Preparation and configuration of racemic and optically active analgesic cycloaminoalkylnaphthalenes

Cycloaminoalkylnaphthalene 3 shows interesting opioid‐like analgesic properties. It possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with receptors is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (2R,3S/2S,3R) racemate and the (2R,3S) and (2S,3R) enantiomers of the 1,2‐dimethyl‐3‐[2‐(6‐hydroxynaphthyl)]‐3‐hydroxypyrrolidine 3 is considered and the determination of absolute configuration is described. The (2R,3S/2S,3R)‐ 3 racemate and the (2R,3S)‐ 3 and (2S,3R)‐ 3 enantiomers were prepared by reaction of the racemic and optically active 1,2‐dimethyl‐3‐pyrrolidone 2, respectively, with the lithiation product obtained from 2‐bromo‐6‐tetrahydropyranyloxy‐naphthalene 1 and acidic hydrolysis. The above‐mentioned enantiomers of 3 were also obtained by optical resolution via fractional crystallization of the salts with d ‐ and l ‐tartaric acids. The configuration of the optically active compounds was determined by X‐ray analysis of a crystal of (−)‐(2S,3R)‐ 3 · HCl · H₂O. The pharmacological test HPT showed that (−)‐(2S,3R)‐ 3 · HCl · H₂O enantiomer is able to induce opioid‐like analgesia with a relative potency 1.5 times that of (2R,3S/2S,3R)‐ 3 and ∼1.5 times that of morphine. Chirality 11:21–28, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis and absolute configuration of the stereoisomers of [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate,a muscarinic antagonist

The compound [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate 1 is a muscarinic antagonist characterized by the presence of three chiral atoms and eight possible stereoisomers. The binding affinities to the five cloned m₁–m₅ muscarinic receptors of the stereoisomers of 1 were previously investigated and proved to be related to the chirality of the molecules. The eight isomers are prepared through the synthesis of their racemates followed by chemical resolution as (+) and (−) tartrate or (+) and (−) dibenzoyltartrate salts. The isomers with cis-configuration of OH and COOH substituents of the cyclohexane are also obtained by coupling optically active (1S, 2S) or (1R,2R)-1-hydroxy-[1,1′-bicyclohexyl]-2-carboxylic acid with (S)- or (R)-1-diethylamino-2-propanol. Chiral GC and HPLC methods are used to determine their optical purity. The absolute configurations of the four cis- and four trans-isomers are established by stereospecific synthesis and X-ray crystallographic data. Chirality 9:713–721, 1997. © 1997 Wiley-Liss, Inc.     

Asymmetric transformation of a racemic α-(phthalimidooxy)arylacetic ester by a combination of preferential crystallization and simultaneous racemization

An asymmetric transformation of racemic t-butyl 2-(3,4-O-carbonyldioxy-phenyl)-2-(phthalimidooxy)acetate [(RS)- 2b ] into one of its optically active forms was carried out by a combination of preferential crystallization of a desired enantiomer and the simultaneous racemization of the antipode. (R)- 2b was easily racemized in diethylketone in the presence of a small amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Under the conditions for racemization, the asymmetric transformation was achieved successfully to give (S)- 2b with 84% optical purity in 80% yield. A potent antipseudomonal cephalosporin M-14659 ( 1 ) was prepared from the pure (S)- 2b which was obtained by the recrystallization of the crude (S)- 2b . © 1993 Wiley-Liss, Inc.     

New optically active 1,3-oxathiolanes

cis- and trans-5-Ethoxy-1,3-oxathiolane-2-carboxylic acids were obtained in pure form. The cis isomer was resolved into its enantiomers through diastereoisomeric salt formation with enantiomerically pure α-methylbenzylamine. Reduction of the salt followed by benzoylation led to 2-benzoyloxymethyl-5-ethoxy-2(R)-5(S)-1,3-oxathiolane and 2-benzoyloxymethyl-5-ethoxy-2(S)-5(R)-1,3-oxathiolane, useful intermediates in nucleoside chemistry. © 1993 Wiley-Liss, Inc.     

