Unprecedented base effect on the synthesis of chiral phosphinate esters: A new route to P-chiral phosphine oxides of high enantiomeric purity

The stereochemical outcome of the reaction of chiral secondary alcohols with a phosphinyl chloride was found to be highly dependent on the achiral base used. Thus, the reaction of the readily available sugar derived carbinols, 1 and 2, with methylphenylphosphinyl chloride in the presence of triethylamine yields stereoselectively the corresponding Snp-phosphinates 3Sp and 5Sp in 94 and 92% diastereomeric excess (de). Simply changing the base from triethylamine to pyridine affords Rp-phosphinates 4Rp and 6Rp epimers to 3Sp and 5Sp at the phosphinyl phosphorus in 50 and 40% de respectively. These phosphinate esters were found to be good P-chiral transferring intermediates, they react with Grignard reagents under very mild conditions to give the corresponding phosphine oxides. Both enantiomers Sp- and Rp-o-anisylmethylphenylphosphine oxide (PAMPO) as well Sp- and Rp- methylphenylpropyl phosphine oxide were obained enantiomerically pure in high yields     

(18)O]-oxygen incorporation reveals novel pathways in spiroacetal biosynthesis by Bactrocera cacuminata and B. cucumis

The origins of the oxygen atoms in 1,7-dioxaspiro[5.5]undecane (1) and hydroxyspiroacetal (2) from Bactrocera cacuminata, and in 2,8-dimethyl-1,7-dioxaspiro[5.5]undecane (3) and hydroxyspiroacetal (4) from B. cucumis, have been investigated by incorporation studies from both [(18)O(2)]-dioxygen and [(18)O]-water. Combined GC-MS examination and high-field NMR analysis have demonstrated that all oxygen atoms in 1 and 2 from B. cacuminata are dioxygen derived, but in contrast, the spiroacetals 3 and 4 from B. cucumis incorporate one ring oxygen from water and one ring oxygen (and the hydroxyl oxygen in 4) from [(18)O(2)]-dioxygen. These results reveal not only the generality of monoxygenase mediation of spiroacetal formation in Bactrocera sp., but also an unexpected complexity in their biosynthesis. A general paradigm accommodating these and other observations is presented.     

Anatoxins and degradation products, determined using hybrid quadrupole time-of-flight and quadrupole ion-trap mass spectrometry: forensic investigations of cyanobacterial neurotoxin poisoning

The potent neurotoxins from cyanobacteria, anatoxin-a (AN), its methyl analogue, homoanatoxin-a (HMAN), and their degradation products, have been studied using nano-electrospray hybrid quadrupole time-of-flight mass spectrometry (QqTOF-MS). The anatoxin degradation products, which are readily produced in vivo by either reduction or epoxidation, were also examined in this study. The high mass accuracy QqTOF-MS data was used to confirm formula assignments for major product ions and quadrupole ion-trap (QIT)-MS was used to construct fragmentation pathways for anatoxins. Significant differences between these fragmentation pathways were observed. Comparisons between the spectra of compounds that differ in side-chain length (the AN and HMAN series) were used to identify ions that are characteristic of the homologues. The application to forensic samples in which the principal neurotoxin had undergone rapid biodegradation has been demonstrated and used to confirm anatoxin poisoning of dogs.     

Secondary and Tertiary Structure of Polysaccharides in Solutions and Gels

Many polysaccharide chains can adopt ordered helical and ribbon-like secondary structures. It seems however that these chains are often so stiff and extended that the cooperative interactions necessary for stability in the solvent environment can only be achieved when inter-chain as well as intra-chain interactions are favorable. Hence we commonly find two-or more-stranded associations of helices, of ribbons, or of helices with ribbons. These can be regarded as tertiary and higher levels of structure. The ordered secondary structure characteristically requires a regular repeating sequence of sugar residues, and the termination of this sequence by insertion of a residue of different type may also terminate the secondary structure and hence the association in which it is involved. This is the mechanism by which native polysaccharides may link up to form three dimensional networks, or gels, in which state they perform their natural roles in maintaining the hydration and integrity of biological tissues. For several polysaccharides there is evidence that the mechanism of biological control over the fine topology and properties of the gel network is mediated by enzymes which modify sugar residues at the polymer level to change the pattern of “interrupting” sugar residues.     

Multiple glass transitions and local composition effects on polymer solvent mixtures

Recent differential scanning calorimetry (DSC) results on polystyrene–solvent mixtures show two distinct glass transitions whose positions and widths vary with composition. Parallel work on the dynamic response in polymer blends has focused on how segmental mobilities are controlled by local composition variations within a “cooperative volume” containing the segment. Such variations arise from both chain connectivity and composition fluctuations. We account for both using a lattice model for polymer–solvent mixtures that yields the composition distribution around polymer and solvent segments. Insights from our lattice model lead us to simplified calculations of the mean and variance of local composition, both in good agreement with lattice results. Applying our model to compute DSC traces leads to an estimate of the cooperative volume, since a larger cooperative volume both reduces the biasing effect of connectivity, and narrows the composition distribution. Comparing our results to data, we are able to account for the composition-dependent broadening with a cooperative length scale of about 2.5 nm. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 3528–3545, 2006     

Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity

UV radiation suppresses the immune response, and UV-induced immune suppression contributes to UV-induced photocarcinogenesis. For UV-induced immune suppression to occur, electromagnetic energy (i.e. UV radiation) must be converted to a biological signal. Two photoreceptors have been identified in the skin that serves this purpose, epidermal DNA and trans-urocanic acid (UCA). Although compelling evidence exists to support a role for each pathway (UV-induced DNA damage or photoisomerization of UCA) in UV-induced immune suppression, it is not clear what determines which photoreceptor pathway is activated. To address this question, we injected UV-irradiated mice with a monoclonal antibody with specificity for cis-UCA or applied liposomes containing DNA repair enzymes to the skin of UV-irradiated mice. The effect that each had on UV-induced suppression of delayed-type hypersensitivity was measured. We asked whether the light source used (FS-40 sunlamps vs solar-simulated UV radiation) altered whichever pathway of immune suppression was activated. Different doses of UV radiation and the viability of the antigen were also considered. Neither the dose of UV nor the light source had any influence on determining which pathway was activated. Rather, we found that the viability of the antigen was the critical determinant. When live antigens were used, UV-induced immune suppression was blocked with monoclonal anti-cis-UCA but not with T4 endonuclease V-containing liposomes. The reverse was observed when formalin-fixed or killed antigens were used. Our findings indicate that antigen viability dictates which photoreceptor pathway predominates after UV exposure.     

A predictive model for unimolecular reactions: Reactions of unsaturated carbonium ions

The major slow unimolecular reactions undergone by C₄H₇⁺, C₅H₉⁺ and C₆H⁺₁₁ are discussed in terms of a potential surface approach and the organic chemist's concept of mechanism. It is shown that the observed decompositions which do not involve σ-bond formation in the dissociation step are precisely those expected from the model. Further use of the model correctly predicts the slow reactions of C₇H⁺₁₃ which have not previously been reported. The approach also permits useful limits to be set on the transition state energies for reactions involving σ-bond formation in the dissociation step (H₂,CH₄ loss). It is concluded that stepwise addition of ethylene to the allyl cation is preferred to a concerted 4-electron process which is symmetry forbidden.     

Field evaluations of the VDmax approach for substantiation of a 25 kGy sterilization dose and its application to other preselected doses

The International and European standards for radiation sterilization require evidence of the effectiveness of a minimum sterilization dose of 25 kGy but do not provide detailed guidance on how this evidence can be generated. An approach, designated VD_max, has recently been described and computer evaluated to provide safe and unambiguous substantiation of a 25 kGy sterilization dose. The approach has been further developed into a practical method, which has been subjected to field evaluations at three manufacturing facilities which produce different types of medical devices. The three facilities each used a different overall evaluation strategy: Facility A used VD_max for quarterly dose audits; Facility B compared VD_max and Method 1 in side-by-side parallel experiments; and Facility C, a new facility at start-up, used VD_max for initial substantiation of 25 kGy and subsequent quarterly dose audits. A common element at all three facilities was the use of 10 product units for irradiation in the verification dose experiment.

The field evaluations of the VD_max method were successful at all three facilities; they included many different types of medical devices/product families with a wide range of average bioburden and sample item portion values used in the verification dose experiments. Overall, around 500 verification dose experiments were performed and no failures were observed. In the side-by-side parallel experiments, the outcomes of the VD_max experiments were consistent with the outcomes observed with Method 1.

The VD_max approach has been extended to sterilization doses >25 and <25 kGy; verification doses have been derived for sterilization doses of 15, 20, 30, and 35 kGy. Widespread application of the VD_max method for doses other than 25 kGy must await controlled field evaluations and the development of appropriate specifications/standards.     

Screening for selected toxic elements in urine by sequential-scanning inductively-coupled plasma atomic emission spectrometry

A rapid screening method for nine elements (Se, As, Cr, Zn, Cd, Pb, Ni, Mn, and Cu) in human urine is described. A sequential-scanning inductively-coupled plasma atomic emission spectrometer, incorporating a cross-flow nebulizer, was used. Internal standardization with yttrium compensated for the differences between the aqueous calibration standards and the undiluted urine specimens. Accuracy was evaluated with aqueous (NBS SRM 1643a, EPA 378-13, and EPA 476-3) and urine (NBS SRM 2670 and Fisher Urichem Level II) reference and control materials. Detection limits for the system were evaluated from analyses of normal urine materials found to contain low levels of the elements investigated.     

pH dependence of tailing in reversed-phase chromatography of a cationic dye: measurement of the strong adsorption site surface density

A question that has interested Dr. J.J. Kirkland is addressed: what is the nature of the silanols that cause tailing to persist at low pH in reversed-phase chromatography? Chromatograms for a cationic dye, 1,1'-didodecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (DiI), were studied at varying pH using an Agilent SB-C8 column and 80% ACN/water for six DiI concentrations ranging from 0.9 to 316 microM. The chromatograms showed increased retention and tailing from pH 1 to 5, as expected. Simulations of the chromatograms agreed well with experiment for a bi-Langmuir isotherm with weak (C8) and strong (silica) adsorption sites. The simulation parameters revealed that the number of strong adsorption sites decreases by 40% from pH 1 to 5, which indicates that the silanols causing tailing are in the SiOH, not the SiO-, form. This seems paradoxical because tailing increases with increasing pH. The simulation parameters reveal that this increased tailing from pH 1 to 5 owes to doubling of the partition coefficient for DiI to the strong adsorption site, which more than compensates for the decreasing number of sites. We attribute this increased partition coefficient to increased long-range coulombic interactions with the increasingly abundant SiO- groups at higher pH, which boosts DiI's partition coefficient for both the C8 and SiOH sites. The picture thus emerges that for DiI, higher pH causes increased tailing because the SiO- groups exacerbate tailing that actually originates from adsorption to SiOH groups.