Racemic Derivatives Research Articles

A Modified Synthesis of (±)-β-Aryllactic acids

The synthesis of racemic forms of the reportedly active principle of Danshen, namely (±)-β-(3,4-dihydroxyphenyl)lactic acid [(±)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid] and its seven racemic derivatives is reported

Analogues of cholecystokinin methylated in the side chain of carboxyterminal phenylalanine

In the course of our study on cholecystokinin (CCK) a series of Boc-CCK-7 was synthesized. Their carboxyterminal part was modified by phenylalanine derivatives containing 2 or 4 and 2,6 or 2,4,6 methylated aromatic side-chain. During the synthesis, the racemic phenylalanine derivatives were used and peptides containing either L- or D- methylated phenylalanine were separated using a preparative HPLC. Gall bladder contraction, anorectic, sedative and analgetic bioassays of these analogues revealed that all of them behaved as CCK-8 agonists. While the analogues containing L-form of the methylated phenylalanines had almost the same potency (80% - 130%) in comparison to CCK-8, the presence of the D-form decreased the biological activity of corresponding analogues to 8 – 62% of the CCK-8 potency. These results are in agreement with the suggestion that phenylalanine residue in C-terminus takes part in biological activity transduction only.

6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. IV. Kidney stability, serum binding and additional biological evaluation of racemic derivatives.

Sodium (5RS)-Z-6-(substituted methylene)penem-3-carboxylates (3) are extremely potent inhibitors of bacterial beta-lactamases, but some members of this group of compounds are highly bound to human serum, while others are readily degraded by renal dehydropeptidase I enzyme. Consequently, the stability of a variety of 6-(substituted methylene)penems (3) to human kidney homogenate, their binding to human serum and their activity in a mouse infection model was investigated at an early stage, and were instrumental in the selection of the 1,2,3-triazolylmethylene derivatives (e.g. 3k) as a class of compounds worthy of further evaluation.

Resolved pyrrolidine, piperidine, and perhydroazepine analogs of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide

A series of conformationally restricted analogues of the partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5; 1) was synthesized. Three of the racemic derivatives were resolved into the enantiomers. The compounds were investigated for muscarinic and antimuscarinic activity in the isolated guinea pig ileum. They were found to be fairly potent muscarinic antagonists or weak partial agonists. The new compounds were either equally or less potent than 1 in inhibiting (-)-[3H]-N-methylscopolamine binding in homogenates of the rat cerebral cortex. Thus, structural modifications to 1 in which the amide moiety and the methyl group in the butynyl chain have been joined to form a six- or seven-membered ring preserve affinity but abolish efficacy. The R enantiomers were found to have 14-79 times higher affinity to ileal muscarinic receptors than the respective antipodes. The enantiomeric affinity ratios were nearly identical in both preparations studied. As suggested by molecular mechanics calculations, the difference in affinity between the five-membered and the six- and seven-membered ring analogues may be rationalized in conformational terms.

Stereocontrol in Bakers' Yeast Reduction Leading to Natural Product Synthesis

Stereocontrol in bakers' yeast reduction can be achieved by introduction of a sulfur functional group into substrates. α-Methylthio-β-keto esters are reduced to give exclusively (3S)-3-hydroxy esters. α-Substituted β-keto thiol esters and dithioesters afford (2R,3S)-3-hydroxy esters with high diastereo-and enantioselectivity. Ketones possessing 1,3-dithiane, phenylsulfenyl, or phenylsulfonyl groups at the α-position are transformed also into the corresponding (S)-secondary alcohols. Optically pure (S)-(phenylsulfinyl)acetones can be obtained by kinetic resolution of racemic derivatives with the yeast. Diastereo- and enantioselective reduction of 1,2-diketones leading into (1S,2S)-1,2-diol derivatives can be also achieved by introduction of 1,3-dithiane, phenylsulfenyl or phenylsulfonyl groups into the α-position. Reductions of carbon-carbon double bond of sulfur-functionalized prenyl derivatives provide both chiral (R)- and (S)-C5-building blocks for terpenoid synthesis. The utility of the reduction produ...

