Syntheses of 2-Deoxy-2-[(2R,3S)-2-fluoro-3-hydroxytetradecanamido]-3-O-[(3R)-3-hydroxytetradecanoyl]-4-O-phosphono-D-glucopyranose and Its (2S,3R)-Isomer

2-Deoxy-2-[(2R,3S)-2-fluoro-3-hydroxytetradecanamido]-3-O-[(3R)-3-hydroxytetradecanoyl]-4-O-phosphono-D-glucopyranose and its (2S,3R)-isomer were respectively synthesized from allyl 2-[(2R,3S)-3-(benzyloxycarbonyloxy)-2-fluorotetradecanamido]-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside and its corresponding (2S,3R)-isomer. Both target compounds did not activate macrophage, but the (2S,3R)-analogue strongly inhibited the binding of LPS to macrophage.     

Absolute configuration of (+)-α-dihydrotetrabenazine,an active metabolite of tetrabenazine

Chiral column liquid chromatography and enantiospecific enzymatic hydrolysis were utilized to separate the enantiomers of α- and β-dihydrotetrabenazine and α-9-O-desmethyldihydrotetrabenazine, three benzo[a]quinolizines derived from the amine-depleting drug tetrabenazine. An X-ray crystal structure analysis of (−)-α-9-O-desmethyldihydrotetrabenazine gave an absolute structure of that compound as the 2S, 3S, 11bS isomer. Therefore, (−)-α-dihydrotetrabenazine also has the 2S, 3S, 11bS absolute configuration. (+)-α-Dihydrotetrabenazine, the single biologically active isomer from the metabolic reduction of tetrabenazine, thus has the absolute configuration of 2R, 3R, 11bR. For further in vitro and in vivo studies of the vesicular monoamine transporter, it is now possible to use the single enantiomer of radiolabeled α-dihydrotetrabenazine. Chirality 9:59–62, 1997. © 1997 Wiley-Liss, Inc.     

Synthesis of hydantoin analogues of (2S,3R,4S)-4-hydroxyisoleucine with insulinotropic properties

The first synthesis of an optically pure (2R,3R,4S)-hydantoin 2, analogue of (2S,3R,4S)-4-hydroxyisoleucine, was achieved in two steps in un-optimized 35% overall yield from previously reported aldehyde synthon 1. (2R,3R,4S)-Hydantoin is stable at acidic pH. This solves the major drawback of (2S,3R,4S)-4-hydroxyisoleucine that easily cyclizes into inactive lactone. Furthermore, (2R,3R,4S)-hydantoin stimulates the insulin secretion by 150% at 25 μM compared with 4-hydroxyisoleucine and insulin secretagogue drug repaglinide. In view of its stability and biological activity, (2R,3R,4S)-hydantoin represents a good candidate for type-2 diabetes management and control.     

Synthesis of Both the Enantiomers of 3-Octanol,the Pheromone of Various Species of Ants

(2S,3R,1′S,2′S)-Serricorole (1) and (2S,3R,1′R)-serricorone (2), sex pheromone components of the cigarette beetle (Lasioderma serricorne F.), were synthesized, starting from the enantiomers of methyl 3-hydroxypentanoate. The stereochemistry of the naturally occurring 1 was determined to be 2S,3R,1′S,2′S, and that of 2 to be 2S,3R,1′RS by comparing between the CD spectra of the natural and synthetic samples.     

Stereoselective Synthesis of a Promising Flower-Inducing KODA Analog, (9R,12S,13R,15Z)-9-Hydroxy-12,13-methylene-10-oxooctadec-15-enoic Acid

Stereoselective synthesis of a promising flower-inducing 9,10-ketol octadecadienoic acid (KODA) analog, (9R,12S,13R,15Z)-9-hydroxy-12,13-methylene-10-oxooctadec-15-enoic acid, was designed to obtain the desired stereoisomer via coupling between chiral sulfone and aldehyde segments. A known chiral cyclopropane derivative was converted to the sulfone segment via carbon-chain elongation and sulfonylation. Dec-9-en-1-ol was converted to the aldehyde segment, whose C-9 configuration was introduced by Sharpless asymmetric dihydroxylation. Coupling of the both segments and subsequent assembly gave the desired (9R,12S,13R,15Z)-analog. The (9S,12S,13R,15Z)-analog was also synthesized by using the enatiomeric aldehyde segment. This strategy made it possible to synthesize the remaining stereoisomeric analogs.     

