Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid vinyl-ACCA) derivatives: key intermediates for the preparation of inhibitors of the hepatitis C virus NS3 protease

(1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is a key building block in the synthesis of potent inhibitors of the hepatitis C virus NS3 protease such as BILN 2061, which was recently shown to dramatically reduce viral load after administration to patients infected with HCV genotype 1. We have developed a scalable process that delivers derivatives of this unusual amino acid in >99% ee. The strategy was based on the dialkylation of a glycine Schiff base using trans-1,4-dibromo-2-butene as an electrophile to produce racemic vinyl-ACCA, which was subsequently resolved using a readily available, inexpensive esterase enzyme (Alcalase 2.4L). Factors that affect diastereoselection in the initial dialkylation steps were examined and the conditions optimized to deliver the desired diastereomer selectively. Product inhibition, which was encountered during the enzymatic resolution step, initially resulted in prolonged cycle times. Enrichment of racemic vinyl-ACCA through a chemical resolution via diastereomeric salt formation or the use of forcing conditions in the enzymatic reaction both led to improvements in throughput and the development of a viable process. The chemistry described herein was scaled up to produce multikilogram quantities of this building block.     

Synthesis of new o-alkyl substituted arylalkylphosphanes: study of their molecular structure and influence on rhodium-catalyzed propene and 1-hexene hydroformylation

A set of new phosphane ligands designed to increase the branched-to-normal ratio of the hydroformylation reaction were prepared in the same way as the previously reported ortho-alkyl substituted arylphosphanes, which have shown increased i/n ratios in the hydroformylation of propene and 1-hexene. In order to determine the relationship between the catalytic behavior and stereoelectronic properties of the ligands, various functional alkyl groups (methyl, isopropyl, cyclohexyl) were placed on the phosphorus atom directly and in the ortho position of the phenyl ring connected to phosphorus. In the hydroformylation reaction of propene and 1-hexene a higher i/n ratio resulted with nearly all the ligands compared with that of triphenylphosphane. Additionally as the ortho-alkyl-substituent became larger, it had a favorable effect on the i-selectivity. Characterization of the ligands was carried out by NMR spectroscopy (mainly ¹H, ³¹P{¹H}, ¹³C{¹H}, HSQC/HETCOR and COSY-90). Properties of the ligands were also studied by quantum mechanical calculations and by synthesizing three Rh(acac)(CO)(PR₃) derivatives. The o-alkyl-substituent was orientated outside the ligands’ cone angle in the X-ray crystal structures of (2-cyclohexylphenyl)dicyclohexylphosphane and (2,5-dimethylphenyl)bis(4-pyridyl)phosphane, and Rh(acac)(CO)(PR₃) complex of (2-methylphenyl)dicyclohexylphosphane.     

Evaluation of semiquantitative analysis mode in ICP-MS

Semiquantitative analysis mode in inductively coupled plasma mass spectrometry (ICP-MS) has been popularly used for fast screening purposes. Although the benefit of it has been studied by many researchers, its performance of application in real-world routine analyses has not been reported.

In this study, we evaluated the reliability of semiquantitative analysis mode through inter-laboratory comparison using two different ICP-MS systems with one multi-element calibration standard. The suitability of semiquantitative analysis mode in routine analysis laboratory was demonstrated by evaluating its application in different laboratories and in real production laboratory practices. Twenty one elements were measured, namely, Be, B, Al, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Ag, Cd, Sn, Sb, Ba, Tl, and Pb in various fresh water reference samples. Good results concerning accuracy (relative percentage error within 10%) and reproducibility (relative standard deviation lower than 5%) were obtained in more than 90% analyzed samples at concentrations equal to or greater than 10 times the detection limit (DL). Semiquantitative analysis mode also enabled the determination of elements that are not present in the calibration standard. The results demonstrated the potential of semiquantitative analysis mode as a reliable approach in routine laboratory determination of simple matrices, where high throughput and cost-effectiveness are desired, as well as in emergency situations where speed of analysis is critical and quite often limited sample information is available.     

Aggregation and Tunable Color Emission Behaviors of l-Glutamine-Derived Platinum(II) Bipyridine Complexes by Hydrogen-Bonding, π–π Stacking and Metal–Metal Interactions

A n l -glutamine-derived functional group was introduced to the bis(arylalkynyl)platinum(II) bipyridine complexes 1 – 4 . The emission could be switched between the ³MLCT excited state and the triplet excimeric state through solvent or temperature changes, which is attributed to the formation and disruption of hydrogen-bonding, π–π stacking, and metal–metal interactions. Different architectures with various morphologies, such as honeycomb nanostructures and nanospheres, were formed upon solvent variations, and these changes were accompanied by ¹H NMR and distinct emission changes. Additionally, yellow and red emissive metallogels were formed at room temperature due to the different aggregation behaviors introduced by the substituent groups on bipyridine. The thermoresponsive metallogel showed emission behavior with tunable colors by controlling the temperature. The negative Gibbs free-energy change (ΔG) and the large association constant for excimer formation have suggested that the molecules undergo aggregation through hydrogen-bonding, π–π, and metal–metal interactions, resulting in triplet excimeric emission.     

Onset of Thermal Convection in a Vertical Porous Cylinder with a Partly Conducting and Partly Penetrative Cylinder Wall

The onset of thermal convection in a vertical porous cylinder in three dimensions is investigated analytically. Top and bottom of the cylinder are set to be perfectly heat conducting and impermeable, and is uniformly heated from below. The convection problem is solved for a cylinder wall that is partly conducting and partly penetrative. The expressions for semi-conduction and semi-penetration are based on a porous medium separated from its surroundings by a thin wall. The eigenvalue problem is split into two Helmholtz equations, and the results are expressed by Bessel functions in the radial direction. Comparisons are made with existing solutions for the limit cases of a closed cylinder wall that is either conducting or insulating. Two different models are compared for the kinematic limit condition of an open boundary.     

Preparation of nanocrystalline titania films with different porosity by water-based chemical solution deposition

This study describes the synthesis of nanocrystalline titania layers on silicon and glass substrates by chemical solution deposition, using a water-based citratoperoxo-Ti(IV) precursor solution. The same aqueous solution–gel precursor is used for deposition of, both, thin dense layers by spin-coating and thicker porous layers by tape-casting. In the latter, the precursor solution is modified by the addition of polyvinyl alcohol (PVA), which acts as a thickener and pore-forming agent. Phase composition, film morphology, and the hydrophilic character of the films are studied by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV–VIS transmission measurements, variable angle spectroscopic ellipsometry (VASE), and by contact angle measurements. The thin 180 nm titania film, deposited from the unmodified precursor solution, shows a density of about 96%. Upon ultraviolet illumination, it acquires a highly hydrophilic surface. One hour of illumination is sufficient to obtain a water contact angle of almost 0°. Furthermore, the hydrophilisation process shows to be reversible. Tape-casting and thermal treatment of the modified precursor solution gives rise to the formation of a 500 nm thick, porous, pure anatase film. The nanocrystalline thick film is composed of 20–40 nm particles, and contains clearly defined pores of 20 nm, homogeneously distributed along the surface.