Diastereomeric Pairs Of Enantiomers Research Articles

Dracomolphin A-E, new lignans from Dracocephalum moldavica

Eight new lignans, dracomolphin A-E (1–8), together with eight known lignans (9–16) were isolated from the aerial part of Dracocephalum moldavica. The structures of the isolated compounds were established based on NMR and HRESIMS data. Dracomolphin A (1–4) was elucidated as a lignan possessed a 5-membered ketal ring formed between C-8′ and C-3, C-4. The two stereogenic centers rendered dracomolphin A as a mixture of two diastereomeric pairs of enantiomers (1–4). All of the four isomers were separated successfully by using chiral HPLC and their stereochemical features were determined by CD spectra. Bioactivity screening revealed that compounds 1–4, 6, 7, 12, 15 and 16 were potential Nrf2 transcriptional activators. Dracomolphin E (8) reduced cell viability of lung cancer NCI-H292 cells associated with apoptosis.

Novel oligomeric neolignans with PTP1B inhibitory activity from the bark of Magnolia officinalis var. biloba

The barks of Magnolia officinalis var. biloba, Magnoliae cortex, have been used as traditional Chinese medicines for several centuries. In this study, phytochemical investigation of M. officinalis var. biloba bark extract afforded five pairs of novel enantiomeric oligomeric neolignans, (±)-mooligomers A–E (1–5). (±)-1 and (±)-2 were two diastereomeric pairs of enantiomers with six C6-C3 subunits, and (±)-4 was a pair of previously unreported tetrameric neolignans bearing eight C6-C3 subunits. (±)-5 is the first example of a naturally occurring trilignan featuring an eight-membered ring with a magnolol moiety. The absolute configurations of (±)-1−(±)-5 were elucidated on the basis of HRESIMS, 1D and 2D NMR spectroscopy and electronic circular dichroism (ECD) calculations. Among the compounds tested for their PTP1B inhibitory activities, (±)-2, (±)-4 and (±)-5 displayed significant PTP1B inhibitory activities with IC50 values of 0.14–2.10 μM. Furthermore, a Molecular docking simulation of PTP1B and active compounds [(±)-2, (±)-4 and (±)-5] exhibited that these active compounds possess low binding affinities ranging from − 5.9 to − 7.7 kcal/mol.

Biotransformation of β-Mangostin by an Endophytic Fungus of Garcinia mangostana to Furnish Xanthenes with an Unprecedented Heterocyclic Skeleton

Biotransformation of β-mangostin (1) by the endophytic fungus Xylaria feejeensis GM06 afforded hexacyclic ring-fused xanthenes with an unprecedented hexacyclic heterocylic skeleton. β-Mangostin (1) was transformed to two diastereomeric pairs of enantiomers, mangostafeejin A [(-)-2a/(+)-2b)] and mangostafeejin B [(-)-3a/(+)-3b)]. The chemical structures of the transformation products were elucidated by analysis of NMR and MS data, and the structure of mangostafeejin A [(-)-2a/(+)-2b)] was confirmed by single-crystal X-ray diffraction analysis. The absolute configurations of 3a and 3b were established on the basis of calculated and measured ECD data using the ECD spectra of 2a and 2b as models. The fungal biotransformation described herein provides an effective method to convert an abundant achiral plant natural product scaffold into new chiral heterocyclic scaffolds representing expanded chemical diversity for biological activity screening.

Synthesis and reactivity of β-stannylated phenylalanines

Abstract The free radical hydrostannation of a series of N-benzoyl and N-acetyl dehydrophenylalanine esters 2a – h yields β-stannylated phenylalanine derivatives 3 and 4. This addition of tin hydride to such unsaturated compounds simultaneously creates two new chiral centers leading to mixtures of two diastereomeric pairs of enantiomers. The reaction of 3-stannylated phenylalanine 3 with methanolic HCl yields chlorostannyl-substituted compounds 5 and 6 and, with one equivalent of bromine, the bromostannylated compounds 7 and 8 are formed. The bromostannylated phenylalanine derivative 7 reacts with one further equivalent of bromine to produce the dibromostannylated compound 9. Even the chlorostannylated phenylalanine derivative 5 reacts with one further equivalent of HCl to give the dichlorostannylated compound 10. The products were characterized by elemental analysis, infrared (IR), and multinuclear (1H, 13C, 119Sn) nuclear magnetic resonance (NMR) spectroscopy. Attempts were made to assign the preferred conformation of the stannylated phenylalanine derivatives using Karplus-type relationship of coupling constants 3 J(H,H), 3 J(Sn,H), and 3 J(Sn,C=O). The results of these analyses have been confirmed by three crystal structure determinations.