Synthesis of ethyl-(3R,5S)-dihydroxy-6-benzyloxyhexanoates via diastereo- and enantioselective microbial reduction: Cloning and expression of ketoreductase III from Acinetobacter sp. SC 13874

Previously we have demonstrated the reduction of ethyl and t-butyl diketoesters 1 to the corresponding syn-(3R,5S)-dihydroxy esters 2a by Acinetobacter sp. 13874. The syn-(3R,5S)-dihydroxy ester 2a was obtained with an enantiomeric excess (e.e.) of 99% and a diastereomeric excess (de) of 63%. In this report, we identified a gene encoding desired ketoreductase III which catalyzed the diastereoselective reduction of diketoesters 1 to syn-(3R,5S)-dihydroxy esters 2a and describe cloning and expression of ketoreductase III into Escherichia coli. Cells or extracts of recombinant E. coli efficiently reduced the diketoester 1 to the corresponding syn-(3R,5S)-dihydroxy ester 2a in 99.3% yield, 100% e.e., and 99.8% de.     

Enantioselective Degradation of (2RS, 3RS)‐Paclobutrazol in Rat Liver Microsomes

Paclobutrazol, with two stereogenic centers, but gives only (2R, 3R) and (2S, 3S)‐enantiomers because of steric‐hindrance effects, is an important plant growth regulator in agriculture and horticulture. Enantioselective degradation of paclobutrazol was investigated in rat liver microsomes in vitro. The degradation kinetics and the enantiomer fraction were determined using a Lux Cellulose‐1 chiral column on a reverse‐phase liquid chromatography–tandem mass spectrometry system. The t_1/2 of (2R, 3R)‐paclobutrazol is 18.60 min, while the t_1/2 of (2S, 3S)‐paclobutrazol is 10.93 min. Such consequences clearly indicated that the degradation of paclobutrazol in rat liver microsomes was stereoselective and the degradation rate of (2S, 3S)‐paclobutrazol was much faster than (2R, 3R)‐paclobutrazol. In addition, significant differences between the two enantiomers were also observed in enzyme kinetic parameters. The V_max of (2S, 3S)‐paclobutrazol was more than 2‐fold of (2R, 3R)‐paclobutrazol and the Cl_int of (2S, 3S)‐paclobutrazol was higher than that of (2R, 3R)‐paclobutrazol after incubation in rat liver microsomes. These results may have potential implications for better environmental and ecological risk assessment for paclobutrazol. Chirality 27:344–348, 2015. © 2015 Wiley Periodicals, Inc.     

Determination of R- and S-3-methyl-2-oxopentanoate enantiomers in human plasma: suitable method for label enrichment analysis

A sensitive method for the determination of S- and R-3-methyl-2-oxopentanoate enantiomers (KMV, (α-keto-β-methylval-erate) in physiological fluids suitable for isotope enrichment analysis is described: after extraction with acid, 2-oxo acids are separated from interfering amino acids by cation-exchange chromatography. Reductive amination of the branched-chain 2-oxo acids by use of - leucine dehydrogenase yields the corresponding -amino acids. -Isoleucine and -alloisoleucine which are formed from S- and R-3-methyl-2-oxopentanoate, respectively, are then quantified by amino acid analysis. The method was used for determination of the R-/S-3-methyl-2-oxopentanoate ratio in plasma of healthy subjects and patients with diabetes mellitus and maple syrup urine disease. Applicability for gas chromatographic-mass spectrometric analysis of ¹³C-label enrichment in plasma S-3-methyl-2-oxopentanoate is demonstrated.     

