Asymmetric bifunctionalization of allenes with aryl iodides and amino acids enabled by chiral aldehyde/palladium combined catalysis.

Even though catalytic asymmetric bifunctionalization of allenes has been extensively studied, almost all of the reported examples have been achieved in a two-component manner. In this study, we report a highly efficient asymmetric bifunctionalization of allenes with iodohydrocarbons and NH2-unprotected amino acid esters. The adopted chiral aldehyde/palladium combined catalytic system precisely governs the chemoselectivity, regioselectivity, and stereoselectivity of this three-component reaction. A wide range of substituted aryl iodides, allenes and amino acid esters can well participate in this reaction and deliver structurally diverse α,α-disubstituted α-amino acid esters with excellent experimental outcomes. One of the resulting products is utilized for the total synthesis of the molecule (S,R)-VPC01091.

Asymmetric three-component Tsuji-Trost allylation reaction enabled by chiral aldehyde/palladium combined catalysis.

Despite the long-standing exploration of the catalytic asymmetric Tsuji-Trost allylation reaction since the mid-20th century, most reported instances have adhered to a two-component approach. Here, we present a remarkably efficient three-component asymmetric allylation reaction enabled by the collaborative action of chiral aldehyde and palladium. A diverse array of NH2-unprotected amino acid esters, aryl or alkenyl iodides, and allyl alcohol esters exhibit robust participation in this reaction, resulting in the synthesis of structurally diverse non-proteinogenic α-amino acid esters with favorable experimental outcomes. Mechanistic investigations reveal the dominance of the allylation/Heck coupling cascade in reactions involving electron-rich aryl iodides, while the Heck coupling/allylation cascade emerges as the dominant pathway in reactions involving electron-deficient aryl iodides. This chiral aldehyde/palladium combining catalytic system precisely governs the chemoselectivity of C-allylation and N-allylation, the regioselectivity of linear and branched allylation, and the enantioselectivity of C-allylation products.

Bifunctional Squaramide-Catalyzed Oxidative Kinetic Resolution: Simultaneous Access to Axially Chiral Thioether and Sulfoxide.

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo- and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene-based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.

Core Structure-Oriented Asymmetric α-Allenylic Alkylation of Amino Acid Esters Enabled by Chiral Aldehyde/Palladium Catalysis.

Aiming at the reported chiral synthons leading to manzacidins A and D, here we report a highly efficient catalytic asymmetric α-allenylic alkylation reaction of NH2-unprotected amino acid esters that is promoted by combined chiral aldehyde/palladium catalysis. Fifty examples of unnatural α,α-disubstituted amino acid esters are reported with good-to-excellent yields and stereoselectivities. Based on this methodology, a key intermediate leading to manzacidin C and its other three stereoisomers is prepared accordingly.

Asymmetric α-Allylation of N-Unprotected Amino Acid Esters with 1,3-Disubstituted Allyl Acetates Enabled by Chiral-Aldehyde/Palladium Catalysis.

A chiral aldehyde/palladium catalysis-enabled asymmetric α-allylation of NH2-unprotected amino acid esters with 1,3-disubstituted allyl acetates is described in this work. With the utilization of different chiral phosphine ligands, both the anti- and syn-selective allylation reactions are achieved enantioselectively. A series of α,α-disubstituted amino acid esters bearing two adjacent chiral centers are produced in moderate-to-excellent yields, diastereoselectivities, and enantioselectivities.

Chiral aldehyde catalysis enables direct asymmetric α-substitution reaction of N-unprotected amino acids with halohydrocarbons.

The direct catalytic α-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α-disubstituted non-proteinogenic α-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct α-hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric α-arylation, α-allylation, and α-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing α,α-disubstituted α-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric α-arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.

Chiral aldehyde-nickel dual catalysis enables asymmetric α-propargylation of amino acids and stereodivergent synthesis of NP25302.

The combined catalytic systems derived from organocatalysts and transition metals exhibit powerful activation and stereoselective-control abilities in asymmetric catalysis. This work describes a highly efficient chiral aldehyde-nickel dual catalytic system and its application for the direct asymmetric α-propargylation reaction of amino acid esters with propargylic alcohol derivatives. Various structural diversity α,α-disubstituted non-proteinogenic α-amino acid esters are produced in good-to-excellent yields and enantioselectivities. Furthermore, a stereodivergent synthesis of natural product NP25302 is achieved, and a reasonable reaction mechanism is proposed to illustrate the observed stereoselectivity based on the results of control experiments, nonlinear effect investigation, and HRMS detection.

Catalytic asymmetric Tsuji-Trost α-benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives.

Catalytic asymmetric Tsuji-Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

Enantioselective synthesis of α-amino ketones through palladium-catalyzed asymmetric arylation of α-keto imines.

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones through a chiral palladium-catalyzed arylation reaction of in situ generated challenging α-keto imines from previously unreported C-acyl N-sulfonyl-N,O-aminals, with arylboronic acids. The current reaction offers a straightforward approach to the asymmetric synthesis of acyclic α-amino ketones in a practical and highly stereocontrolled manner. Meanwhile, the multiple roles of the chiral Pd(ii) complex catalyst in the reaction were also reported.