ChemInform Abstract: Helical, Axial, and Central Chirality Combined in a Single Cage: Synthesis, Absolute Configuration, and Recognition Properties.

The synthesis of eight enantiopure molecular cages (four diastereomeric pairs of enantiomers) comprising a helically chiral cyclotriveratrylene (CTV) unit, three axially chiral binaphthol linkages, and three centrally asymmetric carbon atoms of a trialkanolamine core, is described. These new cages constitute a novel family of hemicryptophanes, which combine three classes of chirality. Their absolute configuration was successfully assigned by a chemical correlation method to overcome the signals overlap in the ECD spectra of the binaphtol and CTV units. Stereoselective recognition of glucose and mannose derivatives was investigated with these new chiral cages. Excellent enantio-and diastereoselectivity were reached, since in some cases, both exclusive enantio-and diastereo-discrimination have been observed. In addition, compared with the most relevant hemicryptophanes, these new cages also exhibit improved binding affinities.

Helical, Axial, and Central Chirality Combined in a Single Cage: Synthesis, Absolute Configuration, and Recognition Properties.

The synthesis of eight enantiopure molecular cages (four diastereomeric pairs of enantiomers) comprising a helically chiral cyclotriveratrylene (CTV) unit, three axially chiral binaphthol linkages, and three centrally asymmetric carbon atoms of a trialkanolamine core, is described. These new cages constitute a novel family of hemicryptophanes, which combine three classes of chirality. Their absolute configuration was successfully assigned by a chemical correlation method to overcome the signals overlap in the ECD spectra of the binaphtol and CTV units. Stereoselective recognition of glucose and mannose derivatives was investigated with these new chiral cages. Excellent enantio- and diastereoselectivity were reached, since in some cases, both exclusive enantio- and diastereo-discrimination have been observed. In addition, compared with the most relevant hemicryptophanes, these new cages also exhibit improved binding affinities.

Comparative study of [RuClCp(HdmoPTA-κP)(PPh3)][CF3SO3] and the heterobimetallic complexes [RuClCp(PPh3)-μ-dmoPTA-1κP:2κ2N,N′-M(acac-κ2O,O′)2] (M = Co, Ni, Zn; dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)

The synthesis of novel heterobimetallic derivatives of general formula [RuClCp(PPh(3))-μ-dmoPTA-1κP:2κ(2)N,N'-M(acac-κ(2)O,O')(2)] (M = Ni (3), Zn (4); dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) is described. The preparations of the ruthenium-cobalt analogue (M = Co (2)) and the starting compound [RuClCp(HdmoPTA-κP)(PPh(3))](CF(3)SO(3)) have been revised and their yield improved. Similar to 2, the solid state structures of 3 and 4 show that the dmoPTA-P and the dmoPTA-N(CH(3)) atoms are involved in the coordination to the {RuCpCl(PPh(3))} and {M(acac)(2)} moieties, respectively. The size of the diffusing units is almost the same for the three binuclear complexes, indicating that they exhibit similar solution structures. The diamagnetic ruthenium-zinc derivative was fully characterized in solution at 193 K by NMR as two diastereomeric pairs of enantiomers (R-Ru, Δ-Zn; R-Ru, Λ-Zn; S-Ru, Δ-Zn; S-Ru, Λ-Zn). Finally, the electrochemical properties of the complexes have been investigated by cyclic voltammetry.

Isobutoxypentabromocyclododecanes (iBPBCDs): A new class of polybrominated compounds

