A Concise Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4‐quinoline moiety via S_N2 displacement of the β‐OBs group located on the 4‐hydroxyl proline intermediate, which was prepared from 4‐α‐hydroxyl proline analog via Mitsunobu reaction with inversion of stereochemistry. In addition, a short and practical synthesis for P3 unit is also described herein. Final assembly of four fragments for BILN 2061 was achieved with an overall yield of 58% in 4 steps from P1 to 15a . Furthermore several analogs of BILN 2061 ( WX‐1 – WX ‐ 5 ) containing modifications on P3 unit were synthesized successfully using the same synthetic route as described for the parent inhibitor BILN 2061 .     

Convergent synthesis of the quinolone substructure of BILN 2061 via carbonylative Sonogashira coupling/cyclization

A convergent synthesis of quinolone 2 (key substructure of the protease inhibitor BILN 2061) was developed via palladium-catalyzed carbonylation of 2-iodo-5-methoxyaniline (4) with thiazolylacetylene 5.     

RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.     

Olefin ring-closing metathesis as a powerful tool in drug discovery and development – potent macrocyclic inhibitors of the hepatitis C virus NS3 protease

Peptidomimetic inhibitors of the hepatitis C NS3 protease often exhibit poor biopharmaceutical properties. Structure modification of a substrate-based tripeptide into a β-strand 15-membered ring scaffold provided a new class of peptidomimetics that are significantly superior as drug candidates to their acyclic precursors. Tripeptide dienes composed of three unnatural amino acid residues with numerous chiral centers were efficiently converted to macrocyclic peptides, in high diastereomeric purity, using ring-closing metathesis (RCM). The conformation of the acyclic diene and the protocol for the RCM reaction were investigated and optimized extensively in order to achieve an efficient synthesis of potential therapeutic agents for the treatment of hepatitis C infections. These studies provided the fist small molecule (BILN 2061) that was clinically validated for the treatment of hepatitis C infection in man and opened the door to a plethora of new pre-clinical pharmaceutical agents that can be made in multi kilogram quantities using RCM chemistry.     

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.     

Headspace mass spectrometry methodology: application to oil spill identification in soils

In the present work we report the results obtained with a methodology based on direct coupling of a headspace generator to a mass spectrometer for the identification of different types of petroleum crudes in polluted soils. With no prior treatment, the samples are subjected to the headspace generation process and the volatiles generated are introduced directly into the mass spectrometer, thereby obtaining a fingerprint of volatiles in the sample analysed. The mass spectrum corresponding to the mass/charge ratios (m/z) contains the information related to the composition of the headspace and is used as the analytical signal for the characterization of the samples. The signals obtained for the different samples were treated by chemometric techniques to obtain the desired information. The main advantage of the proposed methodology is that no prior chromatographic separation and no sample manipulation are required. The method is rapid, simple and, in view of the results, highly promising for the implementation of a new approach for oil spill identification in soils. Figure PCA score plots illustrate clear discrimination of types of crude oil in polluted soil samples (e.g. results are shown for vertisol)     

Convenient method for the preparation of dichloro and dibromodinitromethane

Summary A convenient method was proposed for the preparation of dichlorodinitromethane and dibromodinitromethane, consisting in the reaction of the appropriate halides with the potassium salt of dinitromethane.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2060–2061, November 1965     

Enzyme-free amperometric glucose sensor using a glassy carbon electrode modified with poly(vinyl butyral) incorporating a hybrid nanostructure composed of molybdenum disulfide and copper sulfide

The authors describe an enzyme-free amperometric method for the determination of glucose at nanomolar levels at near neutral pH values. A hybrid nanostructure composed of molybdenum disulfide and copper sulfide (MoS₂-CuS) was prepared using L-cysteine as both the sulfur donor and the reducing agent. The nanohybrid was then immobilized on a glassy carbon electrode (GCE) by incorporating it into a film of poly(vinyl butyral). Transmission electron microscopy and Raman spectroscopy were utilized to characterize the MoS₂-CuS nanohybrids. Three modified GCEs (MoS₂/GCE, CuS/GCE and MoS₂-CuS/GCE) were investigated with respect to their sensitivity to glucose, and the MoS₂-CuS/GCE was found to perform best in displaying a limit of detection as low as 0.3 μM in pH 7.2 buffer at an applied potential of +0.18 V (versus Ag/AgCl). The repeatability and intermediate precision are below 7.0% at 0.05, 0.5 and 1.0 mM concentration levels. The method was applied to the determination of glucose in spiked human serum samples, and recoveries were between 92.3 and 110.7%. This detection scheme is rapid and cost-effective. Natural enzymes and additional electron mediators are not required.

