Trans Diastereoisomers Research Articles

A Convenient Method for the Synthesis of 1,5-benzodiazepin-2-one

New 3-hydroxy-1,5-benzodiazepin-2-ones were synthesized through condensation between o- phenylenediamines with glycidic ester. Alkylation and oxidation of some of the obtained compounds were also explored in different conditions yielding various oxidized and alkylated benzodiazepines. The structural elucidation of the synthe- sized compounds was achieved by MS, NMR spectroscopy and also through X-ray diffraction analysis. The glycidic ester was thus shown to be an interesting synthon in the synthesis of new 1,5-benzodiazepines used in alkylation and oxidation reactions. Synthesis of 3-hydroxy -4-phenyl tetrahydro-1,5- benzodiazepin-2-one (4) and (5) A mixture of o-phenylenediamine 1 or its dimethylated derivative 2 (0.03 mole) and ethyl glycidate (0.03 mole) was refluxed in 80 mL of xylene during 48 hours. The obtained crude mixture was left at room temperature during one night. The trans diastereoisomers 4a or 5a which precipitate were filtered under reduced pressure.

Linear versus Angular Fischer Indole Annulation: Relative Configuration Determines Regioselectivity

AbstractFischer indole synthesis with bicyclic ketones yields regioselectively linear annulated tetracyclic products when starting from ketones with a relative trans configuration. On the other hand, starting materials with a relative cis configuration give exclusively angular annulated indole derivatives. The starting materials were prepared in optically active form in three steps by a sequence of asymmetric Michael reaction, aldol condensation, and catalytic hydrogenation. The last step yields a mixture of cis and trans diastereoisomers which can be separated by column chromatography. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A New Approach to the Synthesis of the Nonpeptide NOP Receptor Antagonist J-113397

A new synthesis that eliminates the need for chromatographic separation in order to obtain multigram quantities of J-113397, a competitive antagonist of the N/OFQ-NOP receptor system, is reported. N-Benzyl protected 4-oxopiperidinecarboxylate was used as the starting material to obtain an N-benzyl intermediate that could be resolved at a relatively early stage in the synthesis. The crucial step in the synthesis was reduction of the double bond of the β-enaminoester functionality of 1-benzyl-4-(3-ethyl-2-oxo-2,3-di-hydrobenzoimidazol-1 -yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester, since Pd/C reduction gave inseparable mixtures. It could be reduced and epimerized to the desired trans diastereoisomer in a one-pot reaction by treatment with magnesium metal in methanol.

Hybrid density functional theory study of fragment ions generated during mass spectrometry of 1,3‐dioxane derivatives

It was recently reported that the cis,cis and trans,trans diastereoisomers of four 2(r)-R-2,4(R),6(S)-trimethyl-1,3-dioxane derivatives show distinct electron ionization mass spectra. As a possible explanation for this finding, the authors suggested that the ions generated during the mass spectrometry of these compounds could follow different fragmentation patterns that initiate from different ion conformations. In this report, hybrid density functional theory methods have been used to investigate the conformational preference of three ions involved in the mass spectrometry of some 1,3-dioxane derivatives. We found that there is indeed more than one stable ion conformation for each of the investigated ions. Energy profiles along the torsional coordinates connecting the conformers are presented, and factors influencing the relative stability of ion conformations are discussed.

The line asymmetry of electron spin resonance spectra as a tool to determine the cis: trans ratio for spin-trapping adducts of chiral pyrrolines N-oxides: The mechanism of formation of hydroxyl radical adducts of EMPO, DEPMPO, and DIPPMPO in the ischemic–reperfused rat liver

