Enantiopure Compounds Research Articles

Enantioselective synthesis of quaternary 3,4-dihydroisoquinolinones via Heck carbonylation reactions: development and application to the synthesis of Minalrestat analogues.

Minalrestat and its analogues represent structurally novel aldose reductase inhibitors, and the asymmetric synthesis of such pharmaceutically privileged molecules has not been reported yet. We have developed a palladium-catalyzed enantioselective intramolecular carbonylative Heck reaction by using formate esters as the source of CO, which represents the first enantioselective synthesis of quaternary 3,4-dihydroisoquinolines. The reaction provides a facile and efficient method for the synthesis of enantiopure nitrogen-containing heterocyclic compounds bearing an all-carbon quaternary stereocenter. The reaction has been successfully applied to the first asymmetric synthesis of Minalrestat analogues.

Synthesis and Application of Substituted 1,16-Dihydroxytetraphenylenes in Catalytic Asymmetric Allylboration of Ketones.

The synthesis and application of a newly designed C2-symmetric chiral-substituted 1,16-dihedroxytetraphenylene (DHTP) is reported. Efficient syntheses of enantiopure substituted DHTP were accomplished, and these enantiopure compounds were used as organocatalysts in asymmetric allylboration of ketones under very mild conditions. Accordingly, several tertiary alcohols were generated in moderate to good yields with up to 99% ee by using the catalyst ( S)-2,15-Br2-DHTP. A gram-scale reaction was achieved in 99% yield with 96% ee.

Enhanced Mechanical and Thermal Strength in Mixed-Enantiomers-Based Supramolecular Gel.

Mixing supramolecular gels based on enantiomers leads to re-arrangement of gel fibers at the molecular level, which results in more favorable packing and tunable properties. Bis(urea) compounds tagged with a phenylalanine methyl ester in racemic and enantiopure forms were synthesized. Both enantiopure and racemate compounds formed gels in a wide range of solvents and the racemate (1-rac) formed a stronger gel network compared with the enantiomers. The gel (1R+1S) obtained by mixing equimolar amount of enantiomers (1R and 1S) showed enhanced mechanical and thermal stability compared to enantiomers and racemate gels. The preservation of chirality in these compounds was analyzed by circular dichroism and optical rotation measurements. Analysis of the scanning electron microscopy (SEM) and atomic force microscopy (AFM) images revealed that the network in the mixed gel is a combination of enantiomers and racemate fibers, which was further supported by solid-state NMR. The analysis of the packing in xerogels by solid-state NMR spectra and the existence of twisted-tape morphology in SEM and AFM images confirmed the presence of both self-sorted and co-assembled fibers in mixed gel. The enhanced thermal and mechanical strength may be attributed to the enhanced intermolecular forces between the racemate and the enantiomer and the combination of both self-sorted and co-assembled enantiomers in the mixed gel.

Asymmetric Rh(I)-Catalyzed Functionalization of the 3-C( sp3)-H Bond of Benzofuranones with α-Diazoesters.

An asymmetric Rh(I)-catalyzed functionalization of the 3-C( sp3)-H bond of benzofuranones with α-diazoesters has been developed, providing a new strategy for the stereoselective 3-alkylation of benzofuranones. With low catalyst loadings (low to 0.02 mol % Rh), a number of benzofuranones bearing consecutive quaternary and tertiary stereogenic centers have been synthesized (up to 94% yield, 95:5 dr, and >99% ee). The synthetic utilities of this methodology have been demonstrated by elaborating the model product 3aa to a series of enantiopure compounds with similarities to natural products and drug candidates.

Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ12, 14-prostaglandin J2

In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ12, 14-prostaglandin J2 (15 d-PGJ2). The exocyclic enone moiety of 15 d-PGJ2 is essential for covalent bonding with the Cys285 residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ2. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)-6a1 was suggested as a potential PPAR-γ ligand.

