Chiral Derivatives Research Articles

Chiral Cyclopentadienyl Ligands: Design, Syntheses, and Applications in Asymmetric Catalysis

AbstractThe creation of new chiral ligands capable of providing high stereocontrol in metal‐catalyzed reactions is crucial in modern organic synthesis. The production of bioactive molecules as single enantiomers is increasingly required, and asymmetric catalysis with metal complexes constitutes one of the most efficient synthetic strategies to access optically active compounds. Herein we offer a historical overview on the development of chiral derivatives of the ubiquitous cyclopentadienyl ligand (CpX), and detail their successful application in a broad range of metal‐catalyzed transformations. Those include the functionalization of challenging C−H bonds and beyond, giving access to an extensive catalogue of valuable chiral molecules. A critical comparison of the existing ligand families, their design, synthesis, and complexation to different metals is also provided. In addition, future research directions are discussed to further enhance the performance and application of CpXligands in enantioselective catalysis.

Enantioselective Synthesis of Tetrahydroquinolines viaOne‐Pot Cascade Biomimetic Reduction†

Summary of main observation and conclusionA novel and efficient protocol for the synthesis of chiral tetrahydroquinoline derivatives with excellent enantioselectivities and high yields has been developed through one‐pot cascade biomimetic reduction. The detailed reaction pathway includes the acid‐catalyzed and ruthenium‐catalyzed formation of aromatic quinoline intermediates and biomimetic asymmetric reduction.

The antidepressant-like activity of chiral xanthone derivatives may be mediated by 5-HT1A receptor and β-arrestin signalling.

Our previous studies showed that xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 (R, S) and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity. We aimed to assess the in vitro and in vivo pharmacological activity of the xanthone derivatives. We evaluated the in vitro affinity for serotonin 5-HT1A and 5-HT2A receptors and serotonin transporter. We also determined the intrinsic activity at the 5-HT1A receptor. We investigated the antidepressant-like properties and safety after acute administration (dose range: 1.25-20 mg/kg) using the forced swim, tail suspension, locomotor activity, rotarod and chimney tests in mice. We also evaluated the basic pharmacokinetic parameters. Our results indicated that the compounds showed a high affinity for the 5-HT1A receptor but very weak antagonistic properties in the Ca2+ mobilization assay; however, they showed significant agonistic properties in the β-arrestin recruitment assay. In both behavioural tests the studied xanthone derivatives showed antidepressant-like activity. Pre-treatment with p-chlorophenylalanine or WAY-100635 abolished their antidepressant-like activity. None of the compounds caused motor impairments at antidepressant-like doses. The racemate penetrated the blood-brain barrier and had a relatively high bioavailability after intraperitoneal administration. Xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment and hydroxypropoxy linker show increased binding to the 5-HT1A receptor and may represent an attractive putative treatment candidate for depression.

Simultaneous Quantitative Determination of Synthetic Cathinone Enantiomers in Urine by GC-NCI-MS/MS using Menthylchloroformate as Chiral Derivatization Reagent

Development and validation of a new analytical method for enantioseparation and quantitation of synthetic cathinones is reported using a chiral derivatization agent (CDA) and GC-MS triple quadrupole mass spectrometry with negative chemical ionization (NCI) mode. Indirect separation of ten synthetic cathinone compounds has been achieved using a commercially available optically pure CDA called (1R)-(-)-menthylchloroformate (MCF). MCF was capable of converting synthetic cathinone enantiomers into diastereoisomers, which were later separated with good resolution on an ultra-inert 60 m achiral stationary phase column. An internal standard (IS), 3-methylmethcathinone (3-MMC) was used for quantitation of synthetic cathinone diastereoisomers. Method validation in terms of calibration curve linearity, sensitivity in terms of limits of detections (LODs), limits of quantitation (LOQs), interday and intra-day reproducibility, and recoveries has been obtained for the ten synthetic cathinone compounds that were analyzed simultaneously as a mixture after being spiked in urine. It was found that LOD’s and LOQ’s for the ten synthetic cathinones mixture in urine were in the ranges of 0.004-3.678 ppm and 0.012-11.14 ppm respectively. The results of four synthetic cathinones (Buphedrone, 3-MethylBP,3,4-DMEC, and Butylone) derivatized with MCF were compared with the same compounds derivatized with N-trifluoroacetyl-L-prolyl chloride (L-TPC). It was found that the later was more sensitive in terms of LOD and LOQ than the former method.

