Alkyne Moiety Research Articles

Asymmetric Friedel-Crafts reaction of unsaturated carbonyl-tethered heteroarenes via vinylogous activation of Pd0-π-Lewis base catalysis.

The alkyne group can undergo facile transformations under palladium catalysis, such as hydropalladation, Wacker reaction, etc. Here we demonstrate that a chiral Pd0 complex can chemoselectively dihapto-coordinate to the alkyne moiety of 2-indolyl propiolates, and raise the Highest Occupied Molecular Orbital (HOMO)-energy ofthe deactivated heteroarenes via π-Lewis base catalysis. As a result, asymmetric C3-selective Friedel-Crafts addition to activated alkenes occurs, finally affording [3 + 2] or [3 + 4] annulation products with high enantioselectivity and exclusive E-selectivity. Moreover, this π-Lewis base vinylogous HOMO-activation strategy can be extended to remote Friedel-Crafts reaction of diverse five-membered heteroarenes tethered to a 2-enone or 2-acrylate motif with imines or 1-azadienes, and excellent enantiocontrol is generally achieved for the multifunctional adducts, which can be effectively converted to diverse frameworks with higher molecular complexity. In addition, NMR and density functional theory calculation studies are conducted to elucidate the catalytic mechanism.

Annealing of acetylene containing cyclotriphosphazene to generate nitrogen- and phosphorus-containing layered graphitic materials

A new strategy to access nitrogen- and phosphorus-containing layered graphitic materials from cyclotriphosphazene bearing reactive terminal acetylene moieties was developed.

Stereoselective Domino Heck‐Suzuki Reactions

AbstractPalladium catalysis enables efficient and versatile domino reactions that are initiated by an intramolecular Mizoroki‐Heck reaction and then terminated by a Suzuki‐Miyaura coupling. The stereochemistry of this cascade is concerned under three aspects: Firstly, as stereoselective formation of carbon−carbon‐double bonds, when the initial carbometalation occurs at an alkyne moiety. Secondly as diastereoselective and thirdly enantioselective formation of stereogenic carbon centers when the intramolecular Heck step is directed to an alkene moiety. Valuable protocols lead to – otherwise not easily accomplished – stereo control in the formation of tri‐ and tetra‐substituted double bonds according to the first conception. The diastereoselective versions permit the formation of multiple stereocenters in mono‐ and polycycles. Enantioselective protocols were developed only recently. The fact that the newly created stereocenters are highly‐substituted, tertiary or quaternary ones, makes the methods that are presented in this review useful and versatile tools in synthesis.

Pseudo-irreversible butyrylcholinesterase inhibitors: Structure–activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead

Alongside reversible butyrylcholinesterase inhibitors, a plethora of covalent butyrylcholinesterase inhibitors have been reported in the literature, typically pseudo-irreversible carbamates. For these latter, however, most cases lack full confirmation of their covalent mode of action. Additionally, the available reports regarding the structure–activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors and the structure–activity relationships of the N-dialkyl O-arylcarbamate warhead are presented in this study. The covalent mechanism of binding was tested by IC50 time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic analysis. Computational studies provided valuable insights into steric constraints and identified problematic, bulky carbamate warheads that cannot reach and carbamoylate the catalytic Ser198. Quantum mechanical calculations provided further evidence that steric effects appear to be a key factor in determining the covalent binding behaviour of these carbamate cholinesterase inhibitors and their duration of action. Additionally, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatisation with azide-containing fluorophore enabled fluorescent labelling of plasma human butyrylcholinesterase. This proof-of-concept study highlights the potential of this novel approach and for these compounds to be further developed as clickable molecular probes for investigating tissue localisation and activity of cholinesterases.

Propargylamine Amino Acids as Constrained Nε-Substituted Lysine Mimetics.