Geographic variation in the field response of male European pine sawflies, Neodiprion sertifer, to different pheromone stereoisomers and esters

The European pine sawfly, Neodiprion sertifer (Geoffroy) (Hymenoptera: Diprionidae), is a widespread and economically important forest insect. The sex pheromone communication system of this species has been previously investigated in North America, Japan and Europe, with the acetate or propionate of the alcohol (2S,3S,7S)-3,7-dimethyl-2-pentadecanol (diprionol) shown to be the main pheromone component. In some locations, male attraction either increased or decreased by the addition of the (2S,3R,7R)-diprionyl acetate isomer. However, these studies were made with different batches of synthetic pheromones, with different types of traps and according to different procedures, so the observed differences might not reflect true geographic variation. Here we investigate the geographic pattern of male sawfly response by using identical chemicals, traps and experimental procedures at eight field sites ranging from Japan in the east to Canada in the west. We found an increased inhibitory effect of the (2S,3R,7R)-isomer from Japan and Siberia to Europe. At the eastern sites, increasing amounts of the (2S,3R,7R)-isomer up to and equal to the amount of the (2S,3S,7S )-isomer, did not influence the trap catch, whereas at sites in Europe, as little as 1% of the (2S,3R,7R)-isomer almost completely inhibited the attraction. The response of the North American population was intermediate. The only site in which the (2S,3R,7R)-isomer was essential for the attraction of males was in Siberia. A similar pattern was found for the (2S,3R,7S)-isomer. Both the acetate and the propionate form of the (2S,3S,7S)-isomer were attractive by themselves in Japan, Europe and North America, and neither the (2S,3R,7S)-isomer nor the (2S,3R,7R)-isomer alone were attractive, in the acetate or propionate form. We discuss the significance of our findings for the development of more efficient monitoring schemes and for the causes of population divergence and speciation in the European pine sawfly.     

Practical access to the proline analogs (S,S,S)- and (R,R,R)-2-methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation

An efficient methodology for the preparation of the α‐tetrasubstituted proline analog (S,S,S)‐2‐methyloctahydroindole‐2‐carboxylic acid, (S,S,S)‐(αMe)Oic, and its enantiomer, (R,R,R)‐(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose‐derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n‐hexane/tert‐butyl methyl ether/2‐propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Characterization of (2S,2'R,3'R)-2-(2',3'-[3H]-Dicarboxycyclopropyl)glycine Binding in Rat Brain

Abstract: [(2S,2′R,3′R)-2-(2′,3′-[³H]Dicarboxycyclopropyl)glycine ([³H]DCG IV) binding was characterized in vitro in rat brain cortex homogenates and rat brain sections. In cortex homogenates, the binding was saturable and the saturation isotherm indicated the presence of a single binding site with a K_D value of 180 ± 33 nM and a B_max of 780 ± 70 fmol/mg of protein. The nonspecific binding, measured using 100 µM LY354740, was <30%. NMDA, AMPA, kainate, l (?)-threo-3-hydroxyaspartic acid, and (S)-3,5-dihydroxyphenylglycine were all inactive in [³H]DCG IV binding up to 1 mM. However, several compounds inhibited [³H]DCG IV binding in a concentration-dependent manner with the following rank order of potency: LY341495 = LY354740 > DCG IV = (2S,1′S,2′S)-2-(2-carboxycyclopropyl)glycine > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid > (2S,1′S,2′S)-2-methyl-2-(2-carboxycyclopropyl)glycine > l -glutamate = ibotenate > quisqualate > (RS)-α-methyl-4-phosphonophenylglycine = l (+)-2-amino-3-phosphonopropionic acid > (S)-α-methyl-4-carboxyphenylglycine > (2S)-α-ethylglutamic acid > l (+)-2-amino-4-phosphonobutyric acid. N-Acetyl-l -aspartyl-l -glutamic acid inhibited the binding in a biphasic manner with an IC₅₀ of 0.2 µM for the high-affinity component. The binding was also affected by GTPγS, reducing agents, and CdCl₂. In parasagittal sections of rat brain, a high density of specific binding was observed in the accessory olfactory bulb, cortical regions (layers 1, 3, and 4 > 2, 5, and 6), caudate putamen, molecular layers of the hippocampus and dentate gyrus, subiculum, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer, reflecting its preferential (perhaps not exclusive) affinity for pre- and postsynaptic metabotropic glutamate mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to GTPγS show that [³H]DCG IV binding is probably to group II metabotropic glutamate receptors in rat brain.     