Assignment of the absolute configuration of [n]-ladderanes by TD-DFT optical rotation calculations

In this study, we report theoretical specific rotation values for a series of cis-/trans-alkylated-[5]-ladderanes and cis-/trans-methylated-[n]-ladderanes. Using time-dependent density functional response theory optical rotation calculations, we can assign (+) and (-) optical rotation signs to trans-(S)-alkyl-[5]-ladderane and trans-(R)-alkyl-[5]-ladderane configurations, respectively. In order to qualitatively validate our absolute configuration predictions, we computed optical rotation values at three different levels of theory--B3LYP, RI-BP86, and Hartree-Fock--using the aug-cc-pVDZ basis set. We observe a novel rung-parity-controlled oscillatory optical rotatory phenomenon in our computations, which, to the best of our knowledge, has never been reported or observed before. Furthermore, this preliminary analysis of optical rotation properties in this class of compounds should facilitate the correct absolute stereochemical assignment of natural and synthetic ladderanes, such as the trans-isomer of pentacyclic C(20)-fatty acid methyl ester (pentacycloanammoxic methyl ester), without the need for derivatization, in particular for cases where NMR or X-ray crystal structures are not readily available.     

Facile preparation of optically active jasmonates and their biological activities in rice

A facile and efficient method has been developed for the optical resolution of racemic jasmonic acid (JA) on a relatively large scale and was successfully utilized for the preparation of optically pure (+)-JA and (?)-JA. We indicated that (+)-JA has lower growth inhibitory activity than (?)-JA in the rice seedling growth test and confirmed in line with an earlier observation that their respective biologically-active forms, (+)-JA-Ile and (?)-JA-Ile, show comparable inhibitory activities. We compared the metabolism of (+)-JA and (?)-JA into (+)-JA-Ile and (?)-JA-Ile, respectively, in the JA-deficient rice cpm2, and found that the exogenously applied (+)-JA was metabolized to the corresponding Ile conjugate less efficiently as compared with (?)-JA. Such metabolic rate difference may cause a discrepancy between biological potencies of (+)-JA and (?)-JA in rice.

Abbreviations: FW: fresh weight; Ile: isoleucine; JA: jasmonic acid; JA-Ile: jasmonoyl-l-isoleucine; LC-ESI-MS/MS: liquid chromatography and electrospray ionization tandem mass spectrometry; MeJA: methyl jasmonate; OPDA: 12-oxophytodienoic acid     

Carbohydrate analysis of bacterial polysaccharides by high-pH anion-exchange chromatography and online polarimetric determination of absolute configuration

A significant problem in structure determination of complex carbohydrates, especially for bacterial polysaccharides, is determination of the absolute configuration of the component monosaccharides. A number of analytical methods have been used for this purpose but, as a result of the wide variety of chemical properties of sugars found in complex polysaccharides, no single method is universally applicable. High-resolution gas chromatography of volatile derivatives with chiral reagents is the most widely used method. Optical activity, although direct and simple, lacks sensitivity generally requiring a large quantity of pure monosaccharide. We report a combination of high-performance anion-exchange chromatography (HPAEC) with combined electrochemical pulsed amperometric detection and in-line detection of optical rotation with an in-line laser polarimeter for analysis of a number of sugars found in complex polysaccharides. We show that application of the method for analysis of capsular polysaccharides of several gram-positive and gram-negative pathogenic bacteria provides useful information simultaneously on carbohydrate composition and the enantiomeric configuration of component sugars.     

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.     