Nonstereospecific addition of free radicals to chiral nitrones yields cis/ trans diastereoisomeric nitroxides often displaying different electron spin resonance (ESR) characteristics. Glutathione peroxidase–glutathione (GPx-GSH) reaction was applied to reduce the superoxide adducts (nitrone/ OOH) to the corresponding hydroxyl radical (HO ) adducts (nitrone/ OH) of two nitrones increasingly used in biological spin trapping, namely 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO) and 5-ethoxycarbonyl-5-methyl-1-pyrroline N-oxide, and of 5-diisopropoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DIPPMPO), a sterically hindered DEPMPO analogue. The method offered improved conditions to record highly resolved ESR spectra and by accurate simulation of line asymmetry we obtained clear evidence for the existence of previously unrecognized isomer pairs of cis- and trans-[DEPMPO/ OH] and [DIPPMPO/ OH]. Additional nitrone/ OH generation methods were used, i.e. photolysis of hydrogen peroxide and the Fenton reaction. We developed a kinetic model involving first- and second-order decay and a secondary conversion of trans to cis isomer to fully account for the strongly configuration-dependent behavior of nitrone/ OH. In the reductive system and, to a lower extent, in the Fenton or photolytic systems cis-nitrone/ OH was the more stable diastereoisomer. In various biologically relevant milieu, we found that the cis: trans-nitrone/ OH ratio determined right after the spin adduct formation significantly differed upon the GPx-GSH vs (Fenton or photolytic) systems of formation. This new mechanistic ESR index consistently showed for all nitrones that nitrone/ OH signals detected in the postischemic effluents of ischemic isolated rat livers are the reduction products of primary nitrone/ OOH. Thus, ESR deconvolution of cis/ trans diastereoisomers is of great interest in the study of HO formation in biological systems.

Diastereoselective Synthesis and ESR Study of 4-PhenylDEPMPO Spin Traps

[reaction: see text] The cis and trans diastereoisomers of 5-(diethoxyphosphoryl)-5-methyl-4-phenylpyrroline N-oxide (4-PhDEPMPOt 8 and 4-PhDEPMPOc 9) were prepared stereoselectively and used as spin traps for hydroxyl and superoxide radicals. The spin adduct formed by reaction of the cis stereoisomer 9with superoxide radical anion exhibited an 8-line ESR spectrum, showing only a reduced alternating line width phenomenon. This spectrum is simpler than the 12-line spectrum of DEPMPO-OOH, which exhibits a strong alternating line width phenomenon. The half-life times of the 4-PhDEPMPOc-OOH and DEPMPO-OOH adducts were of the same order: 14.5 and 15.5 min, respectively.

Synthesis of 3,4-dihydro-2H-pyrans by hetero-Diels–Alder reactions of functionalized α,β-unsaturated carbonyl compounds with N-vinyl-2-oxazolidinone

Cycloadditions of 3-aryl-2-benzoyl-2-propenenitriles and 3-phenylsulfonyl-3-buten-2-one to N-vinyl-2-oxazolidinone proceed regio- and diastereoselectively yielding cis and trans diastereoisomers of 4-aryl-3,4-dihydro-2-(2-oxo-3-oxazolidinyl)-2H-pyrans in 37-65% yield. Cycloadducts cis- were the major products. Reaction of 5-arylidene-1,3-dimethylbarbituric acids with dienophile afforded mixtures of 2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones trans and products resulted from an elimination of 2-oxazolidinone, in 50-52% yield. To confirm the experimental results, semiempirical AM1 and PM3 calculations of frontier orbital energies have been performed.

Stereoselective determination of allethrin by two-dimensional achiral/chiral liquid chromatography with ultraviolet/circular dichroism detection