Enantiomeric resolution of helicochiral paddlewheel complexes and their infrared, Raman, UV–vis and X-ray optical activity

Linear polynuclear paddlewheel complexes-extended atom chains or metal strings-have provided attractive models for the study of metal-metal bonding, magnetism and conductivity since their discovery in the 1990s [1]. Their helicoidal chirality, arising from mutual steric hindrance of the 3-pyridyl protons, resulting in the twisting of the equatorial ligand around the axis (see figure), has been less studied. Nonetheless, in one of the few examples of chiral resolution, the obtained enantiomers of a trinickel complex showed a remarkably high specific rotation of 5000 deg•mL•g −1 •dm −1 [2], motivating us to seek a general technique for the chiral resolution of such racemates. We have developed a procedure based on anion exchange for the chiral resolution of [M3(dpa)4] 2+ salts (M = Co(II) or Ni(II), Hdpa = 2,2'-dipyridylamine). Homochiral arsenyl tartrate (AsT) salts promoted the selective crystallization of [-M3(dpa)4(MeCN)2](NBu4)2[-AsT]2, or [-M3(dpa)4(MeCN)2](NBu4)2[-AsT]2 in the P4212 space group. The enantiopure compounds demonstrated surprisingly large optical activities using UV-vis, Raman and infrared spectroscopy in solution and, for the cobalt derivatives, in the X-ray range at the Co K-edge in single crystals. An intense X-ray linear dichroism was observed in the orthoaxial crystal orientation, whereas it vanished in the axial confirmation, while the angular dependence of the circular dichroism spectra followed the expected (3cos 2 − 1) function, thus spectroscopically confirming the D4 crystal symmetry. X-ray magnetic circular dichroism and X-ray magnetochiral dichroism signals at the Co K-edge were not detected, likely due to a strongly delocalized spin density on the metal-metal bonded tricobalt core. Nevertheless, these results establish that chiral polynuclear paddlewheel complexes can be cleanly resolved using selective crystallization and demonstrate considerable optical activity in the infrared, UV-vis and X-ray energy ranges, thus potentially offering future perspectives in non-linear optics and asymmetric synthesis [3].

Synthesis of 13 C6 -labeled, dual-target inhibitor of cannabinoid-1 receptor (CB1 R) and inducible nitric oxide synthase (iNOS).

Cannabinoid-1 receptor (CB1 R) antagonists/inverse agonists have great potential in the treatment of metabolic disorders like dyslipidemia, type 2 diabetes, and nonalcoholic steatohepatitis. Cannabinoid-1 receptor inverse agonists have also been reported to be effective in mitigating fibrotic disorders in murine models. Inducible nitric oxide synthase is another promising target implicated in fibrotic and inflammatory disorders. We have disclosed MRI-1867 as a potent and selective, peripherally acting dual-target inhibitor of the CB1 R and inducible nitric oxide synthase (iNOS). Herein, we report the synthesis of [13 C6 ]-MRI-1867 as a racemate from commercially available chlorobenzene-13 C6 as the starting, stable-isotope label reagent. The racemic [13 C6 ]-MRI-1867 was further processed to the stable-isotope-labeled enantiopure compounds using chiral chromatography. Both racemic [13 C6 ]-MRI-1867 and S-13 C6 -MRI-1867 will be used to quantitate unlabeled S-MRI-1867 during clinical drug metabolism and pharmacokinetics studies and will be used as a liquid chromatography-tandem mass spectrometry bioanalytical standard.

Highly Enantioselective Desymmetrization of Centrosymmetric pseudo-para-Diformyl[2.2]paracyclophane via Asymmetric Transfer Hydrogenation

Herein we describe the desymmetrization of a centrosymmetric pseudo-para-diformyl[2.2]paracyclophane based on Noyori asymmetric transfer hydrogenations (ATH). The reduction proceeds smoothly in the presence of commercially available ruthenium complexes to afford a monohydroxymethylated product in good yields and excellent enantioselectivities (up to 74% isolated yield and 99% ee). Our approach is operationally simple and can be run in gram-scale without any significant loss in the reaction efficiency. This desymmetrization strategy allows an easy access to an enantiopure compound bearing on each aromatic ring of the pCp core different reactive groups suitable for regioselective orthogonal postfunctionalization.

Chiral Cliffs: Investigating the Influence of Chirality on Binding Affinity.

Chirality is understood by many as a binary concept: a molecule is either chiral or it is not. In terms of the action of a structure on polarized light, this is indeed true. When examined through the prism of molecular recognition, the answer becomes more nuanced. In this work, we investigated chiral behavior on protein-ligand binding: when does chirality make a difference in binding activity? Chirality is a property of the 3D structure, so recognition also requires an appreciation of the conformation. In many situations, the bioactive conformation is undefined. We set out to address this by defining and using several novel 2D descriptors to capture general characteristic features of the chiral center. Using machine-learning methods, we built different predictive models to estimate if a chiral pair (a set of two enantiomers) might exhibit a chiral cliff in a binding assay. A set of about 3800 chiral pairs extracted from the ChEMBL23 database was used to train and test our models. By achieving an accuracy of up to 75 %, our models provide good performance in discriminating chiral cliffs from non-cliffs. More importantly, we were able to derive some simple guidelines for when one can reasonably use a racemate and when an enantiopure compound is needed in an assay. We critically discuss our results and show detailed examples of using our guidelines. Along with this publication we provide our dataset, our novel descriptors, and the Python code to rebuild the predictive models.

