Chiral Derivatives Research Articles

Facile access to chiral 1-pyrrolines through Rh-catalyzed enantioselective partial hydrogenation of unprotected simple pyrroles

Highly enantioselective Rh-catalyzed partial hydrogenation of unprotected simple 2-alkyl-5-aryl-disubstituted pyrroles has been successfully developed, generating a series of chiral 1-pyrroline derivatives generally with excellent results (95%–99% yields, 91%–96% ee). Moreover, 2,5-aryl-1H-pyrroles were hydrogenated well in high yields and good enantioselectivities. This efficient protocol features easily accessible substrates, wide substrate scope, well functional group compatibility, commercially available rhodium precursor and chiral ligand. It provides a versatile route to access chiral 1-pyrroline derivatives that are of great importance in organic synthesis and pharmaceutical chemistry.

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective C -Acetylation of Indolones

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective <i>C</i> -Acetylation of Indolones

In Vitro and In Silico Studies of Human Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibition by Stereoisomeric Forms of Lipophilic Nucleosides: The Role of Carbohydrate Stereochemistry in Ligand-Enzyme Interactions.

Inhibition of human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) by different chiral lipophilic nucleoside derivatives was studied. New Tdp1 inhibitors were found in the series of the studied compounds with IC50 = 2.7–6.7 μM. It was shown that D-lipophilic nucleoside derivatives manifested higher inhibition activity than their L-analogs, and configuration of the carbohydrate moiety can influence the mechanism of Tdp1 inhibition.

Limitations of Trifluoromethylbenzoimidazolylbenzoic Acid as a Chiral Derivatizing Agent to Assign Absolute Configuration for β-Chiral Aminoalcohols.

Axially chiral 2-(2-(trifluoromethyl)-1H-benzo[d]imidazole-1-yl)benzoic acid (TBBA) was used as a chiral derivatizing agent to evaluate the limits of absolute configuration assignment for β-chiral aminoalcohols. Seven Boc-aminoalcohols and eight variously N-substituted (S)-phenylglycinols were prepared, and their TBBA esters were analyzed by NMR spectroscopy. Diverse substitution at the β-position was employed to demonstrate the effect of structure on the general conformational model and reliability of the absolute configuration assignment. It was concluded that hydrogen bond formation and steric hindrance were the main factors affecting the correct assignment for Boc-aminoalcohols.

Nickel-Catalyzed Asymmetric Hydrogenation of γ-Keto Acids, Esters, and Amides to Chiral γ-Lactones and γ-Hydroxy Acid Derivatives.

A highly efficient asymmetric hydrogenation of a series of γ-keto acid derivatives, including γ-keto acids, esters, and amides, using a Ni-(R,R)-QuinoxP* complex as the catalyst has been developed to afford chiral γ-hydroxy acid derivatives with excellent enantioselectivities, up to 99.9% ee. This method provides not only an economical one-pot approach for the synthesis of chiral γ-lactones but also access to (S)-norfluoxetine, an inhibitor of neural serotonin reuptake and an essential intermediate for pharmaceutical synthesis.

Stereochemistry of Dihydropyrimidinones Derivatives Synthesized by Brick Dust Catalytic Reaction

A number of catalytic synthetic reactions have been reported which play the important role in stereochemistry of compounds. The key to the success of this protocol was the generation of stereogenic centers in 1, 4-Dihydropyrimidinones (DHPMs) and the influence of catalysts on their configuration. Waste brick dust was found to be an effective catalyst, generating chiral DHPMs derivatives using aryl aldehyde, urea, and ethyl acetoacetate. This work mainly focuses on the stereochemistry of brick-dust catalyzed DHPMs derivatives. Discovery of brick dust catalyst associated with several benefits such as rapid clean reaction, simple, and ease work-up.

Total Synthesis of ( + )-Swainsonine, (–)- Swainsonine, ( + )-8-epi-Swainsonine and ( + )- Dideoxy-Imino-Lyxitol by an Organocatalyzed Aldolization/Reductive Amination Sequence

A tactical combination of either ( S)- or ( R)-proline catalyzed aldol reaction followed by intramolecular reductive amination enabled the synthesis of a chiral pyrrolidine derivative with 3 contiguous stereocenters in only 2 synthetic steps, starting from achiral precursors. This product, obtainable in both enantiomeric forms, was further exploited as a common intermediate in total syntheses of the biologically active iminosugars: ( + )-swainsonine, (–)-swainsonine, ( + )-8- epi-swainsonine, and ( + )-dideoxy-imino-lyxitol.