Herein, alkylated propargylamines are reported as constrained lysine mimetics and constructed in a single step using a copper(I)-catalyzed A3-coupling reaction. Using multiple secondary amines, the reaction allowed the generation of a structurally diverse set of N-Fmoc protected amino acid derivatives. In addition, the A3-reaction was applied on solid phase via the assembly of short model tripeptides. Moreover, the internal alkyne moiety allowed further functionalization toward novel 1,4,5-trisubstituted 1,2,3-triazole-based amino acids.

4′-(3,5-Dimethoxy-4-propargyloxyphenyl)-2,2′:6′,2″-terpyridine

The preparation and characterization of a new terpyridine molecule containing an acetylenic moiety is described. Part of this molecule, unknown in the literature, is obtained from a biomass-derived synthon that is formed from the naturally occurring syringaldehyde 4-hydroxy-3,5-dimethoxybenzaldehyde. The title compound was fully characterized by NMR spectroscopy (1H and 13C), as well as by high-resolution mass spectrometry and infrared spectroscopy.

A Small-Molecule Probe with a Dual Function of miRNA Inhibition and Target identification.

By virtue of their key roles in pathologies, miRNAs represent a promising class of therapeutic targets. While high-fidelity small-molecule modulators of miRNAs can be identified via high-throughput screening using cellular reporter systems, their modes of action are elusive due to the lack of proper tools. Here, we report a small-molecule probe, 1 a, that is capable of elucidating its biological target along miRNA inhibition. Derived from norathyriol, a nature product, 1 a possessed a bioorthogonal alkyne moiety for subsequent labeling via copper-catalyzed azide-alkyne cycloaddition chemistry. We demonstrated that 1 a inhibited a panel of different miRNAs by blocking their loading onto argonaute 2 (AGO2), which is the key protein responsible for miRNA function. With the alkyne handle, we successfully identified AGO2 as an intracellular target of 1 a. Therefore, this work presents a novel small-molecule tool for suppressing and probing miRNA regulatory pathways.

A 6-endo-dig Thiolative Cyclization of Yne-Ynamides: Access to Thiodihydropyridin-2-ones.

A straightforward regioselective intramolecular 6-endo-dig cyclization of yne-tethered ynamide is herein developed. The reaction involves an intramolecular enolate attack of ketene-N,O-acetals, generated in situ from yne-ynamide and methanesulfonic acid, to the alkyne moiety activated by a sulfonium cation. The transformation enables access to structurally diverse 5-(arylthio)-3,6-dihydropyridin-2(3H)-ones with broad functional group compatibility. The recovery of S-protecting groups and synthetic applications of the products make the transformation useful.

Synthesis of Trifluoromethylated 4H-Pyran and 4H-Thiopyran via Divergent Reaction of β-CF3-1,3-Enynes with β-Ketothioamides.

A chemodivergent tandem intermolecular hydrocarbonation and intramolecular oxy- or thioheterocyclization sequence of β-CF3-1,3-enyne with β-ketothioamides (KTAs) leading to ring-trifluoromethylated 4H-pyran or 4H-thiopyran, respectively, by the combined use of AgNO3 as a catalyst and Et3N as a base was developed. A remarkable substituent effect was observed. The substituent on either the keto moiety or the nitrogen atom of β-ketothioamides has a great impact on the chemoselectivity. Enynes possessing electron-withdrawing aryl groups on the alkyne moiety are generally good candidates for the present transformation.

Synthesis of Azetidine Nitrones and Exomethylene Oxazolines through a Copper(I)-Catalyzed 2,3-Rearrangement and 4π-Electrocyclization Cascade Strategy.