Direct Catalytic Asymmetric α-Allylic Alkylation of Aza-aryl Methylamines by Chiral-Aldehyde-Involved Ternary Catalysis System.

A ternary catalytic system comprising a chiral aldehyde, a transition metal, and a Lewis acid is rationally designed for the asymmetric α-allylic alkylation reaction of aza-aryl methylamines and π-allylmetal electrophiles. Structural diversity chiral amines bearing carbon-carbon double bonds and aza-heterocycles are produced in moderate to good yields with good to excellent enantioselectivities. These products can be readily converted into other chiral amines without the loss of enantioselectivity. A reasonable reaction mechanism is proposed to illustrate the stereoselective control results.

Diastereodivergent chiral aldehyde catalysis for asymmetric 1,6-conjugated addition and Mannich reactions.

Chiral aldehyde catalysis is a burgeoning strategy for the catalytic asymmetric α-functionalization of aminomethyl compounds. However, the reaction types are limited and to date include no examples of stereodivergent catalysis. In this work, we disclose two chiral aldehyde-catalysed diastereodivergent reactions: a 1,6-conjugate addition of amino acids to para-quinone methides and a bio-inspired Mannich reaction of pyridinylmethanamines and imines. Both the syn- and anti-products of these two reactions can be obtained in moderate to high yields, diastereo- and enantioselectivities. Four potential reaction models produced by DFT calculations are proposed to explain the observed stereoselective control. Our work shows that chiral aldehyde catalysis based on a reversible imine formation principle is applicable for the α-functionalization of both amino acids and aryl methylamines, and holds potential to promote a range of asymmetric transformations diastereoselectively.

Organocatalytic Asymmetric Aldol Reaction of Arylglyoxals and Hydroxyacetone: Enantioselective Synthesis of 2,3-Dihydroxy-1,4-diones.

A highly efficient quinine-derived primary-amine-catalyzed asymmetric aldol addition of hydroxyacetone to arylglyoxals is described. Structurally diverse anti-2,3-dihydroxy-1,4-diones were generated in high yields, with good diastereoselectivities and enantioselectivities.

Reduced graphene oxide coated Cu2-xSe nanoparticles for targeted chemo-photothermal therapy.

Recently, copper chalcogenide semiconductors have been reported as new near-infrared (NIR) photothermal agents. However, it is difficult to modify them with recognition molecules, and their photothermal conversion efficiencies are relatively low, making it difficult to achieve the targeted photothermal ablation of cancer cells with a high efficiency. In this study, reduced graphene oxide (rGO) was first coated on the surface of Cu2-xSe nanoparticles (NPs) to provide abundant functional groups for the next modification and to increase the photothermal conversion efficiency. Then, doxorubicin (DOX) was loaded and folic acid (FA) molecules were covalently linked onto the surface of Cu2-xSe/rGO nanocomposites. The formed DOX@Cu2-xSe@rGO-FA nanocomposites were successfully used as chemo-photothermal agents for the targeted killing of cancer cells by utilizing the recognition ability of FA, chemotherapy effect of DOX and photothermal effects of rGO and Cu2-xSe NPs. Under the 980-nm NIR laser irradiation, the nanocomposites showed significantly enhanced chemo-photothermal therapy effect, which can be potentially applied in the nanomedicine field.

Selective colorimetric analysis of spermine based on the cross-linking aggregation of gold nanoparticles chain assembly.

A selective colorimetric assay for spermine was proposed in this work. In a weak alkaline medium, the conformational structure of double-stranded calf thymus DNA (ctDNA) was loosened to install gold nanoparticles (AuNPs) into chains. While, the chain assembly of AuNPs could form cross-linking aggregates when spermine was present, which was attributed to the electrostatic interaction between the positive change of spermine and negative change both of AuNPs and ctDNA, as well as the groove binding between ctDNA and spermine. Under the optimum conditions, the aggregation degree of AuNPs was proportional to the concentration of spermine in the range of 0.1-2.0µM with a limit of detection of 11.6nM. More interestingly, AuNPs changed from red to purple and even to blue depending on the concentration of spermine, which could be developed as the colorimetric analysis of spermine. ctDNA-AuNPs assembly was demonstrated as a novel visual probe for the specific sensing of spermine with high specificity and sensitivity.

Carbon dots: materials, synthesis, properties and approaches to long-wavelength and multicolor emission.

Herein, we summarize recent research developments and progress of carbon dots (CDs), which have been attracting considerable attention as a new type of photoluminescent material. Raw materials, from single carbonaceous compounds to colorful natural substances, for the synthesis of CDs are discussed. A range of diverse synthetic methodologies to achieve better photoluminescence performance and more advanced functions are summarized, and these are basically divided into two classes: top-down and bottom-up. The inspiring properties, mainly including composites, optical properties and cytotoxicity, are listed. In particular, the luminescence mechanism and surface functionalization of the CDs are briefly discussed. Moreover, on the basis of the above, the long-wavelength and multicolor emission properties of CDs and ways to achieve these goals including surface state and size controlled by synthesis strategies, proper precursors, chemical doping and modification, solvatochromic effects and energy transfer are reviewed in detail.

