Diastereoisomeric Forms Research Articles

Chiral Spiro-Tetrathiafulvalenes: Synthesis, Chiroptical Properties, Conformational Issues and Charge Transfer Complexes.

Within this work we have investigated spiro-based tetrathiafulvalenes (TTFs) obtained as mixtures of stereoisomers from racemic spiro[5.5]undeca-1,8-dien-3-one. Compared to previously described spiro-TTFs, enantiomeric and diastereoisomeric forms have been here separated by chiral HPLC and fully characterized both experimentally and theoretically. The two types of spiro-based chiral derivatives contain either one (2) or three (1) chiral centres out of each one is spiro-type. Experimental CD, supported by TD-DFT calculations, shows differences in the optical activity between the 1 and 2 and their intermediates. The low optical activity of 2 and 3 (spiro alone chirality) was attributed to the presence of two conformers in the solution (ax and eq) of opposite Cotton effect whereas in the case of 1 and 5 (spiro and stereogenic centres) the spiro chirality seems to be responsible of the Cotton effect in the high energy region whereas the R and S chirality in the low energy region. Racemic and enantiopure forms have been successfully used for the synthesis of charge transfer complexes with tetracyanoquinodimethane (TCNQ) based acceptors.

Zn(II)-to-Cu(II) Transmetalation in an Amide Functionalized Complex and Catalytic Applications in Styrene Oxidation and Nitroaldol Coupling.

The mononuclear zinc(II) complex cis-[ZnL2(H2O)2] (1; L = 4-(pyridin-3-ylcarbamoyl)benzoate) was synthesized and characterized. By soaking crystals of 1 in a mixture of DMF-H2O solution containing a slight excess of Cu(NO3)2 × 3H2O a transmetalation reaction occurred affording the related copper(II) complex trans-[CuL2(H2O)2] (2). The structures of the compounds were authenticated by single crystal X-ray diffraction revealing, apart from a change in the isomerism, an alteration in the relative orientation of the chelating carboxylate groups and of the pyridine moieties. H-bond interactions stabilize both geometries and expand them into two-dimensional (2D) networks. The transmetalation was confirmed by SEM–EDS analysis. Moreover, the thermodynamic feasibility of the transmetalation is demonstrated by density-functional theory (DFT) studies. The catalytic activities of 1 and 2 for the oxidation of styrene and for the nitroaldol (Henry) C-C coupling reaction were investigated. The copper(II) compound 2 acts as heterogeneous catalyst for the microwave-assisted oxidation of styrene with aqueous hydrogen peroxide, yielding selectively (>99%) benzaldehyde up to 66% of conversion and with a turnover frequency (TOF) of 132 h−1. The zinc(II) complex 1 is the most active catalyst (up to 87% yield) towards the nitroaldol (Henry) coupling reaction between benzaldehyde and nitro-methane or -ethane to afford the corresponding β-nitro alcohols. The reaction of benzaldehyde with nitroethane in the presence of 1 produced 2-nitro-1-phenylpropanol in the syn and the anti diastereoisomeric forms, with a considerable higher selectivity towards the former (66:34).

Hydrosoluble Complexes Bearing Tris(pyrazolyl)methane Sulfonate Ligand: Synthesis, Characterization and Catalytic Activity for Henry Reaction

The catalytic activity of the water-soluble scorpionate coordination compounds [Cu(-NN’O-Tpms)2] (1), [Mn(Tpms)2] (2) and Li[FeCl2(-NN’N’’-Tpms)] (3) [Tpms = tris(pyrazolyl)-methane sulfonate, O3SC(pz)3], were studied towards the (Henry) reaction between benzaldehyde and nitromethane or nitroethane in aqueous medium to afford, respectively, 2-nitro-1-phenylethanol or 2-nitro-1-phenylpropanol, the latter in the syn and the anti diastereoisomeric forms. Complex 1 exhibited the highest activity under the optimum experimental conditions and was used to broaden the scope of the reaction to include several aromatic aldehydes achieving yields up to 94%.

