Reaction of pyridine N-oxides with Grignard reagents: a stereodefined synthesis of substituted dienal oximes

Rapid addition of Grignard reagents to pyridine N-oxides under mild conditions gave stereodefined dienal oximes in good to excellent yields. This reaction provides an efficient access to substituted olefins with defined stereochemistry that are potentially of interest as bioactives themselves or as versatile synthetic intermediates.     

3-(4-Hydroxymethylphenylsulfanyl)propanoic acid (HMPPA) as a new safety catch linker in solid phase peptide synthesis

A new safety catch linker, 3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA), is described for use in solid phase peptide synthesis. The linker is readily synthesized from commercially available chemicals in a more cost efficient way compared to similar reported linkers. The HMPPA linker is easily attached to an amino derivatized solid support followed by on-resin oxidation of the thioether to sulfoxide, thereby making the linker very stable towards strong acid treatment. Final resin cleavage is performed by reductive acidolysis.     

MM-PBSA free energy analysis of endo-1,4-xylanase II (XynII)-substrate complexes: binding of the reactive sugar in a skew boat and chair conformation

The binding of xylotetraose in different conformations to the active site of endo-1,4-beta-xylanase II (XynII) from Trichoderma reesei was studied using molecular dynamics (MD) simulations and free energy analyses employing the MM-PBSA (Molecular Mechanics-Poisson-Boltzmann Surface Area) method. MD simulations of 1 ns were done for the substrate xylotetraose having the reactive sugar, which is bound in the -1 subsite of XynII in the 4C1 (chair) and 2So (skew boat) ground state conformations, and for the transition state of the XynII catalysed hydrolysis of the beta-glycosidic linkage. According to the simulations and free energy analysis, XynII binds the substrate with the -1 sugar in the 2So conformation 59.8 kJ mol(-1) tighter than the substrate with the sugar in the 4C1 conformation. The reactive 2So conformation resembles closely the reaction transition state and has the breaking glycosidic bond in a pseudo-axial orientation ready for facile bond cleavage. The transition state was calculated to be bound 77.1 kJ mol(-1) tighter than the 4C1 ground state conformation. The molecular mechanical interaction energy between the enzyme and the reactive pyranoside unit at the -1 subsite was 75.7 kJ mol(-1) more favorable for the binding of the 2So conformation than the 2C1 conformation, explaining the clearly tighter binding of the reactive structure The results of this study indicate that in the Michaelis complex XynII, a member of the family 11 xylanase, the substrate is bound in a skew boat conformation and in the catalytic reaction, the -1 sugar proceeds from the 4C1 conformation through 2So to the transition state with the -1 sugar in the 2,5B conformation.     

Synthesis of pentacyclic 13-azadibenzo[a,de]anthracenes via anionic cascade ring closure

Bromine-lithium exchange using tert-butyllithium at -78 degrees C initiates a cascade process whereby either xanthone derivatives or pentacyclic 13-azadibenzo[a,de]anthracenes are produced in high yields. The reaction proceeds via a sequential intramolecular trapping of organolithium intermediates.     

(C6H14N2)2[VO(HPO4)5B2O]·H2O·H3PO4, a novel borophosphate cluster containing a single vanadium centre and linked by hydrogen bonds into a three‐dimensional framework

The title novel vanadium borophosphate compound, bis(1,4‐diazo­nia­[2.2.2]­octane) μ₃‐oxo‐oxopenta‐μ‐phosphato‐diboronvanadium monohydrate phosphoric acid solvate, containing the cluster anion [VO(PO₃OH)₅B₂O]⁴⁻, has been synthesized under mild hydro­thermal conditions. Extensive O—H⃛O and N—H⃛O hydrogen bonding is observed between the molecular units.     

Addition of palladium and platinum tri-tert-butylphosphine groups to Re-Sn and Re-Ge bonds

