Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives.

The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29-70%), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate-catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.

Catalytic Site-Selective Acylation of Carbohydrates Directed by Cation-n Interaction.

Site-selective functionalization of hydroxyl groups in carbohydrates is one of the long-standing challenges in chemistry. Using a pair of chiral catalysts, we now can differentiate the most prevalent trans-1,2-diols in pyranoses systematically and predictably. Density functional theory (DFT) calculations indicate that the key determining factor for the selectivity is the presence or absence of a cation-n interaction between the cation in the acylated catalyst and an appropriate lone pair in the substrate. DFT calculations also provided a predictive model for site-selectivity and this model is validated by various substrates.

Kinetic resolution of racemic α-hydroxyphosphonates by asymmetric esterification using achiral carboxylic acids with pivalic anhydride and a chiral acyl-transfer catalyst.

A practical protocol is developed to directly provide chiral α-acyloxyphosphonates and α-hydroxyphosphonates from (±)-α-hydroxyphosphonates utilizing the transacylation process to generate the mixed anhydrides from acid components and pivalic anhydride in the presence of organocatalysts (s-value = 33-518).

Telescoped synthesis of stereodefined pyrrolidines.

Telescoped and one-pot olefination/asymmetric functionalization approaches to disubstituted pyrrolidines (dr up to 99:1, up to 99% ee) have been developed using commercially available tetramisole (0.1 to 5 mol %). Using OTMS-quinidine as the Lewis base gives preferential access to an anti-configured pyrrolidine in high enantioselectivity.

Kinetic resolution of N-acyl-thiolactams via catalytic enantioselective deacylation.

Methanolysis of N-acyl-thiazolidin-2-thiones and -oxazolidin-2-thiones in the presence of acyl transfer catalyst benzotetramisole (BTM) proceeds in a highly enantioselective fashion thus enabling kinetic resolution of these substrates.

Determination of absolute configuration of secondary alcohols using thin-layer chromatography.

A new implementation of the competing enantioselective conversion (CEC) method was developed to qualitatively determine the absolute configuration of enantioenriched secondary alcohols using thin-layer chromatography. The entire process for the method requires approximately 60 min and utilizes micromole quantities of the secondary alcohol being tested. A number of synthetically relevant secondary alcohols are presented. Additionally, (1)H NMR spectroscopy was conducted on all samples to provide evidence of reaction conversion that supports the qualitative method presented herein.

Origin of enantioselectivity in benzotetramisole-catalyzed dynamic kinetic resolution of azlactones.

Density functional theory (DFT) calculations were performed to investigate the origins of enantioselectivity in benzotetramisole (BTM)-catalyzed dynamic kinetic resolution of azlactones. The transition states of the fast-reacting enantiomer are stabilized by electrostatic interactions between the amide carbonyl group and the acetate anion bound to the nucleophile. The chiral BTM catalyst confines the conformation of the α-carbon and the facial selectivity of the nucleophilic attack to promote such electrostatic attractions.

Kinetic resolution of α-substituted alkanoic acids promoted by homobenzotetramisole.

A new method for catalytic nonenzymatic kinetic resolution of α-substituted alkanoic acids has been developed, which relies on their activation with DCC followed by enantioselective alcoholysis of the intermediate symm-anhydrides in the presence of the amidine-based catalyst homobenzotetramisole (HBTM). Moderate to excellent selectivity factors (s=5-96) have been obtained in the case of several classes of substrates, namely, α-aryl-, α-aryloxy/alkoxy-, α-halo-, α-azido-, and α-phthalimido-alkanoic acids. Under similar conditions, α-(arylthio/alkylthio)-alkanoic acids undergo dynamic kinetic resolution providing corresponding esters in up to 92% ee and up to 93% yield.

Kinetic resolution of N-acyl-ß-lactams via benzotetramisole-catalyzed enantioselective alcoholysis.

The first nonenzymatic kinetic resolution of ß-lactams has been achieved. Alcoholysis of their N-aroyl derivatives in the presence of a simple chiral acyl transfer catalyst, benzotetramisole, produces ß-amino acid derivatives with excellent enantioselectivity.

Silylation-based kinetic resolution of monofunctional secondary alcohols.