A variety of azetidine nitrones are prepared in moderate to good yields through copper(I) combined with 2-aminopyridine to catalyze skeletal rearrangement of O-propargylic oximes. Mechanistic studies reveal that the reaction undergoes a copper(I)-catalyzed tandem [2,3]-rearrangement, 4π-electrocyclization, ring opening, and recyclization over four steps in one pot. Substituents at the terminus of alkyne and oxime moieties have a significant impact on the formation of azetidine nitrones and exomethylene oxazolines, respectively. Furthermore, the obtained azetidine nitrone could easily participate in [3 + 2] cycloaddition with alkynoates, and a [2.2]-paracyclophane-derived azetidine nitrone is synthesized in 45% yield over five steps from bromo[2.2]-paracyclophane.

Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having a Domain Structure**

AbstractHeparan sulfate (HS) has a domain structure in which regions that are modified by epimerization and sulfonation (NS domains) are interspersed by unmodified fragments (NA domains). There is data to support that domain organization of HS can regulate binding of proteins, however, such model has been difficult to probe. Here, we report a chemoenzymatic methodology that can provide HS oligosaccharides composed of two or more NS domains separated by NA domains of different length. It is based on the chemical synthesis of a HS oligosaccharide that enzymatically was extended by various GlcA‐GlcNAc units and terminated in GlcNAc having an azido moiety at C‐6 position. HS oligosaccharides having an azide and alkyne moiety could be assembled by copper catalyzed alkyne‐azide cycloaddition to give compounds having various NS domains separated by unsulfonated regions. Competition binding studies showed that the length of an NA domain modulates the binding of the chemokines CCL5 and CXCL8.

Chemoenzymatic Synthesis of Heparan Sulfate Oligosaccharides having a Domain Structure.

Heparan sulfate (HS) has a domain structure in which regions that are modified by epimerization and sulfonation (NS domains) are interspersed by unmodified fragments (NA domains). There is data to support that domain organization of HS can regulate binding of proteins, however, such model has been difficult to probe. Here, we report a chemoenzymatic methodology that can provide HS oligosaccharides composed of two or more NS domains separated by NA domains of different length. It is based on the chemical synthesis of a HS oligosaccharide that enzymatically was extended by various GlcA-GlcNAc units and terminated in GlcNAc having an azido moiety at C-6 position. HS oligosaccharides having an azide and alkyne moiety could be assembled by copper catalyzed alkyne-azide cycloaddition to give compounds having various NS domains separated by unsulfonated regions. Competition binding studies showed that the length of an NA domain modulates the binding of the chemokines CCL5 and CXCL8.

Probing Factor Xa Protein-Ligand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands.

The accurate prediction of protein-ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen-π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.

Two-Step, One-Pot Pyrrole Synthesis by Iron-Catalyzed ­Carboamination/Copper-Mediated Cyclization

AbstractHerein we report a method for pyrrole synthesis via iron-catalyzed carboamination/copper-mediated cyclization that is completely regioselective for the formation of 1,2,4-trisubstituted products. This two-step, one-pot process offers significant improvements to previously reported conditions including the use of a readily available copper(I) source and a markedly less arduous experimental procedure. Exploration of the substrate scope reveals a variety of arylacetylenes undergo pyrrole formation to afford single isomer products. Isotopic labelling data points to a mechanism involving activation of the alkyne moiety by the copper(I) reagent during the cyclization step.

Sulfilimines as Transformable and Retainable Directing Groups in Rhodium-Catalyzed ortho-C-H Bond Functionalization.

Shown herein is the first time that the sulfilimine is utilized as a directing group for Rh(III)-catalyzed C-H activation/annulation with intermolecular and intramolecular alkyne compounds. Sulfilimine serves as a transformable directing group, an internal oxidant, in the annulation with an alkyne moiety via N-S bond cleavage. Notably, the retention of sulfilimine as a directing group is also achieved in the Rh(III)-catalyzed ortho-alkynylation with alkyne bromides.

Highly Fluorinated Peptide Probes with Enhanced In Vivo Stability for 19 F-MRI.

