Cu(I)-catalyzed Azide-alkyne Cycloaddition Research Articles

Preparation of hetero-armed POSS-cored star-shaped PCL-PLA/PLA composites and effect of different diisocyanates as compatibilizer

Eight-armed A4B4-type hetero-arm star-shaped PCL-PLA polymers ((PCL)4-POSS-(PLA)4, SPLA30) with POSS core were successfully prepared via combination of the “arm-first” approach utilizing ring-opening polymerization (ROP) and click chemistry techniques. Firstly, alkyne-functional PLA and PCL polymers having arms with 30 repeating units were synthesized via ROP with utilizing propargyl alcohol as initiator and stannous octoate (Sn(Oct)2) as catalyst. Then, the obtained hetero-armed star-shaped polymers were prepared by Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between alkyne functional polymers (1:1 PCL:PLA) and azido functional polyhedral oligomeric silsesquoxane (POSS-(N3)8) molecules. Finally, these obtained star-shaped SPLA30 was blended with neat PLA at different PLA/SPLA30 ratios (95/5 and 90/10 wt%) via melt blending by utilizing micro-compounder (a lab-scale) to enhance thermal, morphological, and mechanical properties of neat PLA. Also, different diisocyanates (1,4-phenylene diisocyanate (PDI), isophorone diisocyanate (IPDI), methylene diphenyl diisocyanate (MDI), and toluene 2,4-diisocyanate (TDI)) at constant ratio (1 wt%) were used as a chain extender bonding terminal group of polymers. It was found that addition of SPLA30 and SPLA30+ diisocyanates provided improvements in mechanical properties (especially in elongation at break and impact strength) of neat PLA. When the thermal properties were examined, it was seen that the decomposition temperatures of the blends decreased significantly compared to neat PLA and that there was a significant increment in the Tg and Tm values. In addition, it has been found that especially the diisocyanates added to provide good interfacial adhesion with polymer blends and show a homogeneous distribution on the surface.

Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation.

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.

Small-Molecule-Selective Organosilica Nanoreactors for Copper-Catalyzed Azide-Alkyne Cycloaddition Reactions in Cellular and Living Systems.

We reported the synthesis of a tris(triazolylmethyl)amine (TTA)-bridged organosilane, functioning as Cu(I)-stabilizing ligands, and the installation of this building block into the backbone of mesoporous organosilica nanoparticles (TTASi) by a sol-gel way. Upon coordinating with Cu(I), the mesoporous CuI-TTASi, with a restricted metal active center inside the pore, functions as a molecular-sieve-typed nanoreactor to efficiently perform Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reactions on small-molecule substrates but fails to work on macromolecules larger than the pore diameter. As a proof of concept, we witnessed the advantages of selective nanoreactors in screening protein substrates for small molecules. Also, the robust CuI-TTASi could be implanted into the body of animal models including zebrafish and mice as biorthogonal catalysts without apparent toxicity, extending its utilization in vivo ranging from fluorescent labeling to in situ drug synthesis.

Highly Enantioselective CuAAC of Functional Tertiary Alcohols Featuring an Ethynyl Group and Their Kinetic Resolution.

The first highly enantioselective CuI -catalyzed azide-alkyne cycloaddition (CuAAC) of tertiary alcohols and their kinetic resolution is reported. This approach allows facile access to multifunctional tertiary alcohols featuring an α-ethynyl or α-triazole moiety, and represents the first successful kinetic resolution of racemates with a tetrasubstituted carbon stereocenter via CuAAC. Newly developed pyridinebisoxazoline (PYBOX) ligands with a C4 phosphonate group play a key role.

Highly Enantioselective CuAAC of Functional Tertiary Alcohols Featuring an Ethynyl Group and Their Kinetic Resolution

AbstractThe first highly enantioselective CuI‐catalyzed azide‐alkyne cycloaddition (CuAAC) of tertiary alcohols and their kinetic resolution is reported. This approach allows facile access to multifunctional tertiary alcohols featuring an α‐ethynyl or α‐triazole moiety, and represents the first successful kinetic resolution of racemates with a tetrasubstituted carbon stereocenter via CuAAC. Newly developed pyridinebisoxazoline (PYBOX) ligands with a C4 phosphonate group play a key role.

Robust and Versatile Cu(I) metal frameworks as potential catalysts for azide-alkyne cycloaddition reactions: Review

• Cu(I) as robust metal Catalyst to perform 3 + 2 cycloaddition reactions. • Diverse Cu(I)-coordination frameworks for efficient azide-alkyne stitching. • Recovery and reusability of metal catalysts. The use of ‘Click Reaction’ for Cu(I) catalyzed azide–alkyne cycloaddition (CuAAC) has emerged as one of the most powerful tools for the synthesis of library of organic molecules having a wide range of applications. The approach is highly stereoselective that involves the formation of 1,4–disubstituted 1,2,3–triazole derivatives by the combination of diverse structural entities in the presence of Cu(I) as catalyst. There are numerous synthetic Cu (I) complexes with different ligands bound in diverse molecular framework with potential to act as catalyst to stitch organic azide to alkyne producing 1,4-di-substituted products. This review emphasizes on those versatile Cu (I) complexes having tailoring capability similar to those available commercially.