The reaction of Re2(CO)8[mu-eta2-C(H)=C(H)Bu(n)](mu-H) with Ph3SnH at 68 degrees C yielded the new compound Re2(CO)8(mu-SnPh2)2 (10) which contains two SnPh2 ligands bridging two Re(CO)(4) groups, joined by an unusually long Re-Re bond. Fenske-Hall molecular orbital calculations indicate that the bonding in the Re2Sn2 cluster is dominated by strong Re-Sn interactions and that the Re-Re interactions are weak. The 119Sn M?ssbauer spectrum of 10 exhibits a doublet with an isomer shift (IS) of 1.674(12) mm s(-1) and a quadrupole splitting (QS) of 2.080(12) mm s(-1) at 90 K,characteristic of Sn(IV) in a SnA2B2 environment. The IS is temperature dependent, -1.99(14) x 10(-4) mm s(-1) K(-1); the QS is temperature independent. The temperature-dependent properties are consistent with the known Gol'danskii-Kariagin effect. The germanium compound Re2(CO)8(mu-GePh2)2 (11) was obtained from the reaction of Re2(CO)8[mu-eta2-C(H)=C(H)Bu(n)](mu-H) with Ph3GeH. Compound 11 has a structure similar to that of 10. The reaction of 10 with Pd(PBu(t)3)2 at 25 degrees C yielded the bis-Pd(PBu(t)3) adduct, Re2(CO)8(mu-SnPh2)2[Pd(PBu(t)3)]2 (12); it has two Pd(PBu(t)3) groups bridging two of the four Re-Sn bonds in 10. Fenske-Hall molecular orbital calculations show that the Pd(PBu(t)3) groups form three-center two-electron bonds with the neighboring rhenium and tin atoms. The mono- and bis-Pt(PBu(t)3) adducts, Re2(CO)8(mu-SnPh2(2)[Pt(PBu(t)3)] (13) and Re2(CO)8(mu-SnPh2)2[Pt(PBu(t)3)]2 (14), were formed when 10 was treated with Pt(PBu(t)3)2. A mono adduct of 11, Re2(CO)8(mu-GePh2)2[Pt(PBu(t)3)] (15), was obtained similarly from the reaction of 11 with Pt(PBu(t)3)2.     

Artificial glycosyl phosphorylases

alpha- and beta-Cyclodextrin 6(A),6(D)-diacids (1 and 2), beta-cyclodextrin-6-monoacid (14), beta-cyclodextrin 6(A),6(D)-di-O-sulfate (16) and beta-cyclodextrin-6-heptasulfate (19) were synthesised. Acids 1, 2 and 14 were made from perbenzylated alpha- or beta-cyclodextrin, by diisobutylaluminum hydride (DIBAL)-promoted debenzylation, oxidation and deprotection. Addition of molecular sieves was found to improve the debenzylation reaction. Sulfates 16 and 19 were made by sulfation of the appropriately partially protected derivatives and deprotection. Catalysis of 4-nitrophenyl glycoside cleavage by these cyclodextrin derivatives was studied. Compounds 1, 2 and 16 were found to catalyse the reaction, with the catalysis following Michaelis-Menten kinetics and depending first order on the phosphate concentration. In a phosphate buffer (0.5 M, 59 degrees C, pH 8.0), K(M) varied from 2-10 mM and the k(cat)/k(uncat) ratio from 80-1000 depending on the stereochemistry of the substrate and the catalyst, with 2 being the best catalyst and with the sulfated 16 also displaying catalytic ability. The monoacid 14 and the heptasulfate 19 were not catalytic.     

A microfluidic system enabling Raman measurements of the oxygenation cycle in single optically trapped red blood cells

Using a lab-on-a-chip approach we demonstrate the possibility of selecting a single cell with certain properties and following its dynamics after an environmental stimulation in real time using Raman spectroscopy. This is accomplished by combining a micro Raman set-up with optical tweezers and a microfluidic system. The latter gives full control over the media surrounding the cell, and it consists of a pattern of channels and reservoirs defined by electron beam lithography that is moulded into rubber silicon (PDMS). Different buffers can be transported through the channels using electro-osmotic flow, while the resonance Raman response of an optically trapped red blood cell (RBC) is simultaneously registered. This makes it possible to monitor the oxygenation cycle of the cell in real time and to investigate effects like photo-induced chemistry caused by the illumination. The experimental set-up has high potential for in vivo monitoring of cellular drug response using a variety of spectroscopic probes.     

Diffusion-direction-dependent imaging: a novel MRI approach for peripheral nerve imaging

A novel magnetic resonance imaging approach, called diffusion-direction-dependent imaging (DDI), is introduced. Due to inherent anisotropic diffusion properties, peripheral nerves can be visualized on diffusion tensor imaging (DTI). The largest signal attenuation on DTI correlates with the direction of a nerve fiber, and the least signal attenuation correlates with the direction perpendicular to the nerve fiber. Since low signal-to-noise ratio is a concern in peripheral nerve DTI, we explored a new approach focusing on the perpendicular diffusion direction. A 36-gradient diffusion direction scheme was used. A mean expected curve specific for peripheral nerves was calculated based on the sciatic nerve and its division into the common peroneal nerve and the tibial nerve in three healthy volunteers. By a simple postprocessing method, a comparison of the mean expected curve and the measured curve was made voxel by voxel, and the sciatic nerve and its division were reconstructed, excluding other tissues. More studies are needed to investigate whether other postprocessing methods or other diffusion direction schemes are more suited for peripheral nerve imaging with DDI. Further studies may also be of interest to investigate whether DDI can be a complementary method to conventional T(1)-weighted and T(2)-weighted sequences in the imaging of peripheral nerve pathology or even in the visualization of other tissues, possibly with different diffusion direction schemes.