A labeling strategy for in vivo 19 F-MRI (magnetic resonance imaging) based on highly fluorinated, short hydrophilic peptide probes, is developed. As dual-purpose probes, they are functionalized further by a fluorophore and an alkyne moiety for bioconjugation. High fluorination is achieved by three perfluoro-tert-butyl groups, introduced into asparagine analogues by chemically stable amide bond linkages. d-amino acids and β-alanine in the sequences endow the peptide probes with low cytotoxicity and high serum stability. This design also yielded unstructured peptides, rendering all 27 19 F substitutions chemically equivalent, giving rise to a single 19 F-NMR resonance with <10Hz linewidth. The resulting performance in 19 F-MRI is demonstrated for six different peptide probes. Using fluorescence microscopy, these probes are found to exhibit high stability and long circulation times in living zebrafish embryos. Furthermore, the probes can be conjugated to bovine serum albumin with only amoderate increase in 19 F-NMR linewidth to ≈30Hz. Overall, these peptide probes are hence suitable for in vivo 19 F-MRI applications.

Synthesis of 2-Pyrazolines with a CF3- and Alkyne-Substituted Quaternary Carbon Center via [3 + 2] Cycloaddition of β-CF3-1,3-enynes and Diazoacetates.

Given the importance of both the CF3 group and the alkyne moiety in synthetic/medicinal chemistry, we report here the first example of efficient synthesis of 2-pyrazolines with a CF3- and alkyne-substituted quaternary carbon center. This methodology has the advantages of high functional group compatibility, the avoidance of base and open-flask conditions, easily available and easy to handle reagent, and broad substrate scope. Notably, this protocol allows for the late-stage functionalization of biologically active molecules and the gram-scale synthesis.

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes.

Alkynyl selenides have attracted considerable research interest recently, owing to their applications in the biological and pharmaceutical fields. The Cu-catalyzed tandem reaction for the synthesis of novel alkynyl imidazopyridinyl selenides is presented. A one-pot synthesis route afforded alkynyl imidazopyridinyl selenides in moderate to good yields. This was achieved by a two-step reaction between terminal alkynes and diimidazopyridinyl diselenides, generated from imidazo[1,2-a]pyridines and Se powder, using 10 mol % of CuI and 1,10-phenanthroline as the catalytic system under aerobic conditions. The C(sp2)–Se and C(sp)–Se bond-formation reaction can be performed in one-pot by using inexpensive and easy to handle Se powder as the Se source. The reaction proceeded with terminal alkynes having various substitutions, such as aryl, vinyl, and alkyl groups. The obtained alkynyl imidazopyridinyl selenide was found to undergo nucleophilic substitution reaction on Se atom using organolithium reagents and 1,3-dipolar azide–alkyne cycloaddition based on the alkyne moiety.

New Synthetic Routes to Introduce Sp 3-Defects in Carbon Nanotubes with a Variety of Functional Groups

The controlled functionalization of single-walled carbon nanotubes (SWNTs) with luminescent sp 3-defects has emerged as a powerful tool to enhance their usually low photoluminescence quantum yields and has created the potential to employ them for bioimaging and optical sensors. For that, it is necessary to match and adapt the substituents of the sp 3-defects to the desired application. To attach a large variety of complex substituents to sp 3-defects an universal approach is required. Here, we introduce sp 3-defects to polymer-wrapped (6,5) SWNTs via diazonium salt chemistry [ACS Nano 2021, 15, 5147–5157] bearing an alkyne moiety and subsequently add the desired substituent by click-chemistry. This opens up the possibility to introduce many different functional groups such as stable organic radicals, photosensitizers or fluorophores, which are already available for click-reactions. This approach is not limited to E11* defects introduced by diazonium chemistry, but can be further extended to more red-shifted E11*− defects [Nat. Commun. 2021, 12, 2119].

Design, Synthesis, and Applications of ortho -Sulfur Substituted Arylphosphanes

Design, Synthesis, and Applications of <i>ortho</i> -Sulfur Substituted Arylphosphanes