Stereochemical aspects of cyclotriphosphazenes: Prochiral and pseudo-asymmetric phosphorus atoms

Mono-, di- and trispiro derivatives (2–6) from the reaction of hexachlorocyclotriphosphazene, (1) with 3-aminobenzyl alcohol were reported in order to illustrate stereochemical terms such as prochiral, pseudo-asymmetry, homo-, enantio- and diastereotopic atoms or groups. The dispiro derivatives (3 and 4) were shown to exist as trans and cis geometric isomers and be racemic (RR/SS) and meso (RS), respectively, whereas the trispiro derivatives (5 and 6) exist as cis and trans geometric isomers and are achiral. Pseudo-asymmetry was introduced into the meso form (4) containing two constitutionally equivalent chiral units by the reactions with either 3-amino-1-propanol or phenol. The two meso diastereoisomeric forms, which can be assigned as R,s,S (7a) and R,r,S (7b) or S,s,R (8a) and S,r,R (8b), were identified as the systematic examples of cyclophosphazene derivatives including pseudo-asymmetric phosphorus centers. The corresponding racemic form (3) produced only one diastereoisomer (9 and 10) for each reaction. All the compounds were analysed by standard spectroscopic techniques, such as elemental analysis, MALDI-TOF mass spectrometry, NMR spectroscopy and X-ray crystallography (for 2, 4 and 6). The stereogenic properties of the compounds were confirmed by 31P NMR spectroscopy on addition of the chiral solvating agent (CSA) (R)-(+)-2,2,2-trifluoro-1-(90-anthryl)ethanol.

Ultrasound-assisted green bromination of N-cinnamoyl amino acid amides – Structural characterization and antimicrobial evaluation

N-phenylpropenoyl amino acid amides have been brominated using two alternative sonochemically activated green chemistry procedures. The first synthetic procedure has involved an ultrasound assisted bromination in an aqueous medium using ionic liquid as a catalyst of the reaction, whereas in the second one an in situ formation of Br2 via oxidation of HBr by H2O2 has been used. For comparison, the conventional bromination procedure was also used. The newly brominated compounds were characterized by appropriate analytical techniques. A detailed NMR spectroscopic analysis and quantum chemical calculations using Density Functional Theory (DFT) methods have been used to define the stereochemistry of the products. The results confirmed the physicochemical identity and similar yields of the products obtained by the three synthetic procedures employed, and reveal the co-existence of two diastereoisomeric forms of the newly synthesized products. The antibacterial and antifungal activities of the dibrominated amides were evaluated.

Development of an enantioselective capillary electrophoretic method for the simultaneous determination of montelukast enantiomeric and diastereoisomeric forms and its main degradation product.

A stereoselective CD-MEKC system has been developed for the quality control of Montelukast (MK), commercialized as a pure enantiomer. The proposed method is the first one that allows the simultaneous determination of MK, its enantiomeric form, diasteroisomers and its main degradation compound (MK sulphoxide). CD-MEKC system is composed of 10 mM SDS, 10 mM sulfobutylether-β-CD, 10 mM TM-β-CD, and 20 mM borate buffer at pH 9.0. Combination of these two CDs allows high baseline enantioresolution between MK and its enantiomeric impurity, but also, between the diasteroisomeric forms. Moreover, a multivariate design was applied to optimize operational parameters. The method was designed to meet with requirements of the official pharmacopoeias and fully validated according to international guidelines. Linearity of MK was demonstrated in the range from 10.0 to 100.0 μg/mL (r(2) = 0.9908) with a LOD and LOQ of 0.30 and 0.90 μg/mL, respectively. Intra and interday precision were evaluated and RSD values were below 2%, and also, accuracy expressed as percentage of recovery was in a range from 99.0 to 101.9 for the three assayed levels. The method allows determining 0.02% w/w of the enantiomeric and diasteroisomeric impurities, and 0.01% w/w of MK sulphoxide. Robustness was evaluated by a Plackett and Burman design. Finally, the CD-MEKC system was successfully applied to the determination of related substances in MK bulk drug and its quantification in two pediatric pharmaceutical dosage forms.