Isobutoxypentabromocyclododecanes (iBPBCDs) represent a new class of polybrominated compounds found in several flame-proofed polystyrene materials and in a technical mixture of hexabromocyclododecanes (HBCDs). Of the 64 stereoisomers possible, we now have analytical evidence for 16 different stereoisomers. By reversed- and chiral-phase liquid chromatography we distinguished 8 diastereomeric pairs of enantiomers, named α-, β-, γ-, δ-, ε-, ξ-, η-, and θ-iBPBCDs in accordance with their chromatographic retention on a C 18-RP-column. Crystal structure analysis revealed the stereochemistry of the most prominent θ-iBPBCD stereoisomers, which were determined to be (1R)-1-iso-butoxy-(2R,5R,6S,9S,10R)-2,5,6,9,10-pentabromocyclododecane and its enantiomer. The eight iBPBCD diastereomers were also found in several expanded (EPS) and extruded polystyrene materials (XPS). Stereoisomer pattern varied to a large extent with δ-, η-, and θ-iBPBCDs dominating in EPS- and α-, β-, ε-, and ξ-isomers in XPS-materials. The substitution of a bromine atom with an alkoxy group is expected to result in more lipophilic compounds than the parent HBCD compounds. The chromatographic retention on the reversed-phase column supports this assumption. Therefore, we expect that certain iBPBCD stereoisomers may also have the potential to accumulate in biota like e.g. α-HBCDs. The presented spectroscopic and chromatographic data allow the identification of 16 different iBPBCD stereoisomers in plastic materials, environmental samples, and biota. With this, the occurrence, fate, and toxicological relevance of this new class of polybrominated compounds can now be studied in more detail.

Separation and structure determination of two diastereomeric pairs of enantiomers from Dracocephalum rupestre by high-performance liquid chromatography with circular dichroism detection

All of the four stereoisomers of an unprecedented type of flavanones, the dracorupesins, were separated from the aerial parts of Dracocephalum rupestre simultaneously. The dracorupesins were characterized as two diastereomeric pairs of enantiomers by on-line chiral high-performance liquid chromatography-circular dichroism (HPLC-CD) analysis, which was a reliable stereoanalytical tool for natural products. The planar structures of the compounds were elucidated by means of spectroscopic methods including IR, MS, one-dimensional NMR (1D-NMR) and two-dimensional NMR (2D-NMR) techniques.

Self-Sorting Chiral Subcomponent Rearrangement During Crystallization

The incorporation of enantiopure 1-amino-2,3-propanediol as a subcomponent into a dicopper double helicate resulted in perfect chiral induction of the helicate's twist. DFT calculations allowed the determination of the helicity of the complex in solution. The same helical induction, in which S amines induced a Lambda helical twist, was observed in the solid state by X-ray crystallography. Electronic structure calculations also revealed that the unusual deep green color of this class of complexes was due to a metal-to-ligand charge transfer excitation, in which the excited state possesses a valence delocalized Cu2(3+) core. The use of a racemic amine subcomponent resulted in the formation of a dynamic library of six diastereomeric pairs of enantiomers. Surprisingly, this library converted into a single pair of enantiomers during crystallization. We were able to observe this process reverse upon redissolution, as initial ligand exchange was followed by covalent imine metathesis.

Stereoselective laser pulse control of an axial chiral molecular model system supporting four stereoisomers

We present quantum dynamical simulations on the axial chiral model system 2,2′-difluoro-biphenyl which supports four stereoisomers, i.e. two diastereomeric pairs of enantiomers, along the torsion around its central C–C bond. A pump-dump control mechanism is developed which consists of stereo-selective, i.e. enantio- and diastereo-selective, ultrashort laser pulses that convert a racemic mixture to one of its diastereomers. For that purpose the enantioselective laser pulse control of previous theoretical investigations is extended for systems that support more than one pair of enantiomers. Still, the polarization of the laser field determines the stereoselectivity of the control mechanism.

Error-prone Translesion Synthesis by Human DNA Polymerase η on DNA-containing Deoxyadenosine Adducts of 7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene

When human DNA polymerase eta (pol eta) encounters N6-deoxyadenosine adducts formed by trans epoxide ring opening of the 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP DE) isomer with (+)-7R,8S,9S,10R configuration ((+)-BaP DE-2), misincorporation of A or G and incorporation of the correct T are equally likely to occur. On the other hand, the enzyme exhibits a 3-fold preference for correct T incorporation opposite adducts formed by trans ring opening of the (-)-(7S,8R,9R,10S)-DE-2 enantiomer. Adducts at dA formed by cis ring opening of these two BaP DE-2 isomers exhibit a 2-3-fold preference for A over T incorporation, with G intermediate between the two. Extension one nucleotide beyond these adducts is generally weaker than incorporation across from them, but among mismatches the (adducted A*) x A mispair is the most favored for extension. Because mutations can only occur if mispairs are extended, this observation is consistent with the occurrence of A x T to T x A transversions as common mutations in animal cells treated with BaP DE-2 isomers. Adducts with S absolute configuration at the point of attachment of the hydrocarbon to the base inhibit incorporation and extension by pol eta to a lesser extent than their R counterparts. Template-primers containing each of the four isomeric dA adducts derived from BaP DE-2 and two adducts derived from 9,10-epoxy-7,8,9,10-tetrahydrobenzo-[a]pyrene in which the 7- and 8-hydroxyl groups of the DEs are replaced with hydrogens exhibit reduced electrophoretic mobilities relative to the unadducted oligonucleotides. This effect is largely independent of DNA sequence. Decreased mobility correlates with an increased rate of incorporation by pol eta, suggesting a systematic relationship between the overall DNA structure and efficiency of the enzyme.