The Self-Aggregation of Porphyrins with Multiple Chiral Centers in Organic/Aqueous Media: The Case of Sugar- and Steroid-Porphyrin Conjugates.

An overview of the solvent-driven aggregation of a series of chiral porphyrin derivatives studied by optical methods (UV/Vis, fluorescence, CD and RLS spectroscopies) is herein reported. The investigated porphyrins are characterized by the presence in the meso-positions of glycol-, steroidal- and glucosteroidal moieties, conferring amphiphilicity and solubility in aqueous media to the primarily hydrophobic porphyrin platform. Aggregation of the macrocycles is driven by a change in bulk solvent composition, forming architectures with supramolecular chirality, steered by the stereogenic centers on the porphyrin peripheral positions. The aggregation behavior and chiroptical properties of the final aggregated species strongly depend on the number and stereogenicity of the ancillary groups that dictate the mutual spatial arrangement of the porphyrin chromophores and their further organization in larger structures, usually detectable by different microscopies, such as AFM and SEM. Kinetic studies are fundamental to understand the aggregation mechanism, which is frequently found to be dependent on the substrate concentration. Additionally, Molecular Mechanics calculations can give insights into the intimate nature of the driving forces governing the self-assembly process. The critical use of these combined methods can shed light on the overall self-assembly process of chirally-functionalized macrocycles, with important implications on the development of chiral porphyrin-based materials.

Asymmetric Three-Component Propargyloxylation for Direct Assembly of Polyfunctionalized Chiral Succinate Derivatives

An enantioselective three-component propargyloxylation reaction of propargyl alcohols, pyridotriazoles, and imines has been realized by cooperative catalysis with dirhodium complex and chiral phosp...

Insights into the Role of Transient Chiral Mediators and Pyridone Ligands in Asymmetric Pd-Catalyzed C-H Functionalization.

Mechanistic investigations uncover a novel role for 2-pyridone ligands and interrogate the origin of enantioselectivity in the (+)-norbornene-mediated Pd-catalyzed meta-C(aryl)-H functionalization of diarylmethylamines. Observations from kinetic analysis in concert with in situ 19F NMR monitoring allow us to propose that the pyridone ligand plays a role in enhancing the rate- and enantio-determining insertion of an arylpalladium species into a chiral norbornene derivative. The unprecedented features of 2-pyridone ligands in asymmetric 1,2 migratory insertion, and norbornene as a transient chiral mediator in relay chemistry, provide new insights into this ligand scaffold for future developments in stereoselective transition-metal-catalyzed C-H functionalization.

Catalytic Asymmetric Synthesis of Atropisomeric Nitrones: Versatile Intermediate for Axially Chiral Biaryls.

A Cu-catalyzed asymmetric ring-opening reaction of five-membered diaryliodonium salts and oximes is introduced. The reactions undergo selective N-arylation of oximes and provide an efficient protocol for the synthesis of atropisomeric nitrones. The optically active nitrones, serving as versatile intermediates, were converted to diversely functionalized axially chiral aniline derivatives and N-heterocycles.

Theoretical Investigation of the Circularly Polarized Luminescence of a Chiral Boron Dipyrromethene (BODIPY) Dye.