Stereoselective dioxygenation of a racemic tryptophan derivative catalysed by chiral manganese porphyrins

The first asymmetric dioxygenation reactions of the racemic tryptophan derivatives, N-acetyl-L-(+)-[and D-(–)]-tryptophan methyl ester, are reported, in which predominant generation of methyl 2-D-acetoamido-3-(2-formamidobenzoyl)propionate has been acheived in 23.3% enantiometric excess in the cataytic system using the manganese complex of α,α,α,α-tetrakis[O-L(–)-camphanoylamido) phenyl]porphyrin.

Stereoisomers of calcium antagonists discriminate between coronary vascular and myocardial sites.

In the retrogradely perfused, paced rat heart, we studied the effects of the stereoisomers of verapamil (VER), gallopamil (GAL), devapamil (DEV) and bepridil (BEP) on the coronary flow and the maximum systolic left ventricular pressure (MSLVP). In addition, the time courses of onset and recovery of these effects were measured. The verapamil analogues showed high stereoselectivity factors (sf) for MSLVP depression in favour of the (-)-enantiomers and low sf's for coronary flow increase. Bepridil showed a low sf for both parameters with the (+)-enantiomer being more potent. In a previous study we found that in the rat heart, dihydropyridine calcium antagonists clearly possess high selectivity for the vascular isochannel site as compared to the myocardial site, whereas racemic verapamil derivatives were devoid of such selectivity. In the present study the (+)-enantiomers of all verapamil congeners revealed a marked vasoselectivity. This was not found for the (-)-isomers, which surprisingly were virtually equipotent for MSLV depression and coronary flow increase, suggesting a different voltage dependence of the two isochannel verapamil sites for the enantiomers of verapamil and its congeners. Onset and offset velocities were clearly different as well. The kinetics of coronary flow increase were identical and fast for all enantiomers studied. MSLV kinetics were slower. In particular the recovery was markedly different for the enantiomers of each drug, the more potent isomer having the lower velocity. Furthermore, the differences in recovery of MSLVP depression between the verapamil type enantiomers suggest that the recovery rate may directly reflect dissociation from the myocardial isochannel verapamil site.

Characterization of 3H-dihydroalprenolol binding to beta-adrenergic receptors of rat brain: two binding sites of racemic propranolol in displacement experiments.

The binding affinities of racemic derivatives of propranolol to β-adrenoceptors were examined by means of radioligand binding assay to determine whether racemic propranolol shows biphasic binding to β-adrenoceptors in a displacement experiment. Rat brain was used and the β-adrenoceptor binding assay was carried out with 3H-dihydroalprenolol as the radioligand. A higher affinity of l-propranolol than of d-propranolol was observed and d-and l-propranolol each gave a uniphasic curve. However, dl-propranolol showed a biphasic curve. Furthermore, a mixture of d-and l-propranolol also showed a biphasic curve. These results imply that β-adrenoceptors of rat brain may bind the d-and l-isomers at distinct sites.

Calorimetric Investigation of N-Acyl Amino Acids

Abstract The melting characteristics of N-acyl amino acids were examined using a differential scanning calorimeter (DSC). The melting-point temperature of N-dodecanoyl l-amino acid increased with the size of its amino acid residue, while the order was opposite for the Dl-amino acids. The racemic derivatives formed racemic compounds in their solid states. Each N-dodecanoyl l-amino acid had a larger enthalpy and entropy-of-fusion than its racemic isomer. Differences in the thermodynamic quantities between the optically active and racemic isomers were larger for N-dodecanoylvaline and -leucine compared with those of N-dodecanoylalanine. A mixture of these molecules were also studied. Each racemic isomer of N-dodecanoylalanine and -leucine partly formed a racemic pair in the liquid state.

Different stereoselective inhibition of monoamine oxidase-B by the R- and S-enantiomers of MD 780236.