Design, Synthesis, and Enzymatic Evaluation of N-Acyloxyalkyl- and N1-Oxazolidin-2,4-dion-5-yl-Substituted β-lactams as Novel Inhibitors of Human Leukocyte Elastase

Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5'S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.

Structure elucidation of hexabromocyclododecanes—a class of compounds with a complex stereochemistry

Hexabromocyclododecanes (HBCDs) are high production volume chemicals (16 700 t worldwide in 2001) used as flame-retardants for plastics and textiles. HBCDs exhibit typical properties of persistent organic pollutants (POPs). They are highly lipophilic and accumulate in biota. Increasing environmental concentrations of HBCDs, mostly reported as sum values, have been observed. As such, HBCDs have to be considered as potential emerging POPs, but their occurrence and environmental fate have not yet been addressed at the level of individual HBCD stereoisomers. Considering the six stereogenic centers of HBCDs, 16 stereoisomers, six diastereomeric pairs of enantiomers as well as four meso forms, can be deduced. Herein, we report spectroscopic and chromatographic data for eight out of 16 possible HBCD stereoisomers, which were isolated from a technical product. Six stereoisomers were identified as three pairs of enantiomers ((±) α-, β-, and γ-HBCDs), differing in optical rotation and chromatographic retention on a chiral phase. The crystal structures of these pairs of enantiomers were determined. Another two of these eight HBCD stereoisomers, not yet described in the literature, showed no optical rotation and are tentatively assigned as meso forms (δ- and ε-HBCD). The given spectroscopic and chromatographic information allows the unambiguous identification of eight HBCD stereoisomers and the occurrence, fate, and toxicology of these individual stereoisomers can now be studied.

Highly Enriched Mixtures of Methohexital Stereoisomers by Palladium‐Catalyzed Allylation and Their Anaesthetic Activity

AbstractThe stereoselective Pd‐catalyzed allylation of MBA [5‐(2′‐hex‐3′‐ynyl)‐1‐methylbarbituric acid] gives the commercial injection narcotic methohexital, which exists as four isomers: two diastereomeric pairs of enantiomers. The isomer composition produced depends on three stereochemical parameters: catalyst control, substrate control, and kinetic resolution. Judicious choice of these parameters allowed the synthesis of methohexital samples with greatly differing isomer compositions, and these samples were investigated with respect to their anaesthetic doses in rats. Some isomer compositions obtained were much more active than the commercially used drug and showed fewer side effects. As a consequence of the determination of the absolute configuration of the methohexital (SbRh) isomer, the unknown configuration of the trade product, the so‐called α‐racemate, can be established as (RbSh) and (SbRh). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Narcotic drug methohexital: synthesis by enantioselective catalysis.

The narcotic drug methohexital 1 contains two asymmetric carbon atoms and, thus, consists of four isomers, two diastereomeric pairs of enantiomers. The commercial drug is the so-called alpha-racemate, one pair of diastereomers only. A method was developed to prepare differently enriched mixtures of methohexital isomers without resorting to lengthy and expensive optical resolutions. A model reaction for the synthesis of methohexital is the palladium-catalyzed allylation of 1,5-dimethyl-barbituric acid 3, which is optimized and checked by molecular modeling. Catalysts with the best ligands are used in the allylation of the methohexital precursor 7, which contains the C(6) sidechain at the tetrahedral center of the barbiturate skeleton. The product stereochemistry was determined by the contribution of the enantioselective Pd catalysts and by the fact that the allylation is a kinetic resolution. The methohexital isomer mixtures obtained were evaluated with the corneal stimulus test of rats. Methohexital compositions were found, which are superior to the commercially used alpha-racemate (Brevimytal).