Stereoselective Synthesis of 2,15-Dihydroxycalamenene and 2-Methoxycalamenene. Determination of the Configuration of Natural 2,15-Dihydroxycalamenene

The enantioselective preparation of the two diastereoisomeric forms of 2,15-dihydroxycalamelene and 2-methoxycalamenene is here described. The (7S,10R) and (7R,10R) isomers of these natural products were synthesized starting from (5R,8S)-methyl-4-hydroxy-8-isopropyl-5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate and (5R,8R)-methyl-4-hydroxy-8-isopropyl-5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate, respectively, in turn preparable from (-)-menthone and (+)-isomenthone. The NMR analysis of the obtained sesquiterpenes allow assigning (7R,10S) absolute configuration to the natural occurring 2,15-dihydroxycalamelene.

Synthesis of New Silybin Derivatives and Evaluation of Their Antioxidant Properties

AbstractSilibinin, the major flavonolignan of silymarin, displays a broad spectrum of biological features that are generally ascribed to its antioxidant properties. Silibinin occurs in two diastereoisomeric forms, i.e., silybins A and B, in a ratio of ca. 1 : 1. With a simple and robust purification method, it is now possible to obtain silybins A and B in pure forms, in g‐scale amounts, and within a short period of time. Herein, we describe an efficient synthesis strategy to obtain a variety of new and more H2O‐soluble derivatives from the single silybins in which the 9″‐OH group was converted to a sulfate, N3, phosphodiester, or NH2 group via a solution‐phase approach. Thus, eight new compounds have been synthesized, purified by HPLC analysis, and characterized by NMR and MS analyses. To conduct experiments to clarify the many biological properties of pure silibinin diastereoisomers and their derivatives, the synthetic compounds were tested by using the DPPH assay to evaluate their antioxidant activities. The results, even if only for a small number of derivatives, revealed that some of these compounds are much more active than their parent compounds. It is also interesting to consider the synergetic effects.

A regioselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-chromene thiadiazole derivatives

Abstract A variety of 4′-(4-R-phenyl)-4-(methylthio)-2′-phenyl-2′ H -spiro[chromene-2,5′-[1,2,3]thiadiazole] 5a – d and 5′-(4-R-phenyl)-4-(methylthio)-3′-phenyl-3′ H -spiro[chromene-2,2′-[1,3,4]thiadiazole] 6a – d were synthesized regioselectively through the reaction of 4-(methylthio)-2 H -chromene-2-thione 2 with diarylnitrilimines under refluxing dry chloroform. Whilst the reaction of 4-(allylthio)-2 H -chromene-2-thione 3 with diarylnitrilimines under similar reaction conditions afforded the corresponding 4-(allylthio)-5′-(4-R-phenyl)-3′-phenyl-3′ H -spiro[chromene-2,2′-[1,3,4]thiadiazole] 7a – d and 5-(4-R-phenyl)-2′-methyl-3-phenyl-2′,3′-dihydro-3 H -spiro[[1,3,4]thiadiazole-2,4′-thieno[3,2- c ]chromene] 9a – d as two unisolable diastereoisomeric forms. The structures of the obtained spiro cycloadduct thiadiazoles have been assigned by means of spectroscopic measurements.

Cyclopeptide Alkaloids: Stereochemistry and Synthesis of the Precursors of Discarines C and D and Myrianthine A

The stereochemistry of discarines C (1) and D (2) and myrianthine A (3), three cyclopeptide alkaloids isolated from Discaria febrifuga, was determined by a combination of NMR studies of 1-3, enantioselective gas chromatography, and comparison of NMR data with those of synthetic tripeptides. For the synthesis of peptides, the nonproteinogenic amino acid 3-phenylserine was also obtained in its four diastereoisomeric forms (l and d threo, obtained by recrystallization of the diastereoisomeric tripeptide, and l and d erythro, obtained by a Mitsunobu reaction with the threo-tripeptides). The general synthetic strategy described in this paper allows the tripeptide to be obtained with the free N-terminal extremity protected or dimethylated. This strategy also allows the synthesis of the corresponding peptide with an imidazolidinone ring.