Over the last decade, molecules capable of emitting circularly polarized light have attracted growing attention for potential technological and biological applications. The efficiency of such devices depend on multiple parameters, in particular the magnitude and wavelength of the peak of emitted light, and also on the dissymmetry factor for chiral applications. In light of these considerations, molecular systems with tunable optical properties, preferably in the visible spectral region, are particularly appealing. This is the case of boron dipyrromethene (BODIPY) dyes, which exhibit large molecular absorption coefficients, have high fluorescence yields, are very stable, both thermally and photochemically, and can be easily functionalized. The latter property has been extensively exploited in the literature to produce chromophores with a wide range of optical properties. Nevertheless, only a few chiral BODIPYs have been synthetized and investigated so far. Using a recently reported axially chiral BODIPY derivative where an axially chiral BINOL unit has been attached to the chromophore unit, we present a comprehensive computational protocol to predict and interpret the one-photon absorption and emission spectra, together with their chiroptical counterparts. From the physico-chemical properties of this molecule, it will be possible to understand the origin of the circularly polarized luminescence better, thus helping to fine-tune the properties of interest. The sensitivity of such processes require accurate results, which can be achieved through a proper account of the vibrational structure in optical spectra. Methodologies to compute vibrationally-resolved electronic spectra can now be applied on relatively large chromophores, such as BODIPYs, but require more extensive computational protocols. For this reason, particular attention is paid in the description of the different steps of the protocol, and the potential pitfalls. Finally, we show how, by means of appropriate tools and approaches, data from intermediate steps of the simulation of the final spectra can be used to obtain further insights into the properties of the molecular system under investigation and the origin of the visible bands.

The Assignment of the Absolute Configuration of β-Chiral Primary Alcohols with Axially Chiral Trifluoromethylbenzimidazolylbenzoic Acid.

Axially chiral trifluoromethylbenzimidazolylbenzoic acid (TBBA) was used as a chiral derivatization agent for the assignment of the absolute configuration of β-chiral primary alcohols. The structures varied from simple aliphatic alcohols to complex cyclic systems and highly substituted sugar derivatives. The NMR-based method was successfully implemented to evaluate 17 compounds and displayed ΔδPM values higher than 0.1 ppm in most cases, which makes TBBA superior to MTPA and MPA and comparable to 9-AMA.

Synthesis of New Chiral Derivatives of Xanthones with Enantioselective Effect on Tumor Cell Growth and DNA Crosslinking

AbstractA new series of thirty‐two new enantiomerically pure derivatives of xanthones (3–34) were synthesized for antitumor evaluation. Two carboxyxanthones (1 and 2) were used as chemical substrates and coupled with selected chiral building blocks (43–62), achieving yields and enantiomeric excess (ee) values higher than 92 and 99 %, respectively. Carboxyxanthones 1 and 2 were synthesized, by a multi‐step synthetic pathway via diaryl ether intermediate (Ullman reaction), being compound 2 described here for the first time. The evaluation of the growth inhibitory activity allowed to find active chiral compounds for all the tested cells lines, and to establish structure‐activity relationship (SAR) considerations. In some cases, the growth inhibitory effects demonstrated to be dependent on the stereochemistry of the compounds. Interestingly, the most active compound (12) and its enantiomer (11) demonstrated high enantioselectivity for MCF‐7 breast adenocarcinoma cell line. In addition, in vitro DNA crosslinking ability was assessed and the results correlated with in vitro cytotoxicity.

Buclizine crystal forms: First Structural Determinations, counter-ion stoichiometry, hydration, and physicochemical properties of pharmaceutical relevance.

Buclizine (BCZ) is a chiral synthetic piperazine derivative which has antihistaminic, anti-muscarinic and antiemetic properties, and has been reintroduced as an appetite stimulant, especially for pediatric patients. Structural information about this drug, as well as other buclizine crystalline forms (solvates, salts and co-crystals) including the BCZ free-base (BCZ-FB), is non-existent. Here, we present for the first time the crystal structure of the monohydrochloride monohydrate salt of BCZ (BCZHCl·H2O), and of its anhydrous form, BCZHCl. Interestingly, BCZHCl·H2O was obtained by recrystallization from the raw material (BCZH2Cl2) in ethanol:water solution showing that BCZ anhydrous dihydrochloride salt changes easily to a monohydrochloride monohydrate salt modification, which raise concerns about formulation quality control. BCZHCl·H2O and BCZHCl crystallize in the orthorhombic space groups (Pna21 and Pca21) belonging to the mm2 point group and are thus classified as non-centrosymmetric achiral structures (NA). Intuitively, we expect these salts to crystallize in a space group with a center of symmetry, since less than 5% of the known racemic compounds crystallize in the NA type. The crystal structures of BCZH2Cl2 and BCZ-FB were not determined, but their existence was verified by other techniques (chloride ion analysis, PXRD, HPLC, FT-IR, DSC, TGA) and by comparison of the obtained results with those found for BCZHCl. Additionally, we have also performed an evaluation of the equilibrium solubility (at six different aqueous media) and the dissolution profile of the BCZHCl salt compared to the raw material and BCZ-FB. Different equilibrium solubility values were found comparing the three forms in acidic and neutral pH ranges and all of them were insoluble at pH>7.0. Moreover, tablets prepared with BCZH2Cl2, BCZHCl or BCZ-FB show significant differences in terms of dissolution profile.