Dication Containing Three Aromatic Ring Structure-Directs toward a Chiral Zeolite, Spans Three Cavities, and Effectively Traps Water

The chiral zeolite STW has been synthesized using a large dication containing three aromatic rings (two imidazolium moieties plus a benzene one). The integrity of the occluded organics is proven by 1H and 13C liquid NMR of the zeolite dissolved in HF/D2O. Molecular simulations strongly suggest that each aromatic ring is located in a different cavity so that each dication crosses two medium pore 10-membered-ring (MR) windows. This is confirmed by Rietveld refinement against synchrotron powder X-ray diffraction data, which suggests that there is also trapped water in the cavities, explaining a significant excess of H found in this material. The presence of water is very soundly confirmed by Fourier-transform infrared experiments, which also show that this water cannot leave the zeolite even after heating at 180 °C under vacuum. Molecular simulations allow us to conclude that this is due to the blockage of the 10 and 8MR windows by the occluded organics. The peculiar situation of an organic structure-directing agent spanning three cavities has important implications for the structure-direction concept that are briefly discussed. Several chiral derivatives of this dication have also been studied, and their possibility to enantioselectively direct the crystallization of STW has been analyzed.

Synthesis and characterization of aza[7]helicenes

Unsymmetrical aza[7]helicene is synthesized and its photophysical properties are studied. Its functionalization is carried out by Vilsmeier-Haack formylation, followed by its conversion to chiral amino derivative. The two formyl derivatives were characterized by single crystal X-ray diffraction analysis. The diastereomeric 2-aminomethyl aza[7]helicene was obtained in optically pure form, which shows high optical rotation values. Geometry optimization of aza[7]helicene was carried out using B3LYP/6–31G(d,p) level of theory and its HOMO-LUMO energy gap was calculated.

Chiral 1,3-aminosquaramides derived from cis-2-benzamidocyclohexanecarboxylic acid as organocatalysts for asymmetric Michael addition reactions

Herein, chiral 1,3-aminosquaramides derived from cis-2-benzamidocyclohexanecarboxylic acid, which is a chiral β-amino acid derivative, were synthesized and applied as bifunctional organocatalysts for asymmetric Michael addition reaction of 1,3-dicarbonyl compounds to β-nitrostyrenes. The catalyst structure and reaction conditions, such as solvent and temperature, were examined, and then, the optimized organocatalyst was successfully applied to the reaction of 1,3-diketones and 1,3-ketoesters with an enantioselectivity of up to 96%. Plausible transition state was proposed based on the results reported in previous reports and DFT calculations.

Solid-State Photophysical Properties of Chiral Perylene Diimide Derivatives: AIEnh-Circularly Polarized Luminescence from Vacuum-Deposited Thin Films

Abstract Studies on the optical properties of chiral perylene diimide derivatives, (S,S)- and (R,R)-BPP (BPP = N,N′-bis(1-phenylethyl)perylene-3,4,9,10-tetracarboxylic diimide), through absorption, steady-state and time-resolved fluorescence, and chiroptical spectroscopies revealed that the vacuum-deposited thin films of (S,S)- and (R,R)-BPP exhibit aggregation-induced enhanced (AIEnh) circularly polarized luminescence (CPL), as observed when they are dispersed in KBr and polymer matrices. Fluorescence lifetimes revealed that two emissive species exist in the deposited thin film: the dimer state with a fast decay and the weakly coupled excimer state with a slow decay. Unlike the dilute solutions of chiral BPPs, the deposited thin films displayed circular dichroism (CD) and CPL, indicating solid-state aggregation-induced chiroptical properties of chiral BPPs. Time-dependent density functional theory calculations on isolated monomer and π-stacked dimer suggested that the formation of a chirally twisted molecular arrangement through intermolecular π–π interactions is essential for the chiroptical properties of (S,S)- and (R,R)-BPP in the solid states. Moreover, we fabricated organic light-emitting diodes (OLEDs) using (S,S)- and (R,R)-BPP isomers as CPL emitters. The devices exhibited circularly polarized electroluminescence (CPEL) although the EL dissymmetry factor (gEL) was significantly low, as has been frequently noted in earlier studies.