MD 780236, a selective inhibitor of the B form of MAO behaves as an irreversible inhibitor in in-vitro conditions and mainly as a short-acting inhibitor in ex-vivo experiments. The enantiomer with the R absolute configuration (MD 240928) is fully reversible in ex-vivo conditions, whereas the S-enantiomer (MD 240931) has kept the irreversible component of the inhibition seen with MD 780236. The corresponding racemic alcohol derivative (MD 760548) is also a short-acting inhibitor of the B form of MAO; its S-enantiomer, which has an absolute configuration corresponding to that of MD 240928, has a selectivity towards the B form superior to that of the other enantiomer. The mechanism of the MAO inhibition by MD 780236 is discussed.

Structures de modeles de polyesters—I. Separation et etude par RMN [ 13C]des dihydroxy-2,3 butane, 2,4 pentane et 2,5 hexane et de leurs benzoates

[ 13C]NMR spectra have been obtained for a series of diols and benzoates, models of 2,3-dihydroxybutane, 2,4-dihydroxypentane and 2,5 dihydroxyhexane terephthalates after separation of diastereoisomers by gas and liquid-liquid chromatography. Chemical shifts for the meso and racemic derivatives have been interpreted in terms of rotational isomers. The results indicate that [ 13C]NMR is more sensitive than [ 1H]NMR for the differentiation of diastereoisomers. Carbonyl and aromatic quaternary carbon chemical shifts are sensitive to the stereochemistry of the chain (long range effects) but relaxation times and nuclear Overhauser enhancements are identical in the two diastereoisomers.

Self‐association of N‐protected α‐amino acids. Optically active and racemic N‐tert‐butyloxycarbonyl‐alanine

AbstractThe ir absorption and x‐ray diffraction analysis of N‐tert‐butyloxycarbonyl‐DL‐alanine (t‐Boc‐DL‐Ala‐OH) in the solid state has revealed a new mode of self‐association for a N‐urethanyl‐α‐amino acid, i.e., ribbons of hydrogen‐bonded cyclic dimers formed through the —COOH groups. In contrast to the recemate, a water molecule, incorporated into the crystal of the chiral t‐Boc‐D‐Ala‐OH, alters in part that hydrogen‐bonding scheme. In the two independent molecules of the unit cell of the optically active alanine derivative, as in that of the racemic derivative: (i) the conformation of the —CONH group is trans, also a new observation for a N‐urethanyl‐α‐amino acid, and (ii) the overall conformation is quasi‐extended. These findings exclude the occurrence of an oxy‐C7 peptide conformation. In solvents of high polarity, strongly solvated species predominate, as shown by ir absorption spectroscopy. In deuterochloroform nonassociated and associated species occur simultaneously. No differences were observed between the optically active and racemic derivatives. The type of self‐association near saturation seems to differ, at least in part, from that found in the anhydrous racemic compound in the crystal state.

Separation de Racemiques Nematiques en Deux Antipodes Cholesteriques

Abstract Mesomorphic compounds which may exist as enantiomers were prepared: namely (a) alkoxy-biphenylcarboxylic acids having one ssymmetric center in the ether chain (b) arylidene-p-aminocmates eaterified with an alcohol containing an asymmetric center. In these two series we observed nematic phases in the cases of racemic derivatives and cholesteric phases in the cases of enantiomers. Some compounds show two mesomorphic phases of the same kind. The different transitions are determined by microscopic observations and by calorimetric measurements. Phases diagrams between enantiomem are presented: these are charactoristic of solid solutions.

Endocrine studies of the enantiomers of a racemic dodecahydro-phenanthrene derivative.

The dodecahydro-phenanthrene derivative, 2-acetyl-7-oxo-l,2,3,4,4a, 4b,5,6,7,9,10,10a-dodecahydro-phenanthrene, has been shown in previous studies to manifest androgenic, anabolic, antiandrogenic and antigonadotropic activities. The dextro and the levo enantiomers of this phenanthrene derivative have been prepared, and both have been tested for endocrine activity concurrently with the racemate. The results obtained indicate that the dextro enantiometer is responsible for the androgenic, the anabolic, the antiandrogenic and the antigonadotropic activities of the racemate, and that the levo enantiometer is inactive.