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine,and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B₁₆F₁₀, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

Enantioselective pharmacokinetics of (R)‐ and (S)‐ketamine after a 5‐day infusion in patients with complex regional pain syndrome

Introduction: This study determined the pharmacokinetics and pharmacodynamics of (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine following a 5‐day moderate dose, as a continuous (R,S)‐ketamine infusion in complex regional pain syndrome (CRPS) patients. Materials and methods: Ketamine was titrated to 10–40 mg/h and maintained for 5 days. (R)‐ and (S)‐Ketamine and (R)‐ and (S)‐norketamine pharmacokinetic and pharmacodynamic studies were performed. Blood samples were obtained on Day 1 preinfusion, and at 60–90, 120–150, 180–210, and 240–300 min after the start of the infusion, on Days 2, 3, 4, 5, and on Day 5 at 60 min after the end of infusion. The plasma concentrations of (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine were determined using enantioselective liquid chromatography–mass spectrometry. Results: Ketamine and norketamine levels stabilized 5 h after the start of the infusion. (R)‐Ketamine clearance was significantly lower resulting in higher steady‐state plasma concentrations than (S)‐ketamine. The first‐order elimination for (S)‐norketamine was significantly greater than that of (R)‐enantiomer. When comparing the pharmacokinetic parameters of the patients who responded to ketamine treatment with those who did not, no differences were observed in ketamine clearance and the first‐order elimination of norketamine. Conclusion: The results indicate that (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine plasma concentrations do not explain the antinociceptive activity of the drug in patients suffering from CRPS. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

The Structure of Leucanicidin,a Novel Insecticidal Macrolide Produced by Streptomyces halstedii

( – )-Invictolide [(3R,5R,6S,1′R)-3,5-dimethyl-6-(1′-methylbutyl)-tetrahydro-2H-pyran-2-one] was synthesized in 16 steps from 2-methylpentanal.     

Stereoselective Synthesis of the Optically Active Samin Type of Lignan from L-Glutamic Acid

The optically active samin type of lignan, (1R,2S,5R, 6S)-6-(2-methoxy-4,5-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]octan-2-ol, was stereoselectively synthesized from L-glutamic acid via (2R,3R)-2-[(1S and R)- 1-[(tert-butyldimethylsilyl)oxy]-1-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-3-[(tert-butyldiphenylsilyl)oxy]methyl-1,4-butanediol.     

α-Hydroxyphosphonate Oligonucleotides: A Promising DNA Type?

Abstract

The synthesis of monomers ( S )-1, ( R )-1 and 2 derived from (5′ S )-, (5′ R )-2′-deoxythymidine-5′-C-phosphonic acids and 2′,5′-dideoxythymidine-5′-C-phosphonic acids was elaborated. The protection of the 5′-hydroxyl by the methoxycarbonyl group was a key step of the synthesis. Prepared monomers were used for the solid-phase assembly of several types oligothymidylate 15-mers ( S )-3, ( S )-4, ( S )-5, ( R )-4 and ( R )-5 containing the chiral 3′-O-P-CH(OH)-5″ internucleotide linkage. Their hybridization properties with dA₁₅ and rA₁₅ were studied as well as their resistance against nuclease cleavage.     