Antitumor Activity In Vivo and Vitro of New Chiral Derivatives of Baicalin and Induced Apoptosis via the PI3K/Akt Signaling Pathway

In this study, a pair of chiral baicalin (BA) derivatives were synthesized by combining BA with phenylalanine methyl ester based on molecular docking technology, namely BAD and BAL. Cell cytotoxicity trails showed that the cell growth inhibitory effects of both BAD and BAL were increased by 8- to 12-fold compared with BA on A549 cells. Flow cytometry showed that the apoptotic rates of 50 μg/mL BA, BAD, and BAL to A549 cells for 48 h were 17.94%, 24.32%, and 39.69%, respectively. Western blotting analysis showed that BAD and BAL could promote Bax, caspase-3, and caspase-9 expression and inhibit Bcl-2 expression by inhibiting the expression of p-Akt. The tumor inhibition rates of BA, BAD, and BAL in nude mice of tumor-bearing experiment lasting for 24 days were 35.01%, 53.30%, and 59.35%, respectively. These results in vitro and in vivo showed that BAL had higher antitumor activity than did BAD and BA, which were related to promotion of the apoptosis of tumor cells by inhibiting the expression of p-Akt on PI3K/Akt pathway. This study provides an experimental basis for the development of a new configuration of BA for the treatment of cancer.

Preparation of chiral izobenzofuranes based on 3-carene in the presence of halloysite nanocatalysts

The reaction of a 2-carene containing mixture, obtained by 3-carene isomerization, with 4-methoxybenzalde-hyde in the presence of halloysite nanotubes treated with 5.0 % HCl was studied. The main reaction products are the chiral derivatives of isobenzofuran. Selectivity to these compounds (71.4 %) is comparable to that when only 2-carene is used as a reactant. Thus, the possibility is shown how to use halloysite nanocatalysts for selective production of isobenzofuran compounds based on 3-carene isomerization products (major component of turpentine) without preliminary mixture separation.

Atroposelective Access to Oxindole-Based Axially Chiral Styrenes via the Strategy of Catalytic Kinetic Resolution

Atroposelective synthesis of axially chiral molecules has attracted substantial attention from chemists because of the importance of such molecules. However, catalytic asymmetric synthesis of axially chiral styrenes or vinyl arenes is underdeveloped and challenging due to the low rotational barrier and weak configurational stability of such molecules. Therefore, the development of powerful strategies for the catalytic atroposelective synthesis of axially chiral styrenes or vinyl arenes is of great importance. In this work, we have accomplished the first atroposelective access to oxindole-based axially chiral styrenes by the strategy of catalytic kinetic resolution, and this strategy offered two kinds of oxindole-based axially chiral styrene derivatives in good diastereoselectivities (up to 94:6 dr) and excellent enantioselectivities (up to 98% ee) with high selectivity factors (S up to 106). This strategy not only provides easy access to oxindole-based axially chiral styrenes but also offers a robust method for synthesizing bisamide derivatives bearing both axial and central chirality. More importantly, this strategy has added a new class of members to the atropisomeric family, especially to the family of axially chiral styrenes.

Divergent and Diastereoselective Synthesis of α-Monosubstituted and trans-α,β-Disubstituted γ-Lactams from (S)-N,N-Dibenzyl-α-amino Aldehydes via Henry and Michael Reactions

γ-Monosubstituted and trans-α,β-disubstituted γ-lactams were diastereoselectively synthesized from common intermediates (S)-N,N-dibenzylated aldehydes derived from natural l-(α)-amino acids, employing a divergent approach. The key features of the routes include diastereoselective Henry and Michael reactions that produced chiral γ-nitroester derivatives, which were subsequently submitted to a tandem reduction-lactamization sequence providing the title compounds. The versatility of routes can allow the preparation of several other mono-, di-, or tri-substituted γ-lactams.

