest molecule bands which were previously obscured by host lattice bands.Dedicated to Professor H. M. Powell.     

New strategic reactions for organic synthesis: catalytic asymmetric C-H activation alpha to oxygen as a surrogate to the aldol reaction

The C-H activation of silyl ethers by means of rhodium carbenoid-induced C-H insertion represents a very direct method for the stereoselective synthesis of silyl-protected beta-hydroxy esters. The reaction can proceed with very high regio-, diastereo-, and enantioselectivity and represents a surrogate to the aldol reaction. The reaction is catalyzed by the rhodium prolinate complex Rh(2)(S-DOSP)(4). A critical requirement for the high chemoselectivity is the use of donor/acceptor-substituted carbenoids such as those derived from methyl aryldiazoacetates. A range of silyl ethers may be used such as allyl silyl ethers, tetraalkoxysilanes, and even simple trimethylsilyl alkyl ethers. In general, C-H activation preferentially occurs at methylene sites, as the reactivity is controlled by a delicate balance between steric and electronic effects.     

Factors Contributing to Solubility Synergism of Some Basic Drugs with β-Cyclodextrin in Ternary Molecular Complexes

Ternary complexes exploiting solubility synergism (SSn) between basic drugs and β-cyclodextrin (β-CD) in the presence of an organic hydoxy acid have been reported to provide the pharmaceutical technology with highly soluble ternary complexes, even with the least soluble β-CD. In this work, phase solubility techniques were used to study factors affecting SSn in aqueous solution, which may help in understanding the mechanism involved in ternary complex formation in solution, under equilibrium conditions. The equilibrium solubility of both β-CD and each of 8 structurally unrelated drugs were measured in tandem in the presence of different acid types at low and high pHs, and at different time intervals over a period of 1–40 days. The results indicate that SSn is evident regardless of acid type (organic and inorganic) at low pH, but the extent of SSn is acid type dependant and is limited by the drug salt solubility product constant (pK _sp). Among different drugs, no apparent trend exists between drug salt solubility and the extent of SSn, but lowering drug salt solubility by increasing pH depresses SSn. The results also reveal no apparent trend between the magnitude of the complex formation constant (K _ij) and SSn. For example, drugs of low K _ij values such as astemizole, cisapride and sildenafil do not show any SSn, yet ketotifen and pizotifen, which also have low K _ij values, exhibit substantial SSn. However, the solublizing power of β-CD represented by the slope of phase solubility diagram can be used as a marker for SSn (slopes exceeding 0.4 induce SSn).     

The synthesis and electronic structure of a novel [NiS4Fe2(CO)6] radical cluster: implications for the active site of the [NiFe] hydrogenases

A novel [NiS4Fe2(CO)6]cluster (1: 'S(4)'=(CH(3)C(6)H(3)S(2))(2)(CH(2))(3)) has been synthesised, structurally characterised and has been shown to undergo a chemically reversible reduction process at -1.31 V versus Fc(+)/Fc to generate the EPR-active monoanion 1(-). Multifrequency Q-, X- and S-band EPR spectra of (61)Ni-enriched 1(-) show a well-resolved quartet hyperfine splitting in the low-field region due to the interaction with a single (61)Ni (I=3/2) nucleus. Simulations of the EPR spectra require the introduction of a single angle of non-coincidence between g(1) and A(1), and g(3) and A(3) to reproduce all of the features in the S- and X-band spectra. This behaviour provides a rare example of the detection and measurement of non-coincidence effects from frozen-solution EPR spectra without the need for single-crystal measurements, and in which the S-band experiment is sensitive to the non-coincidence. An analysis of the EPR spectra of 1(-) reveals a 24 % Ni contribution to the SOMO in 1(-), supporting a delocalisation of the spin-density across the NiFe(2) cluster. This observation is supported by IR spectroscopic results which show that the CO stretching frequencies, nu(CO), shift to lower frequency by about 70 cm(-1) when 1 is reduced to 1(-). Density functional calculations provide a framework for the interpretation of the spectroscopic properties of 1(-) and suggest that the SOMO is delocalised over the whole cluster, but with little S-centre participation. This electronic structure contrasts with that of the Ni-A, -B, -C and -L forms of [NiFe] hydrogenase in which there is considerable S participation in the SOMO.     

Anomalous NMR behavior of meso compounds with remote stereogenic centers on addition of chiral shift reagent or chiral solvating agent

A problem has arisen in using chiral shift reagents (CSR) and chiral solvating agents (CSA) to determine meso and racemic forms of diastereoisomers in which the stereogenic centers of the molecules are separated by achiral spacers. It is found that NMR signals of both meso and racemic forms of diastereoisomers may exhibit doubling on addition of CSR/CSA, which means that unequivocal assignments cannot be made without characterizing the effects for separate meso and racemic forms; this is particularly important for additions of CSR/CSA at relatively low concentrations, which always result in the splitting of some NMR signals of diastereoisomers. The phenomenon is demonstrated in the (31)P NMR spectra of meso and racemic forms of three spermine-bridged gem-disubstituted cyclotriphosphazatrienes, 1a-c, and compared with analogous achiral molecules, the per-substituted spermine-bridged cyclotriphosphazatrienes 2a-d. As expected, only one set of (31)P NMR signals was observed for the achiral compounds 2a-d, even on addition of CSA. Two sets of (31)P NMR ABX multiplets corresponding to meso and racemic diastereoisomers were observed for compounds 1a-c; on addition of CSA, the signals of at least one of the multiplets for each compound separated into more than the expected groups of three lines with an intensity distribution of 2:1:1. To understand this phenomenon, the meso and racemic forms of 1a and 1b and the meso form of 1c have been separated and characterized by X-ray crystallography. On addition of CSA to the racemic forms of 1a and 1b, the (31)P NMR spectrum shows the expected doubling of signals, but, unexpectedly, the same is observed for each of the meso forms of 1a-c. Analogous results using both CSA and CSR have been obtained for the meso and racemic forms of the diastereoisomeric piperazine-bridged macrocyclic-phosphazene compound, 3, whereas no effect was observed for the two meso forms of the doubly bridged macrocyclic-phosphazene compound 4. The phenomenon of doubling of the (31)P NMR signals of the meso form of singly bridged cyclotriphosphazatrienes, 1a-c and 3, is explained by consideration of the equilibrium in solution of independent complexation of a chiral ligand with molecules that have two chiral cyclophosphazene moieties separated by an achiral spacer group. The results show that the stereogenicity of such diastereoisomeric molecules in solution cannot be characterized unequivocally by NMR measurements on addition of either CSR or CSA.     