Multi-functional, Low Symmetry Pd2 L4 Nanocage Libraries*.

Although many impressive metallo‐supramolecular architectures have been reported, they tend towards high symmetry structures and avoid extraneous functionality to ensure high fidelity in the self‐assembly process. This minimalist approach, however, limits the range of accessible structures and thus their potential applications. Herein is described the synthesis of a family of ditopic ligands wherein the ligand scaffolds are both low symmetry and incorporate exohedral functional moieties. Key to this design is the use of CuI‐catalysed azide‐alkyne cycloaddition (CuAAC) chemistry, as the triazole is capable of acting as both a coordinating heterocycle and a tether between the ligand framework and functional unit simultaneously. A common precursor was used to generate ligands with various functionalities, allowing control of electronic properties whilst maintaining the core structure of the resultant cis‐Pd2L4 nanocage assemblies. The isostructural nature of the scaffold frameworks enabled formation of combinatorial libraries from the self‐assembly of ligand mixtures, generating a statistical mixture of multi‐functional, low symmetry architectures.

Selective analysis of newly synthesized proteins by combining fluorescence correlation spectroscopy with bioorthogonal non-canonical amino acid tagging.

Protein expression is closely related to many biological processes including cell growth, differentiation and signaling. It is a challenge to selectively monitor newly synthesized proteins under both physiological and pathological conditions due to shortage of efficient analytical methods. Here, we proposed a new strategy to selectively monitor newly synthesized proteins in cells by combining fluorescence correlation spectroscopy (FCS) with bioorthogonal noncanonical amino acid tagging (BONCAT) technique. Firstly, homopropargylglycine (HPG), an alkyne surrogate of methionine, was metabolically incorporated into newly synthesized proteins in living cells, and the proteins containing the alkyne functional group were subsequently labeled with chemoselective fluorescence reporters using the Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Then, FCS was used to analyze the newly synthesized proteins based on the difference in the characteristic diffusion times of labeled proteins and free fluorescent dyes. We optimized the conditions of HPG metabolic incorporation and the CuAAC click reaction and applied this new method to study autophagic protein degradation and in situ monitor secreted proteins in cells. Compared to current methods, our method is simple, fast, and without separation, and it may become a promising approach for in situ studying protein expression in living cells.

Synthesis of new 1,4-disubstituted 1,2,3-triazoles using the CuAAC reaction and determination of their antioxidant activities.

This study describes the synthesis and antioxidant activity of new 1,4-disubstituted 1,2,3-triazoles. These compounds were generated semi-synthetically using the Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) reaction between ethyl 2-azidoacetate and terminal acetylenes derived from the natural products carvacrol, eugenol, isovanillin, thymol and vanillin. The products were obtained at 50 to 80% yield and characterised through several spectrographic techniques. Antioxidant activity was assayed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS). The products exhibited moderate antioxidant activity, with ethyl 2-(4-((4-formyl-2-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl) acetate showing the highest antioxidant capacity (EC50 = 75.5 µg/mL) among the generated 1,4-disubstituted 1,2,3-triazoles. In conclusion, the generation of these compounds opens new possibilities for the development of new antioxidant agents.

Synthesis, Biological Evaluation and In silico Studies of Compounds Based on Tryptophan‐Naproxen‐Triazole Hybrids

AbstractA hybrid of three different frameworks e. g. tryptophan, naproxen and triazole has been explored for the identification of potential antibacterial / anticancer agents. A library of new compounds, designed based on this hybrid framework was synthesized via a multi‐step sequence using the Cu(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) as the key reaction step. Thus the terminal alkyne obtained via the reaction of tryptophan ester with naproxen followed by N‐propargylation of the indole ring was coupled with a range of organic azides to give the desired products (through the formation of triazole ring) in good to acceptable yields. The in vitro antibacterial screening of these compounds against S. aureus (Gram‐positive) as well as E. coli and K. pneumoniae (Gram‐negative) strains identified several hits with moderate to good activities with 4‐(4‐((3‐(3‐methoxy‐2‐(2‐(6‐methoxynaphthalen‐2‐yl)propanamido)‐3‐oxopropyl)‐1H‐indol‐1‐yl)methyl)‐1H‐1,2,3‐triazol‐1‐yl)benzoic acid (6 n) being the best (MIC∼25 μg/mL across all the strains). Several compounds e. g. analogues containing a (4‐chlorophenyl)amino)‐2‐oxoethyl moiety (6 e) and (4‐nitrophenyl)amino)‐2‐oxoethyl moiety (6 h) attached to the triazole ring also showed cytotoxic activities when tested against A549 cancer cell line (IC50=39.35 and 28.52 μg/mL, respectively).