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Graphical Abstract MoS₂-CuS hybrid nanostructures on a glassy carbon electrode were utilized for enzyme-free sensing of glucose at nanomolar levels.

     

Preparative synthesis of (<Emphasis Type="Italic">Z</Emphasis>)-5-decenyl acetate

A procedure was developed for preparative synthesis of (Z)-5-decenyl acetate, the sex hormone of Agrotis Segetum.Translated from Zhurnal Prikladnoi Khimii, Vol. 77, No. 12, 2004, pp. 2061–2062.Original Russian Text Copyright © 2004 by Chobanyan.     

A facile cesium fluoride-mediated synthesis of aromatic polyethers from bisphenols and activated aromatic dihalides

A facile method for the synthesis of high-molecular-weight aromatic polyethers was developed with the use of cesium fluoride as a base. The high-temperature solution polycondensation between bisphenols and activated aromatic dihalides with cesium fluoride in polar aprotic solvents readily afforded a series of aromatic polyethers having inherent viscosities of 0.5–1.0 dL/g under essentially neutral and milder reaction conditions, compared with the conventinal method using alkali hydroxides or alkali carbonates. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 2055–2061, 1997     

Stereoselective Allylation of Ketones: Explanation for the Unusual Inversion of the Induced Stereochemistry in the Auxiliary‐Mediated Crotylation and Pentenylation of Butanone by DFT Calculations

The solvent makes the difference : While attack at the Re face of the intermediate oxocarbenium ion becomes less energy demanding with increasing size of R′, it is the solvent effect that makes this attack the main trajectory, leading to inversed stereochemistry (see picture).

     

The reaction of fluorine-containing β-alkoxyvinyl ketones and β-diketones with isocyanides

Conclusions Isocyanides react with fluorine-containing vinyl ketones to form initially 1,4-dycloaddition products. If a mobile hydrogen atom is present in the cycloadduct rearrangement takes place to a product with a migrated multiple bond in the ring or to a linear dienecarboxamide (the result of double isomerization involving ring opening).Translated from Izvestiya Akademiya Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2061–2065, September, 1977.     

Solidlike transition of melt‐intercalated biodegradable polymer/clay nanocomposites

Synthetic biodegradable aliphatic polyester (BAP) intercalated into organoclay was prepared by melt compounding, and its solidlike characteristics were investigated via several rheological test modes: steady shear rotation, oscillation, and creep testing. Structural investigations with X‐ray diffraction and transmission electron spectroscopy were also performed for a better understanding of the characteristic rheological behaviors. The creep, recovery, and stress modulus exhibited a solidlike transition of BAP/clay nanocomposites that depended on the clay content. An increase in the zero shear rate viscosity and a shifting of the crossover point (storage modulus vs loss modulus) to a lower frequency were also observed with increasing clay contents. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 2052–2061, 2003     

Synthesis,characterization, crystal structure and thermal analysis of a copper(II) mononuclear compound with 2,6- bis (3,5-dimethyl- N -pyrazolyl)pyridine (bdmpp) and selenocyanate as ligands

A single crystal of the copper(II) compound, [Cu(bdmpp)(SeCN)₂], 2, was obtained and its crystal structure was determined by X-ray diffraction methods. The complex was characterized by elemental, thermal and FTIR analysis. The FTIR analysis of the complex clearly shows the SeCN peaks at 2096 and 2061?cm^?1 which did not exist in the free organic ligand (bdmpp). X-ray analysis showed that 2 crystallized in the monoclinic space group P2₁/c. Cu(II) has a distorted trigonal bipyramidal coordination involving three N atoms from the ligand and two N atoms from the selenocyanate group.     

Bernoullian,Terminal, Penultimate or Third Order Markov Statistics?

Summary: A series of 7 homogeneous ethylene‐propylene copolymers is modeled by a Bernoullian, a terminal, a penultimate and a third order Markov model and it is found that the penultimate model describes this series best. The Bernoullian and terminal model prove to be insufficient and the third order Markov model is statistically not justified. Based on these results, a criterion to select the optimal Markovian order of homogeneous, single site catalyst produced copolymers is developed.