A two-dimensional achiral/chiral HPLC method with circular dichroism (CD) detection was optimized for the stereochemical resolution and determination of the elution order of the eight stereoisomers of synthetic allethrin. A monolithic silica HPLC column (Chromolith, Merck, 100 mm × 4.6 mm i.d.) was put orthogonally to an enantioselective OJ Daicel column (250 mm × 4.6 mm i.d.) by means of a switching valve. The resolution of cis and trans diastereoisomers on the silica column was obtained by using a mobile phase consisting of n-hexane:tert-butyl methyl ether (96:4) (v/v) at a flow rate of 1 ml min−1. The cis and trans peaks were then switched to the enantioselective OJ column separately in two subsequent injections. The resolution of the four trans stereoisomers was accomplished by using n-hexane:tert-butyl methyl ether (90:10) (v/v), while the mobile phase composition for the four cis stereoisomers consisted of n-hexane:isopropanol (99.3:0.7) (v/v). The CD based detection system allowed the determination of the elution order on the basis of the CD signals of the single stereoisomers, together with the injection of pure stereoisomers. Under the final conditions, the validated method was applied to the determination of stereoisomeric composition and absolute configuration of the prevailing stereoisomers of real samples, i.e. commercial batches of different sources of d-allethrin.

Stereoselective determination of allethrin by two-dimensional achiral/chiral liquid chromatography with ultraviolet/circular dichroism detection

A two-dimensional achiral/chiral HPLC method with circular dichroism (CD) detection was optimized for the stereochemical resolution and determination of the elution order of the eight stereoisomers of synthetic allethrin. A monolithic silica HPLC column (Chromolith, Merck, 100 mm × 4.6 mm i.d.) was put orthogonally to an enantioselective OJ Daicel column (250 mm × 4.6 mm i.d.) by means of a switching valve. The resolution of cis and trans diastereoisomers on the silica column was obtained by using a mobile phase consisting of n-hexane: tert-butyl methyl ether (96:4) (v/v) at a flow rate of 1 ml min −1. The cis and trans peaks were then switched to the enantioselective OJ column separately in two subsequent injections. The resolution of the four trans stereoisomers was accomplished by using n-hexane: tert-butyl methyl ether (90:10) (v/v), while the mobile phase composition for the four cis stereoisomers consisted of n-hexane:isopropanol (99.3:0.7) (v/v). The CD based detection system allowed the determination of the elution order on the basis of the CD signals of the single stereoisomers, together with the injection of pure stereoisomers. Under the final conditions, the validated method was applied to the determination of stereoisomeric composition and absolute configuration of the prevailing stereoisomers of real samples, i.e. commercial batches of different sources of d-allethrin.

Synthesis of the cis diastereoisomer of 5-diethoxyphosphoryl-5-methyl-3-phenyl-1-pyrroline N-oxide (DEPMPPO c) and ESR study of its superoxide spin adduct

The cis and trans diastereoisomers of 5-diethoxyphosphoryl-5-methyl-3-phenyl-1-pyrroline N-oxide (DEPMPPO), the C(3)-phenyl analogue of DEPMPO, were prepared in three steps from phenylacetaldehyde and used in ESR-spin trapping of various carbon-, oxygen- and sulfur-centred radicals. In the case of the cis-isomer, the presence of the phenyl group cancels the alternating line width phenomenon observed for the DEPMPO–OOR (R = H, Bu t ) spin adducts. The ESR spectra of the DEPMPPO c–OOR spin adducts exhibit more straightforward patterns and are more easily assignable.

HPLC determination of sertraline in bulk drug, tablets and capsules using hydroxypropyl-β-cyclodextrin as mobile phase additive

A sensitive and stereospecific high-performance liquid chromatography (HPLC) method for determination of sertraline in bulk drug, tablets and capsules was developed. Chromatography resolution of the sertraline enantiomeric forms and trans diastereoisomers was performed on Alltima C18 (250 mm×4.6 mm i.d., 5 μm) column with hydroxypropyl-β-cyclodextrin (HP-β-CD) as mobile phase additive. The composition of the mobile phase was 68:32 (v/v) aqueous 170 mM phosphate buffer, pH 3.0 (adjusted with 85% phosphoric acid) containing 18 mM HP-β-CD/acetonitrile at a flow rate of 1.0 ml min −1. The UV detector was set at 225 nm. Calibration curves were linear ( r=0.9999, n=9) in the range of 1–120 μg ml −1 for sertraline. Limit of detection and quantitation for sertraline was 0.029 and 0.097 μg ml −1. The values of R.S.D. of repeatability and intermediate precision for bulk drug, tablets and capsules of sertraline hydrochloride were less than 1.0%.