Unusual Circularly Polarized and Aggregation-Induced Near-Infrared Phosphorescence of Helical Platinum(II) Complexes with Tetradentate Salen Ligands.

A series of chiral and helical PtII -Salen complexes with 1,1'-binaphthyl linkers were synthesized and characterized. Owing to the restriction of intramolecular motions of central 1,1'-binaphthyls, the complexes exhibit unusual near-infrared aggregation-induced phosphorescence (AIP). The (R)/(S) enantiopure complexes were characterized by X-ray diffraction, circular dichroism spectra, time-dependent density functional theory calculations, and circularly polarized luminescence (CPL). The present work explores the use of tetradentate ligands that can be easily prepared from commercially available enantiopure compounds, and the subsequent preparation of stable CPL-active square planar PtII complexes with AIP effect that may have interest in many applications.

Gas Antisolvent Fractionation: a New Method to Obtain Enantiopure Compounds, a Case Study on Mandelic Acid

Micronization processes involving supercritical carbon dioxide are rapid methods to produce fine particles. They also might offer the possibility of using less organic solvent than conventional crystallization methods leading to an environmentally friendlier processing. The separation capabilities of such processes are now demonstrated on the diastereomeric resolution of mandelic acid using (R)-1-phenylethanamine as a resolving agent, utilizing the batch type gas antisolvent fractionation as the separation method. A detailed study was conducted on the effects of the operational parameters pressure (12-20 MPa), temperature (35-55 °C) and co-solvent concentration (33-99 mg/ml). At 12 MPa, 35 °C and 99 mg/ml methanol concentration, a selectivity of 0.52 and a diastereomeric excess of 62% was reached. The same operational parameters were applied during the investigation of the recrystallization-based further purification of the diastereomeric salts, applying the resolving agent in molar equivalent quantity to a non-racemic mixture of mandelic acid. It has been found that the more stable (R)-1-phenylethylammonium-(R)-mandelate salt can be purified to de>98% through four additional recrystallization steps following the initial, half-molar equivalent resolution step.

Chirality and spatially pre-organized multi-porphyrinoids

We report herein that chiral and enantiopure compounds such nucleosides and peptides can pre-organize multi-porphyrinic systems and influence their properties. The first example given concerns star-shaped mutli-porphyrins with chiral and enantiopure nucleosidic linkers. If the configuration is indeed a star-shaped nanomolecule, it appears that the induced conformation is nothing as expected. The four peripheral Zn(II) porphyrins collapse over the free-base central one, inducing totally different photo-physical properties. Despite a minor expected light energy harvesting behavior, the principal capability of this system is to quench the collected light energy and convert it from radiative to non-radiative de-activation. The second example concerns polypeptides with pendant porphyrins. The peptidic backbone confers to the systems, after a certain degree of oligomerization, a 3[Formula: see text] right handed helical conformation which induces cavities within the multi-porphyrinc architecture, ready to welcome guests and render, for example, the complexation of C[Formula: see text] much easier. We thus have constructed novel organic photovoltaic systems using supramolecular complexes of porphyrin–peptide oligomers with fullerene clusters. The composite cluster OTE/SnO[Formula: see text] electrode prepared with (P(ZnP)[Formula: see text] C[Formula: see text], exhibits an impressive incident photon-to-photocurrent efficiency (IPCE) with values reaching as high as 56%. The power conversion efficiency of the (P(H[Formula: see text]P)[Formula: see text] C[Formula: see text] modified electrode reaches 1.6%, which is 40 times higher than the value (0.043%) of the porphyrin monomer (P(H[Formula: see text]P)[Formula: see text] [Formula: see text] C[Formula: see text] modified electrode. Thus, the organization approach between porphyrins and fullerenes with polypeptide structures is promising, and may make it possible to further improve the light energy conversion properties by using a larger number of porphyrins in a polypeptide unit.