A study of the precursors of the natural antioxidant phenol 3,4-dihydroxyphenylglycol in olive oil waste

3,4-Dihydroxyphenylglycol (DHPG) is a potent antioxidant recently found in the free form in olive oil and table olives. DHPG can be recovered from olive oil solid waste by a hydrothermal treatment. It was observed that an increase in the concentration of DHPG occurred when alperujo aqueous extracts were subjected to mild thermal conditions (post-treatment). This fact indicates that certain solubilized compounds or precursors containing DHPG which is released with the post-treatment. In the present study, the precursors of DHPG were identified and characterized after extraction from alperujo using thermal treatment and purification by fractionation on Amberlite® XAD16 polyamide and semi-preparative reverse-phase HPLC columns. Their structures were elucidated using HPLC coupled to diode array detector (DAD) and electrospray ionization mass spectrometry (ESI-MS). The results identified three compounds as precursors, and their structures can be attributed to the diastereoisomeric forms of the two β-hydroxy derivatives of verbascoside and isoverbascoside (β-hydroxyacteoside and β-hydroxyisoacteoside), and 2″-hydroxyoleuropein, all of which contain a DHPG moiety, potentially explaining the increases in the concentration of this phenolic compound in olive oil waste.

Stereoselective synthesis of original spirolactams displaying promising folded structures

Access to diastereoisomeric forms of original spirolactam frameworks and investigation of their folded potentials are depicted here. Taking advantage of a stereoselective ring-contraction reaction, the Transannular Rearrangement of Activated Lactams (TRAL), followed by two unprecedented tandem reactions, we describe here an efficient access to elegant spirocyclic scaffolds. After dimerization, NMR analyses, circular dichroism, SEM and molecular modelling indicated the existence of an attractive edifice able to fold and behave as a PPII helix, a common yet neglected peptidic secondary structure.

Chemoenzymatic preparation of the p-menth-1,5-dien-9-ol stereoisomers and their use in the enantiospecific synthesis of natural p-menthane monoterpenes

A study on the preparation and synthetic exploitation of the isomeric forms of p-menth-1,5-dien-9-ol is reported. The latter alcohols were prepared in high enantiomeric purity from the easily available enantiomers of carvone. Thus, a chemoenzymatic procedure based on lipase-mediated acetylation, allowed the separation of their diastereoisomeric forms. Moreover, the purity of the chiral building blocks obtained was improved by fractional crystallisation of their 3,5-dinitrobenzoyl derivatives. A number of synthetic applications have also been described. The stereospecific cyclisation of the isomerically pure dienic alcohols gave the isomeric forms of the terpenes dill and epi-dill ether, which were hydrogenated diastereoselectively to the corresponding (1 R)- or (1 S)-derivatives depending on the catalyst used. The oxidation of the latter ethers turned out to be stereoselective, affording either the corresponding p-menthan-9-oic lactone or the keto-acid derivatives depending on the starting isomer used.

Synthesis and psychotropic activity of 5-cyclohexyl-5-methyl-2-sulfanyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-4-one

Ethyl 2-cyano-3-cyclohexyl-3-methyl-4-phenylbutanoate was synthesized from ethyl (2Z)-2-cyano-3cyclohexylbut-2-enoate using a Grignard reagent. It was shown that the reaction occurred exclusively at the ethylene bond. Because this cyanoester contained two asymmetric centers, PMR spectra showed two diastereoisomeric forms. These were cyclized in the presence of conc. H2SO4 into ethyl 4-amino-2-cyclohexyl-2-methyl-1,2-dihydronaphthalenecarboxylate, which was used to synthesize benzo[h]quinazolines, alkyl-substituted benzo[h]quinazolines, triazole, and tetrazole.