Interaction Between A1 Adenosine and Class II Metabotropic Glutamate Receptors in the Regulation of Purine and Glutamate Release from Rat Hippocampal Slices

Abstract: Electrical stimulation of rat hippocampal slices evoked the release of excitatory amino acids and purines, as reflected by a time-dependent increase in the extracellular levels of glutamate and adenosine, as well as by the increased efflux of radioactivity in slices preloaded with both [¹⁴C]glutamate and [³H]adenosine. The evoked release of excitatory amino acids and purines was amplified when slices were exposed to 8-cyclopentyl-1,3-dipropylxanthine (a selective A1 adenosine receptor antagonist), (+)-α-methyl-4-carboxyphenylglycine [a mixed antagonist of metabotropic glutamate receptors (mGluRs)], or (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (a selective antagonist of class II mGluRs). In contrast, 2-chloro-N⁶-cyclopentyladenosine (CCPA; a selective A1 receptor agonist) or (2S,1R,2R,3R)-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; a selective agonist of class II mGluRs) reduced the evoked release of excitatory amino acids and purines. CCPA and DCG-IV also reduced the increase in cyclic AMP formation induced by either forskolin or electrical stimulation in hippocampal slices. The inhibitory effect of CCPA and DCG-IV on release or cyclic AMP formation was less than additive. We conclude that the evoked release of excitatory amino acids and purines is under an inhibitory control by A1 receptors and class II mGluRs, i.e., mGluR2 or 3, which appear to operate through a common transduction pathway. In addition, although these receptors are activated by endogenous adenosine and glutamate, they can still respond to pharmacological agonists. This provides a rationale for the use of A1 or class II mGluR agonists as neuroprotective agents in experimental models of excitotoxic neuronal degeneration.     

Separation of ephedrine and pseudoephedrine enantiomers using a polysaccharide‐based chiral column: A normal phase liquid chromatography–high‐resolution mass spectrometry approach

Chiral considerations are found to be very much relevant in various aspects of forensic toxicology and pharmacology. In forensics, it has become increasingly important to identify the chirality of doping agents to avoid legal arguments and challenges to the analytical findings. The scope of this study was to develop an liquid chromatography–mass spectrometry (LCMS) method for the enantiomeric separation of typical illicit drugs such as ephedrines (ie, 1S,2R(+)‐ephedrine and 1R,2S(?)‐ephedrine) and pseudoephedrine (ie, R,R(?)‐pseudoephedrine and S,S(+)‐pseudoephedrine) by using normal phase chiral liquid chromatography–high‐resolution mass spectrometry technique. Results show that the Lux i‐amylose‐1 stationary phase has very broad and balancing‐enantio‐recognition properties towards ephedrine analogues, and this immobilized chiral stationary phase may offer a powerful tool for enantio‐separation of different types of pharmaceuticals in the normal phase mode. The type of mobile phase and organic modifier used appear to have dramatic influences on separation quality. Since the developed method was able to detect and separate the enantiomers at very low levels (in pico grams), this method opens easy access for the unambiguous identification of these illicit drugs and can be used for the routine screening of the biological samples in the antidoping laboratories.     

Synthesis and Field Test of a Pheromone Mimic of the Pine Sawfly (Neodiprion sertifer)

A stereochemically pure mimic of the sex pheromone components of the pine sawfly was synthesized. Acetates of (2S,3S)- and (2S,3R)-3-methylpentadecan-2-ol were prepared, and the pheromone activity of their mixture was compared with that of a true pheromone mixture of the acetates of (2S,3S,7S)- and (2S,3R,7R)-3,7-dimethylpentadecan-2-ol. Although the potency of the true pheromone system was 50 times as high as that of the pheromone mimic, the mimic could attract a sufficient number of male sawflies in the field test.     

Production of Cephalosporin Antibiotics by Strains Belonging to the Genera Arachnomyces,Anixiopsis and Spiroidium

The absolute configuration of a phytoalexin “Safynol” (3E, 11E)-3, 11-tridecadiene-5, 7, 9-triyne-l, 2-diol (I), separated from Phytophthora drechsleri-infected safflower (Carthamus tinctorius L.) was confirmed. (R) and (S)-safynol were synthesized from 2, 3-O-isopropyli- dene-(S)- and (R)-glyceraldehyde respectively, and the (R) configuration was assigned to the natural product. The inhibitory effects of (R)- and (S)-safynol on mycelial growth of five fungi were almost the same and their ED₅₀ values ranged from 6 to 70 ppm.