Synthesis of enantiomerically pure (S)-methanocarbaribo uracil nucleoside derivatives for use as antiviral agents and P2Y receptor ligands

We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]hexane system. D-ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5'-hydroxymethyl group. An ester group appended to a tertiary carbon (C1) was transformed to an amino group as a nucleobase precursor.     

Theoretical evidence for C-F bond activation by a fluoro-calix[4]pyrrole-tert-amine macrocycle

Density functional theory as well as highly correlated ab initio molecular orbital theory was used to explore the possibility of activating C-F bonds in fluoroalkanes by organic macrocycles. The results indicate that the reaction between fluoro-calix [4]pyrrole-tert-amine and CH3F via a Menshutkin displacement mechanism is highly favorable and competitive from a thermochemical point of view with the very efficient C-Cl activation by a simple macrocyclic amine recently reported in the literature (Stanger, L. J.; Noll, B. C.; Gonzalez, C.; Marquez, M.; Smith, B. D. J. Am. Chem. Soc. 2005, 127, 4184).     

N-nitrosation of amines by NO2 and NO: a theoretical study

Gas-phase nitrosation of amines implies a nonionic pathway different from the nitrosonium nitrosation via acidification of nitrite. Electronic structure calculations discussed in this work suggest a free radical mechanism, in which NO2 abstracts a hydrogen atom from the nitrogen in primary and secondary amines to form an intermediate complex of an aminyl radical and nitrous acid. The aminyl radical intermediate is then quenched by nitric oxide, leading to the formation of nitrosamine. High-level calculations (CBS-QB3) show that alkyl substitutions on amines can activate the H-abstraction reaction. Thus, while H-abstraction from NH3 was found to exhibit a reaction barrier (DeltaH) of 106 kJ/mol, similar calculations indicate that the corresponding barriers decrease to 72 and 45 kJ/mol for methylamine and dimethylamine, respectively. Heterocyclic secondary amines have also been investigated in a similar manner. The five-membered-ring (5-m-r) amine appears to be the most reactive: pyrrolidine (DeltaH=30 kJ/mol), azetidine (DeltaH=44 kJ/mol), piperidine (DeltaH=44 kJ/mol), and aziridine (DeltaH=74 kJ/mol). The reaction barrier for 1H-pyrrole, an aromatic 5-m-r secondary amine, was found to be 59 kJ/mol. The origin of the high activity for the 5-m-r alkylamine stems from a hydrogen-bond-like interaction between the aminyl radical and the nascent nitrous acid molecule. This theoretical study suggests that, in the presence of nitrogen oxides, the gas-phase nitrosation of secondary amines is feasible.     

High-density microfluidic arrays for cell cytotoxicity analysis

In this paper, we report on the development of a multilayer elastomeric microfluidic array platform for the high-throughput cell cytotoxicity screening of mammalian cell lines. Microfluidic channels in the platform for cell seeding are orthogonal to channels for toxin exposure, and within each channel intersection is a circular chamber with cell-trapping sieves. Integrated, pneumatically-actuated elastomeric valves within the device isolate the microchannel array within the device into parallel rows and columns for cell seeding and toxin exposure. As a demonstration of the multiplexing capability of the platform, a microfluidic array containing 576 chambers was used to screen three cell types (BALB/3T3, HeLa, and bovine endothelial cells) against a panel of five toxins (digitonin, saponin, CoCl(2), NiCl(2), acrolein). Evaluation of on-chip cell morphology and viability was carried out using fluorescence microscopy, with outcomes comparable to microtiter plate cytotoxicity assays. Using this scalable platform, cell seeding and toxin exposure can be carried out within a single microfluidic device in a multiplexed format, enabling high-density parallel cytotoxicity screening while minimizing reagent consumption.     

Enantioselective synthesis of C3 fluoro-MEP

The first enantioselective synthesis of C(3) fluoro-MEP is herein reported. The synthetic pathway developed takes advantage of a selective hydrofluorination of a 2,3-epoxy-1-alcohol to introduce the required tertiary fluoride unit.     

Mayer-vietoris sequences for the hermitian picard group

In this note, we study the functorial behaviour of the hermitian Picard group with respect to centrally induced ring morphisms. As an application, we construct Mayer-Vietoris sequences which provide an efficient tool to concretely calculate the hermitian Picard group.     

An expedient approach to ferrocenyl thioamides via Fischer carbenes

Oxidative demetalation of Fischer ferrocenyl ethoxy carbene complexes (1a–c, M = Cr, Mo, W) and new Fischer ferrocenyl R-amino carbene complexes [2–5 (a–c), 11–15 (a–c), and 21–22 (a–c); M = Cr, Mo, W; R = H, CH₃, C₂H₅, C₃H₇, (CH₂)₂OH, (CH₂)₃OH, (CH₂)₂(OMe)₂, (CH₂)₃N(Me)₂, CH₂CHCH₂, (CH₂)₂OSi(CH₃)₃, (CH₂)₃OSi(CH₃)₃] with elemental sulfur–NaBH₄ were carried out under mild conditions, obtaining O-ethyl ferrocenecarbothioate (6) and novel ferrocenyl thioamides (7–10 and 16–20) in excellent yields.     

A Microfluidic Approach to Encapsulate Living Cells in Uniform Alginate Hydrogel Microparticles

A microfluidic technique is described to encapsulate living cells in alginate hydrogel microparticles generated from monodisperse double‐emulsion templates. A microcapillary device is used to fabricate double emulsion templates composed of an alginate drop surrounded by a mineral oil shell. Hydrogel formation begins when the alginate drop separates from the mineral oil shell and comes into contact with Ca²⁺ ions in the continuous phase. Alginate hydrogel microparticles with diameters ranging from 60 to 230 µm are obtained. 65% of the cells encapsulated in the alginate microparticles were viable after one week. The technique provides a useful means to encapsulate the living cells in monodisperse hydrogel microparticles.

     

Theoretical study on the mechanism of the gas-phase elimination kinetics of alkyl chloroformates

The theoretical calculations on the mechanism of the homogeneous and unimolecular gas-phase elimination kinetics of alkyl chloroformates– ethyl chloroformate (ECF), isopropyl chloroformate (ICF), and sec-butyl chloroformate (SCF) – have been carried out by using CBS-QB3 level of theory and density functional theory (DFT) functionals CAM-B3LYP, M06, MPW1PW91, and PBE1PBE with the basis sets 6-311++G(d,p) and 6-311++G(2d,2p). The chlorofomate compounds with alkyl ester C_β–H bond undergo thermal decomposition producing the corresponding olefin, HCl and CO₂. These homogeneous eliminations are proposed to undergo two different types of mechanisms: a concerted process, or via the formation of an unstable intermediate chloroformic acid (ClCOOH), which rapidly decomposes to HCl and CO₂ gas. Since both elimination mechanisms may occur through a six-membered cyclic transition state structure, it is difficult to elucidate experimentally which is the most reasonable reaction mechanism. Theoretical calculations show that the stepwise mechanism with the formation of the unstable intermediate chloroformic acid from ECF, ICF, and SCF is favoured over one-step elimination. Reasonable agreements were found between theoretical and experimental values at the CAM-B3LYP/6-311++G(d,p) level.     

Long-range J(CH) heteronuclear coupling constants in cyclopentane derivatives

Detailed measurements of long-range heteronuclear spin-spin coupling constants, especially (2, 3)J(CH) spin-spin couplings for various cyclopentane derivatives, are reported. The measurements are based on a 2D heteronuclear correlation experiment named G-BIRD(R, X)-CPMG-HSQMBC.