Further development of a cosmic veto gamma-spectrometer

The Comprehensive Nuclear-Test-Ban Treaty (CTBT) is supported by a network of certified laboratories that perform high-resolution gamma-spectrometry on global air filter samples for the identification of 85 radionuclides. At the UK CTBT Radionuclide Laboratory (GBL15), a novel cosmic veto gamma-spectrometer has been developed to improve the sensitivity of measurements for treaty compliance. The system consists of plastic scintillation plates operated in time-stamp mode to detect coincident cosmic-ray interactions within an HPGe gamma-spectrometer. This provides a mean background reduction of 75.2 % with MDA improvements of 45.6 %. The CTBT requirement for a ¹⁴⁰Ba MDA is achievable after 1.5 days counting compared to 5–7 days using conventional systems. The system does not require dedicated coincidence electronics, and remains easily configurable with dual acquisition of unsuppressed and suppressed spectra. Performance has been significantly improved by complete processing of the cosmic-ray spectrum (0–25 MeV) combined with the Canberra Lynx? multi-channel analyser. The improved sensitivity has been demonstrated for a CTBT air filter sample collected after the Fukushima incident.     

Asymmetric synthesis of β-fluoroaryl-β-amino acids

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to a range of β-fluoroaryl-α,β-unsaturated esters gave the corresponding β-amino esters with high diastereoselectivity and in good isolated yields. Sequential treatment of the resultant β-fluoroaryl-β-amino esters under optimised hydrogenolysis conditions, followed by ester hydrolysis with 2.0 M aq HCl, provided access to a range of β-fluoroaryl-β-amino acids in good yield.     

Chiral analytical method development of liquiritigenin with application to a pharmacokinetic study

Pharmacometric characterization studies of liquiritigenin have historically overlooked its chiral nature. To achieve complete characterization, an analytical method enabling the detection and quantification of the individual enantiomers of racemic (±) liquiritigenin is necessary. Resolution of the enantiomers of liquiritigenin was achieved using a simple high‐performance liquid chromatographic method. A Chiralpak® ADRH column was employed to perform baseline separation with UV detection at 210 nm.The standard curves were linear ranging from 0.5 to 100 µg/mL for each enantiomer. Limit of quantification was 0.5 µg/mL. The assay was applied successfully to stereoselective serum disposition of liquiritigenin enantiomers in rats. Liquiritigenin enantiomers were detected in serum as both aglycones and glucuronidated conjugates. Both unconjugated enantiomers had a serum half‐life of ~15 min in rats. The volume of distribution (V_d) for S‐ and R‐liquiritigenin was 1.49 and 2.21 L/kg, respectively. Total clearance (Cl_total) was 5.12 L/h/kg for S‐liquiritigenin and 4.79 L/h/kg for R‐liquiritigenin, and area under the curve (AUC_0‐inf) was 3.95 µg h/mL for S‐liquiritigenin and 4.23 µg h/mL for R‐liquiritigenin. The large volume of distribution coupled with the short serum half‐life suggests extensive distribution of liquiritigenin into tissues. Copyright © 2012 John Wiley & Sons, Ltd.     

Chiral analytical method development and application to pre‐clinical pharmacokinetics of pinocembrin

An analytical method enabling the detection and quantification of the individual enantiomers of racemic (±) pinocembrin is required to fully characterize its pharmacokinetic disposition. Direct resolution of the enantiomers of pinocembrin was achieved using a novel and simple reversed‐phase high‐performance liquid chromatography method with electrospray ionization and detection by mass spectrometry in rat serum. A Chiralcel® AD‐RH column was employed to perform baseline separation with electrospray positive‐mode ionization with selected ion monitoring detection. The standard curves were linear from 0.5 to 100 µg/mL for each enantiomer. The limit of quantification was 0.5 µg/mL. The assay was applied successfully to stereoselective serum disposition of pinocembrin enantiomers in rats. Pinocembrin enantiomers were detected in serum. Both enantiomers had a serum half‐life of ~15 min in rats. Similar values of volume of distribution between the enantiomers were also observed: 1.76 L/kg for S‐pinocembrin and 1.79 L/kg for R‐pinocembrin. Total clearance was 5.527 L//h/kg for S‐pinocembrin and 5.535 L/h/kg for R‐pinocembrin, and the area under the curve was 1.821 µg h/mL for S‐pinocembrin and 1.876 µg h/mL for R‐pinocembrin. The large volume of distribution coupled with the short serum half‐life suggests extensive distribution of pinocembrin into the tissues. Copyright © 2012 John Wiley & Sons, Ltd.