Iridium-Catalyzed Asymmetric Allylic Substitution of Methyl Azaarenes.

Herein, an Ir-catalyzed asymmetric allylic substitution reaction of methyl azaarenes is described. Azaarenes such as (benzo)thiazole, oxazole, benzoimidazole, pyridine, and (iso)quinoline are all tolerated. The corresponding chiral azaarene derivatives are obtained in good yields with high enantioselectivity (up to 96 % yield and 99 % ee). The utilization of the Knochel reagent TMPZnBr⋅LiBr warrants the in situ formation of benzylic nucleophiles without additional activating reagents. 1 H NMR studies suggested a two-fold function of the Knochel reagent in this reaction. The synthetic utility of this method has been showcased by a concise enantioselective synthesis of an allosteric protein kinase modulator.

Iridium‐Catalyzed Asymmetric Allylic Substitution of Methyl Azaarenes

AbstractHerein, an Ir‐catalyzed asymmetric allylic substitution reaction of methyl azaarenes is described. Azaarenes such as (benzo)thiazole, oxazole, benzoimidazole, pyridine, and (iso)quinoline are all tolerated. The corresponding chiral azaarene derivatives are obtained in good yields with high enantioselectivity (up to 96 % yield and 99 % ee). The utilization of the Knochel reagent TMPZnBr⋅LiBr warrants the in situ formation of benzylic nucleophiles without additional activating reagents. 1H NMR studies suggested a two‐fold function of the Knochel reagent in this reaction. The synthetic utility of this method has been showcased by a concise enantioselective synthesis of an allosteric protein kinase modulator.

Dancing on Ropes ‐ Enantioselective Functionalization of Preformed Four‐Membered Carbocycles

Comprehensive SummaryCyclobutane derivatives have been recognized as useful structural motifs in organic synthesis and drug design. With the revival of photochemistry, the enantioselective synthesis of cyclobutane derivatives using [2 + 2]‐cycloadditions has garnered numerous attentions. On the other hand, enantioselective functionalization of preformed four‐membered carbocycles is emerging as an important complementary approach to access chiral cyclobutane derivatives with versatile structural patterns. Herein, we summarize recent advances in this field from 2012. To avoid undesired C—C bond cleavage driven by strain‐releasing, it is crucial to choose compatible methods for enantioselective functionalization and meanwhile preserving intact four‐membered ring skeleton. Guided by calculated hydrogenation enthalpies, which are used to evaluate the strain energy of indicated C—C bond, a clear picture of the developed methodologies on functionalization of four‐membered carbocycles combining the strain energy and enhanced reactivity is presented.

Procyanidins and Phlobatannins from the Twigs of Rosa multiflora and Their Neuroprotective Activity.

Three new procyanidins (1-3), two new phlobatannins (6 and 7), a new flavan-3,4-diol glycoside (9), and a new neolignan glycoside (10), along with three previously reported compounds (4, 5, and 8) were isolated from the twigs of Rosa multiflora. The chemical structures of the new compounds (1-3, 6, 7, 9, and 10) were characterized by spectroscopic data interpretation, including NMR (1H and 13C NMR, 1H-1H COSY, HSQC, HMBC, and NOESY) and HRESIMS analysis. Experimental ECD data analysis was conducted to assign the absolute configurations of the new compounds (1-3, 6, 7, 9, and 10). The absolute configuration of the sugar moieties was verified through a chiral derivatization method and LC-MS analysis. All the isolated compounds (1-10) were evaluated for their anti-neuroinflammatory activity based on inhibitory effects on nitric oxide production using a lipopolysaccharide-stimulated murine microglia BV-2 cell line and for their neurotrophic effects on nerve growth factor induction in C6 glioma.

