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The synthesis, characterization, and structure-guided application of a new class of highly versatile chiral C2-symmetric diamine-oligothiophene ligands in Pd-catalyzed asymmetric transformations are presented. Experimental investigations of the intimate role of pendant pi-conjugate oligothiophenes in determining the catalytic activity of the corresponding chiral Pd complexes are described. Their unusual behavior opens up new routes toward the logical design of finely tuned organometallic catalysts by remote structural functionalizations.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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The new enantiopure macrocyclic complexes [LnL]Cl3·nH20 or their racemic mixtures [LnracL]Cl3·nH20 (Ln=La+3, Ce+3, Pr+3 and Eu+3) have been synthesised in a template condensation of trans-1,2-diaminocyclohexane and 2,6-diformylpyridine. The complexes have been studied by 1H and 13C NMR spectroscopy. The signal assignment was based on the COSY, NOESY and HMQC measurements. The X-ray crystal structure of [LaracL]Cl3 complex has been determined. The lanthanum ion in this complex is coordinated by six nitrogen atoms of the macrocyclic ligand and three chloride anions. The macrocycle exhibits a twist-bent conformation of approximate C2 symmetry. On the other hand, NMR spectra of the investigated compounds in methanol-chloroform solution indicate effective D2-symmetry that results from the fast dynamic exchange of chloride anions.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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A process is provided for the hydrogenation or asymmetric hydrogenation of dialkyl, alkylalkenyl and dialkenyl imines of formula (II) to provide amines of formula (III), wherein, (i) R1 and R2 are optionally substituted cyclic, linear or branched alkyl or alkenyl; R3 is a hydrogen atom, a hydroxy radical, optionally substituted C1 to C8 cyclic, linear or branched alkyl or alkenyl, optionally substituted aryl; or (ii) R1 is alkyl or alkenyl, R2 is alkyl or alkenyl and the two are linked together or with R3 to form one or more rings; using a catalytic system comprising a base and a ruthenium complex containing (1) a diamine and (2) a diphosphine ligand or monodentate phosphine ligands in hydrogenation and asymmetric hydrogenation processes.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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A series of chiral salan (salalen) ligands, easily prepared from the aldehyde derived from chiral binaphthol, are effective ligands for the titanium-catalyzed asymmetric epoxidation of olefins with aqueous H2O2 as the oxidant. One of the titanium-salan complexes was determined by X-ray crystallography.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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A study was conducted to demonstrate that H-bond based asymmetric organocatalysis can be performed under the so-called in the presence of water conditions. Nitroalkane, catalyst, dimethylcyclohexylamine, benzaldehyde and aniline were mixed to a 0C cooled and vigorously stirred aqueous solution of NaOAc/AcOH saturated with NaCl. The organic residues were taken into dichloromethane and decanted off. The combined organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel) using a mixture of hexanes/ethyl acetate. From a synthetic point of view, the reaction furnishes enantioenriched b-nitroamines decorated with aromatic or aliphatic substituents at the amine center and a different set of alkyl chains or rings attached to the carbon bearing the nitro functionality. Importantly, the reaction can be scaled up without losing yield and stereoselectivity and with full recovery of the catalyst.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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The design and synthesis of a novel, supramolecular allosteric catalyst system, assembled via the weak-link approach, is presented. The catalyst contains two structural Rh(I) centers in thioether- and phosphine-rich hemilabile pockets, and two functional Cr(III) centers bound within salen-based moieties. The catalytic properties of the supramolecular catalyst are compared to those of a Cr(III)-salen monomeric analogue in the context of the asymmetric ring opening of cyclohexene oxide by TMSN3. Allosteric control is afforded via reactions that occur at distal sites which open the macrocyclic cavity and facilitate the catalytic reaction. Kinetic data show a significant rate increase upon opening of the catalyst’s flexible macrocyclic cavity and enhanced selectivity and reactivity with respect to the monomeric Cr(III)-salen analogue. The work presented represents a new approach to the construction of abiotic allosteric catalysts. Copyright

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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A facile and mild reduction procedure is reported for the preparation of chiral secondary alcohols prepared from alpha-substituted ketones using sodium borohydride and the chiral boronate ester (l)-TarB-NO2. Direct reduction of substituted ketones bearing Lewis basic heteroatoms generally provided secondary alcohols of only modest enantiomeric excess likely due to either competition between the target carbonyl and the functionalized sidechains at the Lewis acidic boron atom in TarB-NO2 or the added steric bulk of the alpha-sidechain. As an alternative method, these substrates were synthesized using TarB-NO2 via a two-step procedure involving the reduction of an alpha-halo ketone to a chiral terminal epoxide, followed by regioselective/regiospecific epoxide opening by various nucleophiles. This procedure provides access to a variety of functionalized secondary alcohols including beta-hydroxy ethers, thioethers, nitriles, and amines with enantiomeric excesses of 94% and yields up to 98%.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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A series of Schiff base bridged bis(indolyl) ligands were developed for aluminum chemistry. The reactions of AlEt3 or AlMe3 with the Schiff base bridged bis(indolyl) proligands R1(-NCHC8H5NH)2 (R1 = -CH2CH2- (H2L1); -CH2CH2CH2- (H2L2); -CH2CMe2CH2- (H2L3); rac-Cy (H2L4); and R,R-Cy (H2L5)) were studied leading to the synthesis of a series of aluminum alkyl complexes L1AlEt (1)-L5AlEt (5) and L3AlMe (3b) in good yields, while the reaction of H2L3 with Al(OiPr)3 gave the aluminum alkoxide complex L3AlOiPr (3a). These aluminum complexes were characterized by spectroscopic methods and elemental analyses. The solid state structures of the aluminum complexes 1-5 and 3a were confirmed by the X-ray diffraction study. X-ray analyses revealed that the aluminum centre in these complexes is five-coordinated. The coordination geometry is between square pyramidal and trigonal bipyramidal. In the presence of 1 equiv. of isopropanol, the aluminum alkyl complexes exhibited notable activity towards the ring-opening polymerization of rac-lactide at 70 C in toluene, with good control over molecular weights and dispersities. The substituents and the length of the bridging part between the two Schiff base nitrogen atoms have an influence on either the tacticity of isolated polymers or the rate of polymerization. The kinetics of complex L3AlOiPr (3a) in C6D6 was also investigated, and the experimental results revealed that the rate of polymerization was first-order with respect to rac-lactide.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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Recently, a novel chiral cubane-based Schiff base ligand was reported to yield modest enantioselectivity in the Henry reaction. To further explore the utility of this ligand in other asymmetric organic transformations, we evaluated its stereoselectivity in cyclopropanation and Michael addition reactions. Although there was no increase in stereocontrol, upon computational evaluation using both M06L and B3LYP calculations, it was revealed that a pseudo six-membered ring exists, through H-bonding of a cubyl hydrogen to the copper core. This decreases the steric bulk above the copper center and limits the asymmetric control with this ligand.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI

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Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC50 = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.

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Reference:
Metal catalyst and ligand design,
Ligand Template Strategies for Catalyst Encapsulation – NCBI