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ Ki being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.

Photoconjugation of temperature- and pH-responsive polymer with silica nanoparticles for separation and enrichment of bacteria

A new photoconjugation approach was developed to prepare nanoparticle-supported boronic acid polymer for effective separation and enrichment of bacteria. The photo-activated polymer immobilization was demonstrated by coupling an azide-modified copolymer of N-isopropylacrylamide and glycidyl methacrylate to a perfluorophenyl azide-modified silica surface. The thermoresponsive polymer was synthesized using reversible addition fragmentation chain transfer polymerization followed by conversion of the pendant epoxides into azide groups. The perfluorophenyl azide-modified silica nanoparticles were synthesized by an amidation reaction between amino-functionalized silica and pentafluorobenzoyl chloride, and a subsequent treatment with sodium azide. Bacteria-capturing boronic acid was conjugated to the silica-supported polymer chains via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. The particle size, morphology and organic content of the composite nanoparticles were characterized systematically. The capability of the nanocomposite to bind Gram-positive and Gram-negative bacteria was investigated. The nanocomposite exhibited high binding capacities for E. coli (13.4 × 107 CFU/mg) and S. epidermidis (7.66 × 107 CFU/mg) in phosphate buffered saline. The new photoconjugation strategy enables fast and straightforward grafting of functional polymers on surface, which opens many new opportunities for designing functional materials for bioseparation and biosensing.

An optimal “Click” formulation strategy for antibody-drug conjugate synthesis

As a versatile reaction for bioconjugation, Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) has enormous potential in the synthesis of antibody-drug conjugates (ADCs). In order to optimize CuAAC-based ADC synthesis, we characterized kinetically different formulation processes by mimicking ADC synthesis using small molecules and subsequently revealed unique kinetic behaviors of different combinations of alkyne and azide conditions. Our results indicate that under ADC synthesis conditions, for an alkyne-containing drug, its concentration has minimal impact on the reaction rate when an antibody has a non-metal-chelating azide but is proportional to concentration when an antibody contains a metal-chelating azide; however, for an alkyne-containing antibody, the ADC synthesis rate is proportional to the concentration of a drug with a non-metal-chelating azide but displays almost no dependence on drug concentration with a metal-chelating azide. Based on our results, we designed and tested an optimal “click” formulation strategy that allowed rapid and cost-effective synthesis of a new ADC.

Pyridinyl-triazole ligand systems for highly efficient CuI-catalyzed azide-alkyne cycloaddition

Pyridinyl-triazole ligand systems (including N2-2-pyridinyl 1,2,3-triazoles and N1/N2-substituted 2-(NH-1,2,3-triazol-4-yl)pyridines) were found to be superior ligands for CuI-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. Low catalyst loadings, short reaction times, facile catalyst recyclability, ambient temperature, and open-flask conditions made this catalytic system very practical. The iodide anions could form iodine bridges to construct stable dinuclear Cu(I) complexes with these ligands, which was the key to achieve high catalytic activities. While CuBr and CuCl were not suitable for this ligand system because of the improper size of Br and Cl atoms for the formation of the corresponding dinuclear Cu(I) complexes.

Large ultrafast nonlinear optical response and excellent optical limiting behaviour in pyrene-conjugated zinc(II) phthalocyanines at a near-infrared wavelength

The design and synthesis with full structural utilization of a new type of nonlinear photonic material, Zinc(II) phthalocyanine macrocycle (Pc-pyrene), bearing binary oriented (up/down) pyrene units is reported. The novel pyrene-based macrocycle has been successfully obtained in high yield upon coupling multiple azido pyrene derivatives on a previously fabri-cated alkynyl-substituted macrocyclic platform (Pc1) via multiple tandem Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) reactions. The ultrafast nonlinear optical characteristics of both Pc1 and Pc-pyrene have been investigated in solution using a near-infrared femtosecond pulsed laser. The femtosecond Z-scan results reveal a low optical limiting threshold and a good set of figures of merit that make these macrocycles feasible for optical limiting as well as switching applications. In a major breakthrough, ultrafast laser-induced deformations in Pc-pyrene-embedded PMMA films results in a very large enhancement of the three-photon absorption coefficient at 800 nm by up to ~105 times that of Pc solutions. Furthermore, the deformed Pc-pyrene PMMA films having the advantage of flexibility and possess an excellent optical limiting threshold (0.0018 J/cm2), much lower than various previously reported values, which enables them to be one of the best optical limiters.