Organocatalytic Diastereodivergent Enantioselective Formal oxa-Diels-Alder Reaction of Unsaturated Ketones with Enoates Under Liquid-Assisted Grinding Conditions.

Chiral heterocycles occur in many compounds of interest, but their efficient synthesis is challenging. This study concerns the enantioselective and diastereoselective synthesis of densely substituted chiral pyran derivatives. Diastereodivergence of the oxa-Diels-Alder reaction is achieved by using either a bifunctional amino-thiourea or a monofunctional quinine organocatalyst under ball-milling conditions. Liquid-assisted grinding proves a highly efficient means of affording pyrans in high yield, with high enantiomeric purities and short reaction times.

Nickel-Catalyzed Enantioselective C(sp 3 )–H Arylation of Ketones with Aryl Ethers via Selective C Ar –O Cleavage to Construct All-Carbon Quaternary Stereocenters

Nickel-Catalyzed Enantioselective C(sp ³ )–H Arylation of Ketones with Aryl Ethers via Selective C _Ar –O Cleavage to Construct All-Carbon Quaternary Stereocenters

Chiral Selenide/Achiral Sulfonic Acid Cocatalyzed Atroposelective Sulfenylation of Biaryl Phenols via a Desymmetrization/Kinetic Resolution Sequence.

Enantioselective synthesis of axially chiral sulfur-containing biaryl derivatives through the electrophilic sulfenylation of biaryl phenols has been achieved for the first time. This catalytic asymmetric system, which involves sequential desymmetrization and kinetic resolution, is enabled by a combination of a novel 3,3'-disubstituted BINOL-derived selenide catalyst and an achiral sulfonic acid. Control experiments and computational studies suggest that multiple noncovalent interactions between the cocatalysts and substrate, especially a network of hydrogen bond interactions, play a crucial role in determining the enantioselectivity and reactivity.

Axially Chiral Dodecanuclear Lanthanide Clusters Constructed by “Bottom‐Up” Self‐assembly for Enantioselective Sensing

Comprehensive SummaryVia the bottom‐up synthetic strategy, we synthesized a pair of dodecanuclear metal clusters of Eu12(C2O4)9(R/S‐BNP)18(EtOH)6(H2O)6·8EtOH·7H2O (complex 2), which represent the largest axial chiral lanthanide metal clusters. In the structure, rare four‐pointed star coordination mode of oxalic acid is reported by this work. In addition, as a fluorescence sensor, the complex 2 exhibits high enantioselectivity for R‐/S‐BINOL‐TF2 (EF = 2.87) and other chiral binaphthyl derivatives.

A Highly Selective and Sensitive Chiral Derivatization Method for High- Performance Liquid Chromatographic Determination of the Stereoisomer Composition of Natural Products With Chiral Branched Alkyl Chains.

In the study of chiral biologically active compounds such as pheromones, the analysis of the stereoisomer composition is essential to gain more insight into their stereochemical diversity, which affects the pheromone communication channels and therefore the diversification of species. This mini-review summarizes the development of fluorescence derivatization reagents for high-performance liquid chromatographic (HPLC) determination of the absolute configuration and stereoisomer composition of natural products with a chiral branched alkyl chain. The diastereomeric separation of anteiso fatty acids bearing a branched methyl group up to the C-26 position was achieved by reversed-phase HPLC under very low column temperature conditions using (1S,2S)-2-(2,3-anthracenedicarboximido)cyclohexanol as a derivatization reagent, enabling fluorescent detection of these compounds at femtomole levels. This method was also applicable to chiral alcohols and amines with chiral branched methyl groups using similar reagents containing a carboxyl group. These reagents were successfully applied to determine the absolute configurations and stereoisomer composition of the chiral alkyl chain of natural compounds including some insect pheromones, miyakosyne A, and plakoside A. The combination of these reagents and two-dimensional HPLC constitutes a very powerful tool for the analysis of the stereoisomers of natural crude samples. Furthermore, the analysis of some natural bioactive substances using this method demonstrated that natural substances are not always optically pure, consisting instead of stereoisomer mixtures exhibiting stronger activity than optically pure enantiomers. These results cast doubts on the concept of biological homochirality and demonstrate that natural pheromones do not always show the highest activity among all stereoisomers.