Nonpeptide RGD Antagonists: A Novel Class of Mimetics, the 5,8‐Disubstituted 1‐Azabicyclo[5.2.0]nonan‐2‐one Lactam.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Nonpeptide RGD antagonists: A novel class of mimetics, the 5,8-disubstituted 1-azabicyclo[5.2.0]nonan-2-one lactam

The 1-azabicyclo[5.2.0]nonan-2-one lactam 1 adequately substituted on both cycles A and B as scaffolds mimics the conformationally constrained β-turn of the tripeptide RGD signaling motif of fibronectin. Using an in vitro assay, we establish that trans diastereoisomer 1b dissociates a soluble fibronectin–integrin α 5β 1 complex at concentrations comparable to those of a linear RGDS peptide as a competitor.

Dearomatizing disrotatory electrocyclic ring closure of lithiated N-benzoyloxazolidines.

Loss of aromaticity ensues when N-benzoyl oxazolidines are lithiated and undergo a 6.pi. disrotatory electrocyclization. The stereochem. of the cyclization shows it to be a new example of an electrocyclic ring closure. The cis-tricyclic products epimerize to their more stable trans diastereoisomers in aq. acid. [on SciFinder (R)]

The structure of McN-5652

The configuration of the diastereoisomers of 6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1- a]isoquinoline 1 (McN-5652) is determined and unequivocally assigned by NMR spectroscopy (NOE measurements) and an X-ray structural analysis of the trans diastereoisomer. The enantiomers of cis- 1 are separated by preparative HPLC on a chiral phase. One of the enantiomers of cis- 1 represents the precursor for imaging the serotonin 5-HT transporter with positron emission tomography (PET).

Synthesis of 3,4-Dihydro-2H-pyrans by Hetero-Diels-Alder Reactions of Functionalized α,β-Unsaturated Carbonyl Compounds with Styrenes

Abstract Cycloadditions of 3-aryl-2-benzoyl-2-propenenitriles 1a,b to styrene (2a) and its methyl or methoxy-substituted derivatives 2b-d proceed regio- and diastereoselectively yielding cis and trans diastereoisomers of 2,4,6-triaryl-3,4-dihydro-2H-pyran-5-carbonitriles 3 and 4 in 59-72% yield. Cycloadducts cis-3 were the major products. Reaction of 5-(4-nitrobenzylidene)-1,3-dimethylbarbituric acid (5) with styrenes 2a-d afforded diastereoisomeric mixtures of 2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones cis-6 and trans-7 in 71 - 78% yield.

Complexation and conformational analysis studies of 11-membered ring crown trithioethers

We wish to report the synthesis of a series of transition metal complexes with two isomeric 11-membered ring trithioethers, 1,4,7-trithiacycloundecane (11S3-147) and 1,4,8-trithiacycloundecane (11S3-148). With respect to Ni(II), Fe(II), Co(II), Co(III), and Ru(II), the two function as relatively strong field ligands, but their ligand field strengths fall between the stronger field and smaller ring trithioether ligands such as 1,4,7-trithiacyclononane(9S3) and the larger ring and weaker field ligand, 1,5,9-trithiacyclododecane(12S3). Complexes of both ligands with first row transition metals are much more sensitive to solvolysis reactions than the analogous 9S3 complexes. 13C NMR spectroscopy shows that there is little stereoisomer selectivity between the cis and trans diastereoisomers for the bis complexes of 11S3-147. The complex [Pd(11S3-147) 2] 2+ does not display the unusual spectroscopic and electrochemical properties observed in smaller ring Pd(II) complexes. Its absorption spectrum does not show any d–d transitions and an irreversible ligand-centered oxidation is observed. A conformational analysis study for both macrocycles showed that neither has a lowest energy conformation suitable for tridentate coordination. The effects of the lack of pre-organization dominate the complexation behavior of the two macrocyclic ligands.