Absolute configuration of eschscholtzxanthin

The chirality of eschscholtzxanthin (all-trans (3S,3′S)-4′,5′-didehydro-4,5′-retro-β,βcarotene-3,3′-diol) at 3,3′ was assigned from the CD correlation of the natural material and the semi-synthetic carotenoid prepared by (NBS-dehydrogenation of natural zeaxanthin ((3R,3′R)-β,β-carotene-3,3′-diol). The δ^6(6′)-trans configuration followed from ¹H NMR evidence, including nuclear Overhauser experiments with rhodoxanthin, retrodehydro-carotene (4′,5′-didehydro-4,5′-retro-β,β-carotene) and smaller retro model compounds revealing a general preference for the δ⁶-trans configuration in retro compounds. Biosynthetic considerations are made.     

Crystal structure and absolute configuration of (+)546-[copy4Cl2]HDBT: An example of torsional isomerism

The crystal structure and absolute configuration of the (?)₅₈₉-dibenzoylmonohydrogentartrate salt of the cation [Co(pyridine)₄Cl₂]⁺ have been determined from a three-dimensional X-ray analysis. Single crystals were grown from dimethylsulfoxide: space group P2₁2₁2₁, Z = 4, and cell dimensions a = 21.463(4), b = 23.112(3), and c = 7.490(1) Å. Full-matrix least-squares refinement on F converged at R = 0.075, 196 variables and 2029 observations. The cation has pseudotetragonal coordinate geometry, with axial Cl and equatorial N atoms. The dihedral angles between the pyridine ligands and the equatorial plane are 47(1), 39(1), 50(1), and 45(1)° and torsional isomerism is responsible for the solid-state chiroptical properties of the cation. The preferential crystallization of the P atropisomer of the cation is attributed to a general electrostatic attraction between cation and anion.     

Configurational assignment of optically active hydroperoxy homoallylic alcohols and the corresponding diols by circular dichroism and multidimensional gas chromatography

Allylic hydroperoxides are a class of compounds of versatile synthetic utility. Optically active diastereomeric hydroperoxy homoallylic alcohols and their corresponding diols are easily available through horseradish peroxidase (HRP)-catalyzed kinetic resolution of racemic hydroperoxides. Here we describe the assignment of the absolute configuration of the optically active products and substrates obtained after HRP-catalysis by the circular dichroism exciton chirality method. Moreover, the analytical-scale separation of the enantiomers based on multidimensional gas chromatography on chiral columns is presented. Since the enantiomeric elution order on the ciral columns was constituted, the absolute stereochemistry of optically active allylic diols can easily be deduced by their retention times on β-cyclodextrins. Chirality 9:69–74, 1997. © 1997 Wiley-Liss, Inc.     

Optical rotation: recent advances in determining the absolute configuration

The field of optical rotations is currently undergoing a renaissance, which is a direct result of the advances in quantum mechanics and the availability of faster desktop computers. In the last few years, the field of optical rotations has taken an important role for determining the three-dimensional molecular structure (absolute configuration and conformations) with confidence. The purpose of this review is to present the latest advances in this area so that practicing chemists can utilize them in their respective areas of research and development.     

Stereospecific synthesis and absolute configuration of mexiletine

Data on the absolute configuration of mexiletine (MEX) do not appear to have been published, although in several published reports the configuration is referred to as (?)-(R) and (+)-(S), based on information from manufactures providing the drug stereoisomers. We demonstrate that (?)-MEX has the (R)-configuration by mean of a new stereospecific synthesis. X-Ray analysis of an optical active sample of (+)-MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mixture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure–activity relationships. We also report the NMR analysis in presence of Eu(hfc)₃ as shift reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well-known chiral HPLC methods. © 1994 Wiley-Liss, Inc.     