Using One Photoredox Catalyst to Simultaneously Mediate Two Different Polymerizations for Photo-Triggered Multi-Component Orthogonal Polymerizations.

The development of multi-component orthogonal polymerizations (MOPs) with simple procedure and high efficiency is crucial for rational polymer synthesis. In this work, photo-triggered Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) polymerization are first investigated, employing copper(II) thioxanthone carboxylate (Cu(TX)2 ) as photoredox catalyst and sunlight as stimuli. Then, the novel MOPs using one photoredox catalyst, Cu(TX)2 to simultaneously mediate two different photopolymerizations, are successfully realized in one-pot, where photo-induced electron transfer atom transfer radical polymerization and photo-activated CuAAC polymerization can effectively proceed in a one-pot and non-interfering fashion to afford predetermined copolymers with well-defined structure.

1,4-Disubstituted 1,2,3-Triazoles as Amide Bond Surrogates for the Stabilisation of Linear Peptides with Biological Activity.

Peptides represent an important class of biologically active molecules with high potential for the development of diagnostic and therapeutic agents due to their structural diversity, favourable pharmacokinetic properties, and synthetic availability. However, the widespread use of peptides and conjugates thereof in clinical applications can be hampered by their low stability in vivo due to rapid degradation by endogenous proteases. A promising approach to circumvent this potential limitation includes the substitution of metabolically labile amide bonds in the peptide backbone by stable isosteric amide bond mimetics. In this review, we focus on the incorporation of 1,4-disubstituted 1,2,3-triazoles as amide bond surrogates in linear peptides with the aim to increase their stability without impacting their biological function(s). We highlight the properties of this heterocycle as a trans-amide bond surrogate and summarise approaches for the synthesis of triazole-containing peptidomimetics via the Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC). The impacts of the incorporation of triazoles in the backbone of diverse peptides on their biological properties such as, e.g., blood serum stability and affinity as well as selectivity towards their respective molecular target(s) are discussed.

DNAzyme-Catalyzed Click Chemistry for Facilitated Immobilization of Redox Functionalities on Self-Assembled Monolayers

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), the representative reaction of modern “click chemistry”, has been broadly employed in organic synthesis, bio-labeling, and surface functionalizat...

Substituent‐Biased CO2 Reduction on Copper Cathodes Modified with Spaced Organic Structures

AbstractCO2 reduction directed by organic moieties on Cu cathodes was studied by adopting a newly developed on‐surface modification method. Organic groups compatible with exposed Cu surface atoms were introduced by electrochemically activated Cu(I)‐catalyzed azide alkyne cycloaddition (CuAAC). Three different ethylnyl precursors, each containing 1,3,5‐phenyl, tertiary amine, and 2,5‐pyridyl moieties, were introduced onto a Cu cathode, by reacting with a three‐way azide precursor. The structural characterization of modified electrodes revealed that the modification yielded surfaces composed of exposed surface Cu atoms capable of cooperating with the introduced, barely soluble, organic polymer. The presence of an organic layer on the Cu resulted in improved CO2 reduction efficiency over H2 evolution. The methane/ethylene selectivity was dependent on the kind of moieties used. The proton supplier ability of the modified organic moiety turned out to be involved in the selectivity, as well as with surface copper rearrangement upon anodization. These findings demonstrate that the organic groups at cooperating sites on the surface Cu can offer a powerful tool for selective CO2 reduction.

Visible-Light-Mediated Click Chemistry for Highly Regioselective Azide-Alkyne Cycloaddition by a Photoredox Electron-Transfer Strategy.

Click chemistry focuses on the development of highly selective reactions using simple precursors for the exquisite synthesis of molecules. Undisputedly, the CuI -catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most valuable examples of click chemistry, but it suffers from some limitations as it requires additional reducing agents and ligands as well as cytotoxic copper. Here, we demonstrate a novel strategy for the azide-alkyne cycloaddition reaction that involves a photoredox electron-transfer radical mechanism instead of the traditional metal-catalyzed coordination process. This newly developed photocatalyzed azide-alkyne cycloaddition reaction can be performed under mild conditions at room temperature in the presence of air and visible light and shows good functional group tolerance, excellent atom economy, high yields of up to 99 %, and absolute regioselectivity, affording a variety of 1,4-disubstituted 1,2,3-triazole derivatives, including bioactive molecules and pharmaceuticals. The use of a recyclable photocatalyst, solar energy, and water as solvent makes this photocatalytic system sustainable and environmentally friendly. Moreover, the azide-alkyne cycloaddition reaction could be photocatalyzed in the presence of a metal-free catalyst with excellent regioselectivity, which represents an important development for click chemistry and should find versatile applications in organic synthesis, chemical biology, and materials science.