Lanthanide(III) and yttrium(III) coordination compounds of diastereomeric (2+2) macrocyclic imines derived from 2,6-diformylpyridine and trans-1,2-diaminocyclopentane

The enantiopure mononuclear coordination compounds [Ln(L1)]Cl3·nH2O (Ln = Y(III), Nd(III), Sm(III), Eu(III), Tb(III), Yb(III)) of the chiral macrocyclic (2+2) imine L1 (L1RRRR and L1SSSS), derived from (1R,2R) and (1S,2S)-1,2-diaminocyclopentane (DACP) and 2,6-diformylpyridine (DFP), have been synthesized in the templated condensation of the precursors in the presence of the appropriate metal salts. From the racemic trans-DACP and DFP in the templated condensation, a series of racemic mononuclear coordination compounds [Ln(L1rac)]Cl3·nH2O (Ln = Y(III), Nd(III), Sm(III), Eu(III), Tb(III), Yb(III)) have been obtained. In the absence of metal salt, the condensation of the achiral precursors leads to a meso type Schiff base L2, which in the presence of lanthanide(III) salts produced the mononuclear coordination compounds [Ln(L2)]Cl3·nH2O (Ln = Y(III), Nd(III), Sm(III), Eu(III), Tb(III)). The mononuclear coordination compounds with the L1 and L2 ligands have been characterised by NMR spectroscopy, mass spectrometry, elemental analyses and/or circular dichroism (CD). 1H NMR signals of CDCl3/CD3OD solutions of the Y(III), Nd(III), Sm(III) and Eu(III) coordination compounds have been assigned on the basis of their COSY and HMQC spectra, and for the remaining lanthanide coordination compounds (Tb(III) and Yb(III)) the signals were tentatively assigned on the basis of linewidths analyses. The properties and stability of the lanthanide(III) and yttrium(II) coordination compounds of the racemic macrocycle L1rac have been compared with those of the isomeric meso type macrocycle L2 in organic solvents and water. Axial ligand exchange for several coordination compounds was investigated by 1H NMR titration experiments in organic solvents. The X-ray crystal structures of the representative mononuclear coordination compounds [Nd(L1RRRR)Cl(H2O)2]Cl2·0.5MeOH·H2O, [Nd(L1rac)Cl(H2O)2]Cl2·1.6MeOH·0.2H2O, [Y(L1rac)Cl(H2O)2]Cl2·3.5H2O, [Y(L1rac)Cl(H2O)2][Y(L1rac)(H2O)3]Cl5·6.8H2O and [Nd(L2)Cl2(H2O)]Cl with the diastereomeric ligands L1 and L2 have been determined.

Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

New water soluble, enantiopure arene ruthenium compound SRuSN-(1R,4S)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (Bn = benzyl, 1a′) has been synthesized. The novel compound along with that previously described RRuRN-(1S,4R)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a′ was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a′ induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a′ towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells.

Easy Access to Enantiopure (S)‐ and (R)‐Aryl Alkyl Alcohols by a Combination of Gold(III)‐Catalyzed Alkyne Hydration and Enzymatic Reduction

AbstractChemoenzymatic one‐pot processes based on the combination of metal catalysis and biocatalysis open up highly attractive perspectives regarding the production of enantiopure compounds. By combining a gold‐catalyzed hydration reaction with an enzymatic reduction, we present a straightforward and atom‐economical chemoenzymatic method for the synthesis of secondary alcohols with excellent optical purity. Efficient cofactor recycling exploits the solvent of the metal‐catalyzed step as an auxiliary substrate for the enzymatic step.

Elucidation of the Chromatographic Enantiomer Elution Order Through Computational Studies.

During the last twenty years, the interest towards the development of chiral compound has exponentially been increased. Indeed, the set-up of suitable asymmetric enantioselective synthesis protocols is currently one of the focuses of many pharmaceutical research projects. In this scenario, chiral HPLC separations have gained great importance as well, both for analytical- and preparative-scale applications, the latter devoted to the quantitative isolation of enantiopure compounds. Molecular modelling and quantum chemistry methods can be fruitfully applied to solve chirality related problems especially when enantiomerically pure reference standards are missing. In this framework, with the aim to explain the molecular basis of the enantioselective retention, we performed computational studies to rationalize the enantiomer elution order with both low- and high-molecular weight chiral selectors. Semi-empirical and quantum mechanical computational procedures were successfully applied in the domains of chiral ligand-exchange and chiral ion-exchange chromatography, as well as in studies dealing with the use of polysaccharide-based enantioresolving materials.