Absolute configuration of the ocimene monoterpenoids from Artemisia absinthium

The absolute configuration (AC) of the naturally occurring ocimenes (−)‐(3S ,5Z )‐2,6‐dimethyl‐2,3‐epoxyocta‐5,7‐diene ( 1 ) and (−)‐(3S ,5Z )‐2,6‐dimethylocta‐5,7‐dien‐2,3‐diol ( 2 ), isolated from the essential oils of domesticated specimens of Artemisia absinthium , followed by vibrational circular dichroism (VCD) studies of 1 , as well as from the acetonide 3 and the monoacetate 4 , both derived from 2 , since secondary alcohols are not the best functional groups to be present during VCD studies in solution due to intermolecular associations. The AC follows from comparison of experimental and calculated VCD spectra that were obtained by Density Functional Theory computation at the B3LYP/DGDZVP level of theory. Careful nuclear magnetic resonance (NMR) measurements were compared with literature values, providing for the first time systematic ¹H and ¹³C chemical shift data. Regarding homonuclear ¹H coupling constants, after performing a few irradiation experiments that showed the presence of several small long‐range interactions, the complete set of coupling constants for 3 , which is representative of the four studied molecules, was determined by iterations using the PERCH software. This procedure even allowed assigning the pro ‐R and pro ‐S methyl group signals of the two gem ‐dimethyl groups present in 3 .     

Synthesis and cytotoxic and analgesic activities of some 1, 5-diaryl-3-ethoxycarbonylpyrrole derivatives

Some 1,5-diaryl-3-ethoxycarbonyl-2-methylpyrrole derivatives were obtained by reacting 1-aryl-3-ethoxycarbonylpent-1,4-diones and a suitable aniline derivative or sulfanilamide under Paal-Knorr pyrrole synthesis conditions. The cytotoxicity of the compounds was tested and all compounds, except for compound 2 h, showed a time-dependent increase in cytotoxic activity. Analgesic activities of the compounds were determined by using the tail-flick and tail-immersion methods; some of the compounds showed potent analgesic activity.     

Pimarane diterpenes: Natural source,stereochemical configuration,and biological activity

Plants and fungi are seemingly inexhaustible sources of interesting natural products with remarkable structural and biological diversity. One of the most important groups is the terpenes, ubiquitous natural products that are generated by 2 now well‐established biosynthetic pathways: the older mevalonate and the more recently discovered 1‐deoxyxylulose‐5‐phosphate. Among the diterpenes, the pimarane diterpenes are a very representative subgroup with several and interesting biological activities resulting from different functional group modifications. In this review, we outline the method of their structure determination, mainly spectroscopic results, their absolute configuration, and structure‐activity relationships, were reported, as well as the mode of action for selected examples from plants, marine organisms, and fungi. The pimarane, isopimarane, and ent‐pimarane diterpenes covered in this review have a wide range of biological activities including antimicrobial, antifungal, antiviral, phytotoxic, phytoalexin, cytotoxicity, and antispasmodic and relaxant effects.     

Synthesis and stereochemical characterization of optically active 1,2-diarylethane-1,2-diols: useful chiral controllers in the Ti-mediated enantioselective sulfoxidation

The series of phenylsubstituted 1,2-diphenylethane-1,2-diols 2a-h was prepared in high chemical (70--80%) and optical yields (approximately 90%) by Sharpless syn-dihydroxylation of the corresponding (E)-1,2-diarylethenes, in turn obtained by McMurry or Wittig reactions. The enantiomeric excesses of the samples were determined by HPLC analysis using Chiralcel OD chiral stationary phase (CSP). This CSP was able to resolve all the diols, except for 2g, with alpha values ranging between 1.10--1.64. In all cases the (R,R) antipode was eluted first. (R,R) absolute configuration was assigned to the dextrorotatory (CHCl(3)) diols 2a--h by analyzing the CD spectra of their 2,2-dimethyl-1,3-dioxolanes 3a--h. In fact, the CD spectra of all these dioxolanes present a positive couplet (210--180 nm range) which can be nonempirically related to an (R,R) absolute configuration of the two stereocenters.     

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Synthesis,anti-inflammatory,analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC₅₀ value 31.59 μg/mL.