Schematic of the [(3‐MePh)(4‐MePh)C(2,7‐di‐tert‐BuFlu)(Cp)]ZrCl₂ metallocene copolymerizing ethene and propene.     

Polar addition of perfluoro-tert-hexyl iodide to alkenes and alkynes

The effective charges on the atoms in molecules of perfluoroalkyl halides of general formula (CF₃)_nCF_3–nX (X=Cl, Br, I) have been calculated by the AM1 semiempirical method. In polar solvents perfluoro-tert-hexyl iodide is reduced under the action of alkenes and aromatic hydrocarbons to form 2-hydroperfluoro-2-methyl-pentane and perfluoro-2-methyl-2-pentene. In ethyl acetate the regio- and stereo-specific addition of perfluoro-tert-hexyl iodide to alkenes, butadiene, and alkynes takes place, which is associated with the realization of a polar ion-radical mechanism for the reaction.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2057–2061, September, 1989.     

Poly(acrylonitrile) ultrafiltration membranes. I. Polymer‐salt‐solvent interactions

Fourier transform infrared spectroscopy was used to study the interactions among LiCl, ZnCl₂, and AlCl₃ with N,N‐dimethylformamide (DMF) and poly(acrylonitrile) (PAN). It was observed that all three salts complex with DMF as well as PAN. The strength of the cation interaction with the >C?O oxygen of DMF was found to be higher than that with the ? CN group of PAN. The >C?O stretching frequency of DMF with ZnCl₂ was red shifted, indicating stronger complex formation compared with other two cations. With the addition of salt, the salt–DMF pseudo solvent was found to become a θ solvent for PAN compared with neat DMF. This change in PAN solvation power was primarily the result of DMF–salt complexation. As a result of the complexation, Mark‐Houwink constant a, was found to reduce from 0.75 (for pure DMF) to ～0.6 for DMF–salt solvents, indicating decreased PAN chain expansion. Comparison of intrinsic viscosity [η] values indicated that addition of salts to PAN–DMF solutions resulted in: (i) decrease in the DMF solvation power, which causes less expanded polymer coils, and (ii) increased interpolymer chain entanglements via salt‐promoted chain association. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2061–2073, 2005     

Methylenecyclopropane in the [2+2+1]-cycloaddition reaction with dicobalt-hexacarbonyl complexes of acetylenes

The ability of methylenecyclopropane to undergo [2+2+1]-cycloaddition reactions with dicobalt-hexacarbonyl complexes of alkynes with formation of spiro[2,4]-heptenone derivatives has been revealed for the first time. The conditions for carrying out this reaction on the surface of adsorbents and zeolites have been established, so that it can be considered as a general preparative method for the preparation of various derivatives of spiro[2,4]heptenones (yields up to 80%). With monosubstituted acetylenes, the [2+2+1]-cycloaddition proceeds regioselectively, giving preferentially cyclopentenones containing a spiro fragment in the -position to the carbonyl. In the case of disubstituted acetylenes, -isomers are formed exclusively.For previous communication; see [1].Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2061–2068, September, 1989.     

Thermal stability of methacrylic acid copolymers of Eudragits L,S, and L30D and the acrylic acid polymer of carbopol

The thermal stability of the powder or film forms of Eudragits L, S, and L30D and carbopol polymers was qualitatively investigated by microscopic reflectance Fourier transform infrared spectroscopy equipped with differential scanning calorimetry (FT-IR/DSC microscopic system). DSC and thermogravimetric analysis (TGA) were also used to study the thermal behavior of the pulverized powders of the raw material and the films of these polymers. The results indicate that a 6-membered ring cyclic anhydride formation was respectively produced by a heating process in the molecular structures of Eudragits L, S, and L30D and carbopol polymers via inter- or intrapolymer condensation. The peak intensity of the carbonyl stretching absorption of cyclic anhydride-related IR peaks appeared sharply near 1801 and 1759 (1751) cm⁻¹, and a peak near 1006 (1018) cm⁻¹ related to the antisymmetric stretching mode of C O C also appeared suddenly beyond the marked reaction temperature. The initial reaction temperature of anhydride formation for the Eudragits L, S, and L30D and carbopol polymers was observed respectively from near 186, 180, 170, and 100°C, whereas the rapid and marked reaction temperature from about 206, 188, 170, and 183°C appeared accurately from the reflectance FT-IR spectra. The DSC thermograms and TGA curves also confirmed these results. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 2061–2067, 1999