Lateral sorting of chiral nanoparticles using Fano-enhanced chiral force in visible region.

Chiral gradient force allows a passive separation of an enantiomer since its direction is dependent on the handedness of its chiral entities. However, chiral polarisability is much weaker than electric polarisability. As a consequence, the non-chiral gradient force dominates over chiral force, which makes enantioselective sorting challenging. We present here, both numerically and analytically, that the chiral gradient force acting on chiral nanoparticles can overcome the non-chiral force when specimens are placed in a Fano-enhanced chiral gradient near-field using a plasmonic nanoaperture. Under circularly polarized light illumination, the interaction between the resonant modes of symmetric outer and asymmetric inner Au split-rings results in a splitting of the modal energies, which excites multipolar interference Fano resonances (FRs). This enables a local aperture between the two split-rings to possess very large optical chirality gradients while maintaining low gradients of electromagnetic energy density around the FRs from the visible region. By way of the lateral resultant force composed of both chiral and non-chiral gradient forces, we can accomplish a helicity-dependent transverse deflection of the chiral nanoparticles positioned above the aperture, which may offer a good platform for all-optical enantiopure compounds.

Levoglucosenone and Its New Applications: Valorization of Cellulose Residues

The need to find sustainable alternatives to reduce the dependence on fossil sources has led to significant research efforts on the conversion of biomass into platform chemicals. Modern organic chemistry requires easily obtainable chiral building blocks that show high chemical versatility for their application in the synthesis of enantiopure compounds. The selective pyrolytic conversion of cellulose or cellulose‐containing materials produces levoglucosenone, a highly functionalized chiral structure. This compound has been innovatively used as a template for the synthesis of key intermediates of biologically active products and for the preparation of chiral auxiliaries, catalysts, and organocatalysts for their application in asymmetric synthesis.

Highly Efficient and Robust Enantioselective Liquid-Liquid Extraction of 1,2-Amino Alcohols utilizing VAPOL- and VANOL-based Phosphoric Acid Hosts.

The large-scale production of enantiopure compounds in a cost-effective and environmentally friendly manner remains one of the major challenges of modern-day chemistry. The resolution of racemates through enantioselective liquid-liquid extraction was developed as a suitable solution but has remained largely underused, owing to a lack of highly efficient and robust chiral hosts to mediate the process. This paucity of hosts can in part be attributed to a poor understanding of the underlying principles behind these processes hindering the design of more efficient selectors. A previously untested class of hosts, VAPOL and VANOL derived phosphoric acids, has been studied in depth for the efficient enantioselective liquid-liquid extraction of 1,2-amino alcohols. A systematic investigation of extraction parameters was conducted, revealing many key interactions and DFT calculations illustrate the binding modes for the 1:1 complexes that are involved in chiral recognition. The resulting, now-optimized, procedures are highly robust and easy to implement. They are also easily scalable, as demonstrated by U-tube experiments.

Learning epistatic interactions from sequence-activity data to predict enantioselectivity.

Enzymes with a high selectivity are desirable for improving economics of chemical synthesis of enantiopure compounds. To improve enzyme selectivity mutations are often introduced near the catalytic active site. In this compact environment epistatic interactions between residues, where contributions to selectivity are non-additive, play a significant role in determining the degree of selectivity. Using support vector machine regression models we map mutations to the experimentally characterised enantioselectivities for a set of 136 variants of the epoxide hydrolase from the fungus Aspergillus niger (AnEH). We investigate whether the influence a mutation has on enzyme selectivity can be accurately predicted through linear models, and whether prediction accuracy can be improved using higher-order counterparts. Comparing linear and polynomial degree = 2 models, mean Pearson coefficients (r) from [Formula: see text]-fold cross-validation increase from 0.84 to 0.91 respectively. Equivalent models tested on interaction-minimised sequences achieve values of [Formula: see text] and [Formula: see text]. As expected, testing on a simulated control data set with no interactions results in no significant improvements from higher-order models. Additional experimentally derived AnEH mutants are tested with linear and polynomial degree = 2 models, with values increasing from [Formula: see text] to [Formula: see text] respectively. The study demonstrates that linear models perform well, however the representation of epistatic interactions in predictive models improves identification of selectivity-enhancing mutations. The improvement is attributed to higher-order kernel functions that represent epistatic interactions between residues.