Structural variety and stereochemical features of bis(diphenylphosphinyl)[3]ferrocenophane gold(I) complexes

The P, N-[3]ferrocenophane ligand 3 forms a (κ P-ligand)AuCl complex ( 5) upon treatment with (Me 2S)AuCl. The corresponding P, P-[3]ferrocenophane system 4 yields a binuclear (κ P,κ P-chelate ligand)(AuCl) 2 complex ( 6) when reacted with 2 equivalents of the (Me 2S)AuCl reagent. Complex 6 features an intramolecular aurophilic Au⋯Au interaction. Treatment of the P, P-[3]ferrocenophane 4 with 1.0 equiv. of (PPh 3)AuCl gives the tetra-coordinated mono-gold(I) complex ( P, P-ligand)(PPh 3)AuCl ( 7), whereas the cationic [( P, P-ligand) 2Au] +[Cl −] system is obtained from 4 and 0.5 equivalents of (Me 2S)AuCl. The [( P, P-ligand) 2Au] + system is obtained in different diastereoisomeric forms ( 8 and 9) depending on the stereochemistry of the pair of P, P-[3]ferrocenophane chelate ligand used. Examples of the complexes 5, 6, 7 and 8 were characterized by X-ray diffraction.

Conformational and Solvation Studies via Computer Simulation of the Novel Large Scale Diastereoselectively Synthesized Phosphinic MMP Inhibitor RXP03 Diluted in Selected Solvents

Structure-activity relationship studies, regarding the influence of side chains of phosphinic pseudotripeptidic inhibitors on matrix metalloproteinases (MMPs), provided potent and selective inhibitors for this family of structurally and functionally related proteases. Among them, phosphinic pseudopeptide CbzPhepsi[P(O)(OH)CH(2)] phenylpropyl TrpNH(2), known as RXP03, has been extensively used for in vivo and in vitro studies so far. The large quantities of RXP03 required for in vivo studies, as well as the necessity for diastereoisomeric purity, motivated us to further explore and develop an efficient synthetic methodology, which allows separation of the four diastereoisomers of RXP03 based on the astonishing observed differences in solubility of the four isomers in various solvents. This fact prompted us to examine theoretically the conformational differences of these four isomers via computer simulations in the solvents used experimentally. Given the fact that the four examined diastereoisomeric forms of the phosphinic peptides exhibit different behavior in terms of potency and selectivity profiles toward zinc-metalloproteases, this theoretical study provides valuable information on the conformation of phosphinic inhibitors and therefore improves the design and synthesis of active structures. The differences in solubility of RXP03 diastereoisomers in the used solvents were examined in terms of intra- and intermolecular structure. It is found that the different solubility of the RRS and RSS diastereoisomers in EtOH is a result of the different number of hydrogen bonds formed by each isomer with EtOH molecules. In the case of SRS and SSS in Et(2)O, their different solubility might be attributed to the different intramolecular hydrogen bonds formed on these diastereoisomers.

Analysis of S‐adenosylmethionine and related sulfur metabolites in bacterial isolates of Pseudomonas aeruginosa (BAA‐47) by liquid chromatography/electrospray ionization coupled to a hybrid linear quadrupole ion trap and Fourier transform ion cyclotron resonance mass spectrometry

A comprehensive and highly selective method for detecting in bacterial supernatants a modified sulfur nucleoside, S-adenosyl-L-methionine (SAM), and its metabolites, i.e., S-adenosylhomocysteine (SAH), adenosine (Ado), 5'-deoxy-5'-methylthioadenosine (MTA), adenine (Ade), S-adenosyl-methioninamine (dcSAM), homocysteine (Hcy) and methionine (Met), was developed. The method is based on reversed-phase liquid chromatography with positive electrospray ionization (ESI+) coupled to a hybrid linear quadrupole ion trap (LTQ) and 7-T Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS). A gradient elution was employed with a binary solvent of 0.05 M ammonium formate at pH 4 and acetonitrile. The assay involves a simultaneous cleanup of cell-free bacterial broths by solid-phase extraction and trace enrichment of metabolites with a 50-fold concentration factor by using immobilized phenylboronic and anion-exchange cartridges. While the quantitative determination of SAM was performed using stable-isotope-labeled SAM-d3 as an internal standard, in the case of Met and Ade, Met-13C and Ade-15N2 were employed as isotope-labeled internal standards, respectively. This method enabled the identification of SAM and its metabolites in cell-free culture of Pseudomonas aeruginosa grown in Davis minimal broth (formulation without sulphur organic compounds), with routine sub-ppm mass accuracies (-0.27 +/- 0.68 ppm). The resulting contents of S(C)S(S)-SAM, S(S)-dcSAM, MTA, Ado and Met in the free-cell supernatant of P. aeruginosa was 56.4 +/- 2.1 nM, 32.2 +/- 2.2 nM, 0.91 +/- 0.10 nM, 19.6 +/- 1.2 nM and 1.93 +/- 0.02 microM (mean +/- SD, n = 4 extractions), respectively. We report also the baseline separation (Rs > or = 1.5) of both diastereoisomeric forms of SAM (S(C)S(S) and S(C)R(S)) and dcSAM (S(S) and R(S)), which can be very useful to establish the relationship between the biologically active versus the inactive species, S(C)S(S)/S(C)R(S) and S(S)/R(S) of SAM and dcSAM, respectively. An additional confirmation of SAM-related metabolites was accomplished by a systematic study of their MS/MS spectra.

