Highly enantioselective phase-transfer-catalyzed alkylation of protected alpha-amino acid amides toward practical asymmetric synthesis of vicinal diamines, alpha-amino ketones, and alpha-amino alcohols

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.     

Determination of acrolein in serum by high‐performance liquid chromatography with fluorescence detection after pre‐column fluorogenic derivatization using 1,2‐diamino‐4,5‐dimethoxybenzene

Acrolein is a major unsaturated aldehyde that is generated during the lipid peroxidation process. The measurement of acrolein in biological samples should be useful to estimate the degree of lipid peroxidation and to evaluate the effect of hazardous properties of acrolein on human health. In this study, a highly sensitive and selective high‐performance liquid chromatography with fluorescence detection method was developed for the determination of acrolein in human serum. The proposed method involves the pre‐column fluorogenic derivatization of acrolein with 1,2‐diamino‐4,5‐dimethoxybenzene (DDB) as a reagent. The fluorescent derivative of acrolein could be detected clearly without any interfering reagent blank peaks because DDB does not have intrinsic fluorescence itself, and the detection limit was 10 nM (signal‐to‐noise ratio = 3). The proposed method could selectively detect acrolein in human serum with a simple protein precipitation treatment. Copyright © 2015 John Wiley & Sons, Ltd.     

The Discrete Relativistic Toda Molecule Equation and a Padé Approximation Algorithm

The relativistic Toda molecule equation (RTM) describes a one-parameter deformation of coefficients of the recurrence relation of a class of biorthogonal polynomials including the Szegö polynomials. In this paper, we present (i) explicit solutions of the discrete relativistic Toda molecule equation (d-RTM), (ii) a new Padé approximation algorithm for a given power series.     

Liquid chromatographic determination of ethambutol in serum samples based on intramolecular excimer-forming fluorescence derivatization.

A selective liquid chromatographic method has been developed for the assay of ethambutol in serum samples. The assay involves intramolecular excimer-forming derivatization with 4-(1-pyrene)butanoyl chloride (PBC) and isocratic reversed-phase chromatography with fluorescence detection. After acetonitrile-deproteinization of the serum sample, the derivatization reaction of ethambutol with PBC was completed within 30 min at 50 degrees C. N,N'-Diethylethylenediamine was used as an internal standard. The detection limit of ethambutol was 23 ng/ml serum, corresponding to 180 fmol on column at a signal-to-noise ratio of 3. The present method was selective enough to analyze ethambutol in rabbit serum without any tedious sample clean-up procedure because biogenic monoamines gave no peak in the chromatogram. The method was applicable to drug monitoring in rabbit serum.     

An ab initio approach to the mechanism of the Grignard reaction

The mechanism of the Grignard reaction is investigated for the first time in the light of ab initio SCF MO theory. The possible advantage of a single-electron transfer over a polar mechanism is discussed.     

Simultaneous determination of histamine and histidine by liquid chromatography following intramolecular excimer-forming fluorescence derivatization with pyrene-labeling reagent.

A highly sensitive and selective fluorometric method for the determination of histamine and histidine has been developed. This method is based on an intramolecular excimer-forming fluorescence derivatization with a pyrene reagent followed by reversed-phase liquid chromatography. The analytes, containing two amino moieties in a molecule, were converted to the corresponding dipyrene-labeled derivatives by derivatization. The derivatives afforded intramolecular excimer fluorescence (440 - 540 nm), which can clearly be discriminated from the normal fluorescence (360 - 420 nm) emitted from reagent blanks. The detection limits (signal-to-noise ratio = 3) were femto mole levels.     

Advantage of in situ generation of N-arylsulfonyl imines from α-amide sulfones in the phase-transfer-catalyzed asymmetric Strecker reaction

Highly efficient, catalytic enantioselective synthesis of N-arylsulfonyl α-amino nitriles from the corresponding α-amido sulfones has been achieved under toluene-aqueous potassium cyanide biphasic conditions using chiral quaternary ammonium iodide (R,R,R)-1 as an effective phase-transfer catalyst. This Strecker synthesis involving the in situ generation of the reactive N-sulfonyl imines is advantageous for the cyanation of the substrates having primary and secondary alkyl substituents.     

Practical determination of methotrexate in serum of rheumatic patients by LC-MS/MS

A rapid and simple liquid chromatography tandem mass spectrometry method for determination of methotrexate (MTX) in rheumatic patients' serum is described. Serum spiked with pterin as an internal standard was deproteinized with methanol. The separation of MTX from interfering peaks in matrix was achieved on a Luna 3 µm C₁₈ (100 × 4.6 mm i.d.) column with a mixture of 1% acetic acid and acetonitrile (88:12, v/v) within 5 min. Multiple reaction monitoring transitions monitored for MTX were m/z 455.2–308.1. The calibration curve of MTX in serum showed a good linearity (r = 0.999). Limits of detection and quantification of MTX at a signal‐to‐noise ratio of 3 and 10 were 3.0 n m (4.4 fmol/injection) and 10.0 n m (14.5 fmol/injection), respectively. The accuracy and precision for intra‐ and inter‐day assays were 94.6–106.5% and <5.5 and <5.1%, respectively. Furthermore, the proposed method was successfully applied to the sera nine rheumatic patients receiving MTX treatment. Copyright © 2012 John Wiley & Sons, Ltd.     

Existence of sections of line bundles over a toroidal group and its applications

Dedicated to Professor Joji Kajiwara on the occasion of his sixtieth birthday