Carbon dots with aggregation induced emission enhancement for visual permittivity detection.

Photoluminescent carbon dots (CDs), hydrothermally prepared using tannic acid (TA), show visual aggregation induced emission enhancement (AIEE) properties at 455 nm when excited at 350 nm owing to the rotational hindering of the surface groups on CDs such as aromatic rings and phenolic hydroxyl ones, causing exponential decay between the ratio of the photoluminescence intensity in organic solvents to that in water and the permittivity of the solvent, and thus dazzling emissions of the CDs in the presence of solvents with small permittivity, tetrahydrofuran (THF), for instance, could be visually observed.

Germanium-doped carbon dots as a new type of fluorescent probe for visualizing the dynamic invasions of mercury(II) ions into cancer cells.

Carbon dots doped with germanium (GeCDs) were firstly prepared by a new simple 15 min carbonation synthesis route, exhibiting excitation-independent photoluminescence (PL), which could avoid autofluorescence in bioimaging applications. The as-prepared GeCDs have low cell toxicity, good biocompatibility, high intracellular delivery efficiency, stability and could be applied for detection of mercury(II) ions with excellent selectivity in complicated medium. It is to be noted that the as-prepared GeCDs used as a new type of probe for visualization of dynamic invasions of mercury(II) ions into Hep-2 cells display greatly different properties from most of the previously reported CDs which are regularly responsive to iron ions. All the results suggest that the GeCDs can be employed for visualization and monitoring of the significant physiological changes of living cells induced by Hg(2+).

Reduced graphene oxide gated mesoporous silica nanoparticles as a versatile chemo-photothermal therapy system through pH controllable release.

Synergistic therapy has become a potential treatment in the battle against disease. In this work, we developed a novel versatile folate targeted system for cancer cells with the combination of chemotherapy and phototherapy by using mesoporous silica nanoparticles (MSNs) as a drug loading carrier, in which reduced graphene oxide (rGO) gated the MSNs by pH responsive detachment. That is, rGO herein acts not only for gating control of the drug release but also for near-infrared photothermal therapy. With this drug loading system, high photothermal conversion efficiency and excellent doxorubicin (DOX) loading capacity have been achieved, making the DOX loaded MSN@rGO-FA (DOX@MSN@rGO-FA) nanocomposites able to kill 68% of HEp-2 cells in synergistic therapy, as compared with 54% in photothermal therapy and 33% in chemotherapy, respectively, illustrating that a synergistic therapy strategy using this newly developed versatile drug loading system is much more efficient as evaluated in vitro.

One-pot hydrothermal synthesis of orange fluorescent silver nanoclusters as a general probe for sulfides.

Water-soluble fluorescent silver nanoclusters (AgNCs) with almost seven and nine silver atoms and a quantum yield (QY) of 5.38 ± 0.25% were successfully prepared via one-pot hydrothermal synthesis using polymethacrylic acid sodium salt (PMAA-Na) as a template. The as-prepared PMAA-AgNCs displayed a mono-distribution, they were uniform in size and the color of the fluorescence, emitting at 579 nm, was orange when excited at 502 nm. What is more, we found that the as-prepared PMAA-AgNCs could be quenched by sulfides based on the formation of a metal-ligand bond Ag-S, and thus sulfides could be sensitively detected by spectrofluorometry. As proof of concept, thiourea (TU) and other sulfides including cysteine (Cys), glutathione (GSH) and dl-methionine could be detected. For example, the color of the orange fluorescent AgNCs solutions darkened upon the addition of TU and the fluorescence of PMAA-AgNCs was quenched. The detection limit for TU was 6.10 µM in the linear range from 8.57 µM to 2.29 mM.

A general quantitative pH sensor developed with dicyandiamide N-doped high quantum yield graphene quantum dots.

A general quantitative pH sensor for environmental and intracellular applications was developed by the facile hydrothermal preparation of dicyandiamide (DCD) N-doped high quantum yield (QY) graphene quantum dots (GQDs) using citric acid (CA) as the carbon source. The obtained N-doped GQDs have excellent photoluminesence (PL) properties with a relatively high QY of 36.5%, suggesting that N-doped chemistry could promote the QY of carbon nanomaterials. The possible mechanism for the formation of the GQDs involves the CA self-assembling into a nanosheet structure through intermolecular H-bonding at the initial stage of the reaction, and then the pure graphene core with many function groups formed through the dehydration between the carboxyl and hydroxyl of the intermolecules under hydrothermal conditions. These N-doped GQDs have low toxicity, and are photostable and pH-sensitive between 1.81 to 8.96, giving a general pH sensor with a wide range of applications from real water to intracellular contents.