The nucleophilic small molecule catalyst (-)-tetramisole was found to catalyze the kinetic resolution of monofunctional secondary alcohols via enantioselective silylation. Optimization of this new methodology allows for selectivity factors up to 25 utilizing commercially available reagents and mild reaction conditions.

Kinetic resolution of racemic alpha-arylalkanoic acids with achiral alcohols via the asymmetric esterification using carboxylic anhydrides and acyl-transfer catalysts.

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic alpha-substituted carboxylic acids using achiral alcohols, aromatic or aliphatic carboxylic anhydrides, and chiral acyl-transfer catalysts. The combination of 4-methoxybenzoic anhydride (PMBA) or pivalic anhydride with the modified benzotetramisole-type catalyst ((S)-beta-Np-BTM) is the most effective for promotion of the enantioselective coupling reaction between racemic carboxylic acids and a novel nucleophile, bis(alpha-naphthyl)methanol, to give the corresponding esters with high ee's. This protocol was successfully applied to the production of nonracemic nonsteroidal anti-inflammatory drugs from racemic compounds utilizing the transacylation process to generate the mixed anhydrides from the acid components with the suitable carboxylic anhydrides.

Benzotetramisole-catalyzed dynamic kinetic resolution of azlactones.

Enantioselective acyl transfer catalyst benzotetramisole (BTM) has been found to promote dynamic kinetic resolution of azlactones providing di(1-naphthyl)methyl esters of alpha-amino acids with up to 96% ee.

Homobenzotetramisole: an effective catalyst for kinetic resolution of aryl-cycloalkanols.

Homobenzotetramisole (HBTM), a ring-expanded analogue of the previously reported catalyst BTM, displays higher catalytic activity and a different structure-selectivity profile. It displays good enantioselectivities in kinetic resolution of secondary benzylic alcohols but is particularly effective for 2-aryl-substituted cycloalkanols.

Kinetic resolution of propargylic alcohols catalyzed by benzotetramisole.

[reaction: see text] Kinetic resolution of variously substituted secondary propargylic alcohols catalyzed by benzotetramisole (BTM) proceeds with selectivity factors up to 32, the highest ever achieved with nonenzymatic catalysts for this class of substrates.

Benzotetramisole: a remarkably enantioselective acyl transfer catalyst.

[reaction: see text] A commercially available pharmaceutical, tetramisole, was found to be a competent enantioselective acylation catalyst. Its benzannellated analogue, benzotetramisole (BTM), produced outstanding enantioselectivities in kinetic resolution of secondary benzylic alcohols.

Enantioseparations by capillary electro-chromatography: differences exhibited by normal- and reversed-phase versions of polysaccharide stationary phases.

The influence of using normal-phase and reversed-phase versions of four commercial polysaccharide stationary phases on chiral separations was investigated with capillary electrochromatography (CEC). Both versions of the stationary phases, Chiralcel OD, OJ, and Chiralpak AD, AS were tested for the separation of two basic, two acidic, a bifunctional, and a neutral compound. Different background electrolytes were used, two at low pH for the acid, bifunctional and neutral substances, and three at high pH for the basic, bifunctional and neutral ones. This setup allowed evaluating differences between both stationary-phase versions and between mobile-phase compositions on a chiral separation. Duplicate CEC columns of each stationary phase were in-house prepared and tested, giving information about the intercolumn reproducibility. In general, reversed-phase versions of the current commercial polysaccharide stationary phases are found to be best for reversed-phase CEC, even though at high pH no significant differences were seen between both versions. Most differences were observed at low pH. For acidic compounds, it was seen that an ammonium formate electrolyte performed best, which is also an excellent electrolyte if coupling with mass spectrometry is desired. For basic, bifunctional and neutral compounds, no significant differences between the three tested electrolytes were observed at high pH. Here, a phosphate buffer is preferred as electrolyte because of its buffering capacities. However, if coupling to mass spectrometry is wanted, the more volatile ammonium bicarbonate electrolyte can be used as an alternative.

Facile colorimetric methods for the quantitative determination of tetramisole hydrochloride.