Comparative action of carbocyclic thromboxane A 2 stereoisomers on platelets

Stereospecific requirements for the interaction of the thromboxane A 2 carbocyclic mimetic CTA 2 1 with the human platelet PGH 2/TXA 2 receptor have been explored. The two pairs of trans- 1, 2 and cis- 3, 4 side chain diastereoisomers were synthesised and evaluated for agonist and antagonist activity in human platelet rich plasma. Interestingly, the natural and unnatural trans diastereoisomers, both possessed potent aggregatory activity and equipotently inhibited platelet responses to subsequent addition of agonists, whereas, the respective unnatural cis isomers proved only weakly active or inert.

Palladium-Catalyzed Self-Cross Coupling ofo-Bromo-trans-stilbenes To Yield 9,10-Bis(arylmethylene)-9,10-dihydroanthracenes©

Under Palladium catalysis [Pd(OAc)2, K2CO3, LiCl, Bu4NBr, DMF] o-bromo-trans-stilbene (trans-7a) reacts to give 9,10-dibenzylidene-9,10-dihydroanthracene (4a) with formation of a new six-membered ring. The (Z) diastereomer crystallizes preferentially to give pure (Z)-4a, as proved by X-ray crystal structure analysis. A variety of substituted o-bromostilbenes and heterocyclic analogs 7 were prepared by Wittig olefination of o-bromobenzaldehyde with substituted benzyltriphenylphosphonium ylides, Wittig-Horner-Emmons olefination of arenecarbaldehydes with diethyl o-bromobenzylphosphonate or Wittig olefination of substituted benzaldehydes with substituted (o-bromobenzyl)-diphenylphosphonium ylides, respectively. The cis-o-bromostilbenes were photoisomerized to the trans diastereoisomers trans-7 by irradiation in the presence of diphenyl disulfide. All of these o-bromo-trans-stilbenes trans-7a–g and trans-7j, k under palladium catalysis reacted to the corresponding 9,10-bis(arylmethylene)-9,10-dihydroanthracenes 4, mostly as mixtures of (E) and (Z) diastereomers (50-97 % yield). The (Z) diastereomer of the parent 4a and the alkyl-substituted compounds 4c and 4e could be purified by simple crystallization, and in some runs, only (Z)-4a, c, e were obtained. Among the heterocyclic analogs trans-7h, i only the furyl derivative trans-7h reacted (76 % yield) cleanly, whereas the pyridine analog trans-7i gave a mixture of products from which the rather sensitive product 4i could not be isolated in pure form. The cis-o-bromostilbenes cis-7a, c cyclized to phenanthrenes under the same conditions (70-71 % yield). The UV spectra of compounds 4a, c–k are similar to that of anthracene, and so are the oxidation and reduction potentials of (Z)-4a.

Asymmetric synthesis of (2 S,3 S)- and (2 S,3 R)-3-prolinomethionines: 3-methylsulfanylmethyl-pyrrolidine-2-carboxylic acids

The synthesis of 3-prolinomethionine can be easily achieved in a diastereoselective and enantioselective way via zinc-enolate cyclisation. After transmetallation by CuCN.2LiCl, the zinc-copper derivative was reacted with S-methyl methanesulfonothioate leading in a “one-pot” procedure, to N-(α-methylbenzyl)-3-prolinomethionine benzyl ester. The α-methylbenzyl group was transformed in vinyl-oxycarbonyl and tertiobutyl-oxycarbonyl groups successively. Reprotonation of cis Voc prolinomethionine enolate at low temperature yielded the enantiomerically pure trans diastereoisomer.