Isomerism in Copper(I)-Induced Folding of Homoditopic Macrocyclic Ligands with Bis(dithiadiimine) Donor Sets

The structural properties of the dicopper(I) compounds of the two large macrocyclic Schiff base ligands para-222 and meta-222 with two dithiadiimine coordination sites, where the two sites are linked by two para- or two meta-xylylene spacer groups and all bridges between the donors of each site are ethylene groups (32- and 30-membered macrocycles for the para- or meta-xylylen-bridged para-222 and meta-222 species, respectively) are studied, in solution and by computer modeling. Solid-state structural data have been reported elsewhere. The coordination of the 32-membered macrocycle para-222 to two copper(I) centers leads to a helical figure-of-eight-shaped structure. Two diastereomeric pairs of enantiomers have been observed for this type of compound in solution. The crystallized form is more stable than the second isomer by approximately 6–10 kJ/mol (solution-NMR spectroscopy and force-field calculations). Both experimentally detected isomers are more than 15 kJ/mol more stable than the other five possible configurations (force-field calculations). For the meta-222 macrocycle (30-membered ring) an achiral structure has been observed in the solid while two of the 21 possible isomers have been detected in solution (3:1, NMR spectroscopy). The computed structures and isomer distributions (force-field calculations) are compared with the solid-state structures and with observed isomer distributions from NMR experiments, and dynamic processes are analyzed in detail.

Synthesis and structure of silylene complexes of silacyclobutanes

Reactions of 1.1-dichloro-2-neopentyl-3-vinyl-l-silacyclobutane ( 1a, b) with carbonyl metallates [{M(CO) n } m ] 2- (M = Fe, m = 1, n = 4; M = Cr, m = 1, n = 5; M = W, m = 2, n = 5) in THF/HMPA lead to novel compounds [(CO) nMSiC 10H 18] · HMPA (M = Fe, n = 4; M = Cr, W, n = 5). 1H, 13C and 29Si NMR spectroscopic studies in solution support the formation of four diastereomeric pairs of enantiomers. The X-ray structure analyses of the crystals show folded 1-metallated 1-silacyclobutane units in which the HMPA ligand increases the coordination number of Si to 3 + 1. Crystals of [(CO) 5CrSiC 10H 18] · HMPA ( 2) and of [(CO) 5WSiC 10H 18] · HMPA ( 3) (corresponding values in brackets) are isotypic: P2 1/ n (No. 14); a = 1084(1)/[1099(1)], b= 1927(1)/[1937(1)], c= 1342.1(8)/[1342(1)] pm, β = 97.11(7)/[97.18(7)]°, Z = 4. In both crystals enantiomeric [1 S,2 S,3 S]/[1 R,2 R,3 R] pairs are present. In orthorhombic crystals of [(CO) 4FeSiC 10H 18]. · HMPA ( 4) ( P2 12 12 1 (No. 19), a = 896.4(5), b = 1693(1), c = 1753(1) pm, Z= 4) only the [1 S,2 S,3 S]-isomer is detected.

Synthesis and fungicidal activities of CGA 80000 (α-[N-(3-chloro-2,6-xylyl)-2-methoxyacetamido]-ν-butyrolactone) and of its four isomers

The preparation of CGA 80000 (α-[N-(3-chloro-2,6-xylyl)-2-methoxy-acetamido]-ν-butyrolactone) and the separation of the four optical isomers and the diastereomeric pairs of enantiomers are described. The relationships between their absolute configurations and fungicidal activities have been examined. Biological tests have proved that one of the four isomers, with the absolute configuration (aS, 3R) is mainly responsible for the fungicidal activity of CGA 80000.

Diastereospecific HPLC Analysis of the Antiulcer Drug, Enprostil, in a Soft Elastic Gelatin Capsule Formulation

Abstract Enprostil, an E-type prostaglandin analog, is formulated as a 0.3 mM propylene carbonate solution filled into soft elastic gelatin capsules. A characteristic structural feature of enprostil is the presence of two unresolved chiral centers, yielding a drug molecule that exists as two diastereomeric pairs of enantiomers. This report describes an HPLC method for quantitatively determining the relative amounts of enprostil diastereomers in soft elastic gelatin capsules. Using a Spherisorb ODS 5 μym, 250 × 4.5 mm column and a mobile phase mixture of 59:40:1 methanol:water:tetrahydrofuran separates the enprostil diastereomeric pairs and also resolves the enprostil diastereomers from potential interferences arising from placebo and drug degradation. The method performs well as evidenced by the usual statistical tests for: response linearity, recovery efficiency, precision, and lower quantitation limit. Also, the demonstrated dependence of chromatographic retention on mobile phase composition and system ...