Functionalised azetidines as ligands: some basic coordination chemistry

Crystal structure determinations on Cu(II) and Zn(II) complexes of tridentate and quadridentate azetidine derivatives show the ligands to be facultative for square-pyramidal and trigonal bipyramidal coordination geometries. While various contributions to the chirality of the complexes are possible, single diastereoisomeric forms (as enantiomer mixtures) have been isolated in all cases in the solid state. Analysis of lattice interactions indicates that H-bonding and aromatic stacking interactions are generally important.

Configurational and Conformational Properties of 1,3,7,9-Tetraphospha-Cyclododeca-1,2,7,8-tetraene: An Ab Initio Study and NBO Analysis

An investigation employing the ab initio molecular orbital (MO) and density functional theory (DFT) methods to calculate structural optimization and conformational interconversion pathways for the two diastereoisomeric forms, (±) and meso configurations of 1,3,7,9-tetraphospha-cyclododeca-1,2,7,8-tetraene (1) was undertaken. Two axial symmetrical conformations are found for (±)-1 configuration. (±)-1-TB axial symmetrical form is found to be about 0.35 and 0.99 kcal mol−1 more stable than (±)-1-Crown axial symmetrical conformation, as calculated by HF/6-31G*//HF/6-31G* and B3LYP/6-31G*//HF/6-31G* levels of theory, respectively. The unsymmetrical meso-1-TBCC form is found to be the most stable geometry, among the various conformations of meso-1 configuration. HF/6-31G*//HF/6-31G* and B3LYP/6-31G*//HF/6-31G* results showed that between the two most stable conformations of (±) and meso configurations, (±)-1-TB is more stable than meso-1-TBCC by about 3.35 and 2.43 kcal mol−1, respectively. In addition, MP2/6-31G* and B3LYP/6-311+G** results showed that the (±)-1-TB form is about 1.10 and 2.36 kcal mol−1 more stable than the meso-1-TBCC form. Further, NBO results revealed that in the most stable form of meso configuration (meso-1-TBCC), the sum of the π* allenic antibonding orbital occupancies (Σ π *occupancy) is greater than dl configuration ((±)-1-TB). Also, NBO results indicated that in the (±)-1-TB conformer, the sum of σ and π allenic moieties bonding orbital deviations (Σ σ dev+Σ π dev) from their normal values, is lower than in the meso-1-TBCC form.

Stereostructure Assignment of Flexible Five-Membered Rings by GIAO 13C NMR Calculations: Prediction of the Stereochemistry of Elatenyne

The stereochemistry of conformationally mobile five-membered rings is often hard to assign from NMR data, and [2,2']bifuranyl systems are even more challenging. GIAO (13)C NMR chemical shifts have been calculated for a series of [2,2']bifuranyl and pyranopyran species, taking into account their conformational flexibility using weighted averages of the data for all low energy conformers. We show that calculation of (13)C NMR chemical shifts using the geometries obtained using molecular mechanics greatly reduces the computational expense without a significant loss of accuracy, even in this demanding system. The results were sufficiently accurate to distinguish not only the pyran and furanyl isomers but also between all the diastereoisomeric forms. As a result of this validation, we predict the stereochemistry for the recently proposed revised structure of the natural product elatenyne, which contains a [2,2']bifuranyl core.