A facile, rapid and sensitive methods for the determination of tetramisole hydrochloride in pure and in dosage forms are described. The procedures are based on the formation of coloured products with the chromogenic reagents alizarin blue BB (I), alizarin red S (II), alizarin violet 3R (III) and alizarin yellow G (IV). The coloured products showed absorption maxima at 605, 468, 631 and 388 nm for I-IV, respectively. The colours obtained were stable for 24 h. The colour system obeyed Beer's law in the concentration range 1.0-36, 0.8-32, 1.2-42 and 0.8-30 microg ml(-1) respectively. The results obtained showed good recoveries with relative standard deviations of 1.27, 0.96, 1.13 and 1.35%, respectively. The detection and determination limits were found to be 1.0 and 3.8, 1.2 and 4.2, 1.0 and 3.9 and finally 1.4 and 4.8 ng ml(-1) for I-IV complexes, respectively. Applications of the method to representative pharmaceutical formulations are represented and the validity assessed by applying the standard addition technique, which is comparable with that obtained using the official method.

Kinetic comparison of tissue non-specific and placental human alkaline phosphatases expressed in baculovirus infected cells: application to screening for Down's syndrome.

BACKGROUND: In humans, there are four alkaline phosphatases, and each form exhibits a characteristic pattern of tissue distribution. The availability of an easy method to reveal their activity has resulted in large amount of data reporting correlations between variations in activity and illnesses. For example, alkaline phosphatase from neutrophils of mothers pregnant with a trisomy 21 fetus (Down's syndrome) displays significant differences both in its biochemical and immunological properties, and in its affinity for some specific inhibitors. RESULTS: To analyse these differences, the biochemical characteristics of two isozymes (non specific and placental alkaline phosphatases) were expressed in baculovirus infected cells. Comparative analysis of the two proteins allowed us to estimate the kinetic constants of denaturation and sensitivity to two inhibitors (L-p-bromotetramisole and thiophosphate), allowing better discrimination between the two enzymes. These parameters were then used to estimate the ratio of the two isoenzymes in neutrophils of pregnant mothers with or without a trisomy 21 fetus. It appeared that the placental isozyme represented 13% of the total activity of neutrophils of non pregnant women. This proportion did not significantly increase with normal pregnancy. By contrast, in pregnancies with trisomy 21 fetus, the proportion reached 60-80% of activity. CONCLUSION: Over-expression of the placental isozyme compared with the tissue-nonspecific form in neutrophils of mother with a trisomy 21 fetus may explain why the characteristics of the alkaline phosphatase in these cells is different from normal. Application of this knowledge could improve the potential of using alkaline phosphatase measurements to screen for Down's syndrome.

Partitioning of (+-)-5,6-dihydro-6-phenyl-2-n-alkyl-imidazo- [2,1-b]thiazoles into large unilamellar liposomes: a steady-state fluorescence quenching study.

The interaction of the tetramisole derivative (+-)-5,6-dihydro-6-phenyl-imidazo[2,1-b]thiazole and a number of its 2-n-alkyl homologues (-ethyl through -n-pentyl and -n-heptyl) with large unilamellar phosphatidylcholine/phosphatidylethanolamine/dipalmitoylphosphatidic acid (2:1:0.06, w/w) vesicles was studied by means of steady-state fluorescence quenching using 8-(2-anthryl)octanoic acid as membrane probe. Linear Stern-Volmer plots were obtained for each derivative, indicating dynamic quenching. The slopes of the plots decreased with increasing liposomal concentration. For four short-chain homologues (-H, -ethyl, -n-propyl and -n-butyl), the respective membrane partition coefficients Kp and bimolecular quenching rate constants kq were determined from the plots of the reciprocal of the apparent quenching rate constant (kappq)-1 against the lipid volume fraction alpha L of the liposomes. The partition coefficients increased with increasing chain-length of the tetramisoles. A linear relationship was found between the free energy of partitioning and the number of methylene units of the homologues (-delta G degrees per methylene group = 1.6 +/- 0.1 kJ mol-1). For the n-pentyl and n-heptyl derivatives, the fluorescence quenching technique did not allow one to determine their membrane partition coefficients. Analysis of the fluorescence intensity measurements with Scatchard plots gave further evidence for the partitioning nature of the tetramisole derivatives' association with the liposomal membranes.