Microchemical enantioseparation of betaxolol and orciprenaline by reversed phase HPLC

AbstractEnantioseparation of (RS)‐orciprenaline and (RS)‐betaxolol was achieved by synthesizing their diastereomeric derivatives with chiral derivatizing reagents prepared on a cyanuric chloride platform. There were three dichloro‐triazine derivatives with amino acid amides as chiral auxiliaries and three monochloro‐triazine derivatives with methoxy as achiral moiety and amino acid amides as chiral auxiliaries in cyanuric chloride. A total of 12 pairs of diastereomeric derivatives were synthesized under microwave irradiation and were separated using reversed phase high‐performance liquid chromatography by applying different mobile phases on a C18 column in gradient eluting mode with ultraviolet detection at 230 nm. Resolutions were compared and interpreted on the basis of structure of chiral auxiliaries. Besides, diastereomeric derivatives were separated by open column chromatography and the samples so obtained were used for confirmation of their elution order and configuration by 1H‐NMR spectroscopy. In addition, lowest energy optimized structures of diastereomeric derivatives were developed using the density functional theory based Gaussian software that were interpreted to supplement the absolute configurations. The method validation was carried out for detection limit, linearity, accuracy, and precision. Limits of detection were 0.005 and 0.007 µg/mL.

Enantioselective Synthesis of Cyclopropanone Equivalents and Application to the Formation of Chiral β-Lactams.

Cyclopropanone derivatives have long been considered unsustainable synthetic intermediates because of their extreme strain and kinetic instability. Reported here is the enantioselective synthesis of 1-sulfonylcyclopropanols, as stable yet powerful equivalents of the corresponding cyclopropanone derivatives, by α-hydroxylation of sulfonylcyclopropanes using a bis(silyl) peroxide as the electrophilic oxygen source. This work constitutes the first general approach to enantioenriched cyclopropanone derivatives. Both the electronic and steric nature of the sulfonyl moiety, which serves as a base-labile protecting group and confers crystallinity to these cyclopropanone precursors, were found to have a crucial impact on the rate of equilibration to the corresponding cyclopropanone. The utility of these cyclopropanone surrogates is demonstrated in a mild and stereospecific formal [3+1] cycloaddition with simple hydroxylamines, leading to the efficient formation of chiral β-lactam derivatives.

Catalytic Asymmetric Substitution Reaction of 3-Substituted 2-Indolylmethanols with 2-Naphthols

A catalytic asymmetric substitution of 3-substituted 2-indolylmethanols with 2-naphthols has been established under the catalysis of chiral phosphoric acid. By this approach, a series of structurally diversified triarylmethane derivatives were obtained in moderate to high yields with good enantioselectivities (up to 97% yield, 95:5 er). This approach not only enriches the chemistry of 2-indolylmethanol-inolved catalytic asymmetric substitutions, but also provides a useful method for the enantioselective synthesis of chiral triarylmethane derivatives.

Quasi-relativistic study of nuclear electric quadrupole coupling constants in chiral molecules containing heavy elements

A quasi-relativistic (two-component) zeroth-order regular approximation model potential approach is employed to calculate nuclear electric quadrupole coupling tensors of the chiral polyhalomethane derivatives CHBrClF and CHClFI. Each of these two chiral compounds contains two nuclei with electric quadrupole moments, which poses special challenges for an analysis of high-resolution rovibrational spectra and, thus, renders predictions of electric field gradients and resulting nuclear electric quadrupole coupling tensors in such molecules particularly valuable. The theoretical approach is studied with respect to the influence of relativistic effects, by comparison to scalar-relativistic and non-relativistic calculations, and electron correlation effects, which are included within different flavours of density functional theory. The quality of the calculations is assessed by comparison to results from experiments reported previously by Bauder et al. and Soulard et al., respectively. It is shown that the local density approximation exchange-correlation functional gives results that agree with experiment within 12 % for all nuclear quadrupole coupling tensor components of 79Br and 127I. This benchmark test of the quasi-relativistic approach indicates its applicability to support upcoming microwave experiments with chiral heavy-element containing main group compounds.