Alkyne Moiety Research Articles

Enhancing the Cumulene Character of One-Dimensional Acetylene-Based Systems by Stimuli-Induced Planarization of Their Two Pro-diradicaloid Cyclopenta[h,i]aceanthrylene Units.

Acetylene/polyynes -(C≡C-)n and cumulenes =(C=)n are connectors widely used for the realization of one-dimensional (1-D) π-conjugates. Although both π-moieties are constituted by sp carbon atoms, their different bond connectivity confers distinct physicochemical properties to the resulting systems. In this context, while many acetylene/polyyne- and cumulene-based derivatives have been prepared and studied, no reports have tackled the possibility to reversibly alter the acetylene/polyyne-cumulene electronic character of these derivatives using mild conditions. Herein, we present a novel approach to enhance the cumulene character of 1-D acetylene-based conjugates consisting in the preparation of derivatives featuring an acetylene moiety connecting two pro-diradicaloid species, namely cyclopenta[h,i]aceanthrylene (CPA), at their pro-radical positions. A thoughtful spectroscopic study of the prepared dimers, complemented by theoretical calculations, suggest a high π-electronic delocalization of the pro-diradicaloid CPAs through the central acetylene spacer upon the dimers' planarization which, in turn, increases the cumulenic character of the acetylenic π-bridge, a feature enhanced for one of the two dimers at low temperature and in methylcyclohexane due to an aggregation-induced planarization process. We reckon that the proposed approach offers an interesting avenue towards the realization of 1-D systems which cumulenic character of the acetylenic π-connector could be altered in response to external stimuli.

Enhancing the Cumulene Character of One‐Dimensional Acetylene‐Based Systems by Stimuli‐Induced Planarization of Their Two Pro‐diradicaloid Cyclopenta[h,i]aceanthrylene Units

Acetylene/polyynes –(C≡C–)n and cumulenes =(C=)n are connectors widely used for the realization of one‐dimensional (1‐D) π‐conjugates. Although both π‐moieties are constituted by sp carbon atoms, their different bond connectivity confers distinct physicochemical properties to the resulting systems. In this context, while many acetylene/polyyne‐ and cumulene‐based derivatives have been prepared and studied, no reports have tackled the possibility to reversibly alter the acetylene/polyyne‐cumulene electronic character of these derivatives using mild conditions. Herein, we present a novel approach to enhance the cumulene character of 1‐D acetylene‐based conjugates consisting in the preparation of derivatives featuring an acetylene moiety connecting two pro‐diradicaloid species, namely cyclopenta[h,i]aceanthrylene (CPA), at their pro‐radical positions. A thoughtful spectroscopic study of the prepared dimers, complemented by theoretical calculations, suggest a high π‐electronic delocalization of the pro‐diradicaloid CPAs through the central acetylene spacer upon the dimers’ planarization which, in turn, increases the cumulenic character of the acetylenic π‐bridge, a feature enhanced for one of the two dimers at low temperature and in methylcyclohexane due to an aggregation‐induced planarization process. We reckon that the proposed approach offers an interesting avenue towards the realization of 1‐D systems which cumulenic character of the acetylenic π‐connector could be altered in response to external stimuli.

Cascade Reactions of Alkynyl Ketones and Amides to Generate Unsaturated Oxacycles and Aromatic Carbocycles.

We describe novel amine-mediated transformation of alkynyl ketones and amides to generate 2-methylene-2H-pyrans, substituted 3-hydroxy-9H-fluoren-9-ones, and amine-incorporated arenes. These cascade processes are initiated by conjugate addition of secondary amine followed by hydrolysis of the enamine/vinylogous amide intermediates. The product distribution is highly sensitive to the steric and electronic effects of the substituents on both the alkyne moieties, the tether structure connecting them, and the nature of the amine. Alkynyl amide participates in the Alder-ene reaction favorably to generate more reactive allene amide that reacts with amine to generate amine-incorporated arene products. These metal-free cascade reactions are a useful synthetic method that can be exploited for the construction of various hetero- and carbocyclic systems.

Targeting the Plasmodium falciparum IspE Enzyme.

The enzyme IspE in Plasmodium falciparum is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the PfIspE enzyme. Our approach toward a PfIspE inhibitor comprises in vitro screening, structure-activity relationship studies, examining the docking position using an AlphaFold model, and finally target verification through probe binding and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The newly synthesized probe containing a diazirine and an alkyne moiety (23) allowed us to demonstrate its binding to IspE in the presence of a lysate of human cells (HEK293 cells) and to get evidence that both probe 23 and the best inhibitor of the series (19) compete for the same IspE binding site.

Cyclohexanediamine Triazole (CHDT) Functionalization Enables Labeling of Target Molecules with Al18F/68Ga/111In.

The Al18F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of (±)-H3RESCA, which allows Al18F-labeling already at ambient temperature. While the suitability of (±)-H3RESCA for functionalization and radiofluorination of proteins is well established, its use for small molecules or peptides is less explored. Herein, we advanced this acyclic pentadentate ligand by introducing an alkyne moiety for the late-stage functionalization of biomolecules via click chemistry. We show that in addition to Al18F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of 68Ga and 111In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al18F-, 68Ga-, and 111In-labeled analogs were subjected to a detailed in vitro radiopharmacological characterization. Stability studies in vitro in human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al18F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, Al[18F]F-CHDT-PSMA-1, bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an in vivo performance comparable to that of [18F]PSMA-1007 but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min p.i. Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al18F, 68Ga, and 111In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.

Axial Ligand Enables Synthesis of Allenylsilane through Dirhodium(II) Catalysis.

Described herein is a dirhodium(II)-catalyzed silylation of propargyl esters with hydrosilanes, using tertiary amines as axial ligands. By adopting this strategy, a range of versatile and useful allenylsilanes can be achieved with good yields. This reaction not only represents a SN2'-type silylation of the propargyl derivatives bearing a terminal alkyne moiety to synthesize allenylsilanes from simple hydrosilanes, but also represents a new application of dirhodium(II) complexes in catalytic transformation of carbon-carbon triple bond. The highly functionalized allenylsilanes that are produced can be transformed into a series of synthetically useful organic molecules. In this reaction, an intriguing ON-OFF effect of the amine ligand was observed. The reaction almost did not occur (OFF) without addition of Lewis base amine ligand. However, the reaction took place smoothly (ON) after addition of only catalytic amount of amine ligand. Detailed mechanistic studies and density functional theory (DFT) calculations indicate that the reactivity can be delicately improved by the use of tertiary amine. The fine-tuning effect of the tertiary amine is crucial in the formation of the Rh-Si species via a concerted metalation deprotonation (CMD) mechanism and facilitating β-oxygen elimination.

Axial Ligand Enables Synthesis of Allenylsilane through Dirhodium(II) Catalysis

AbstractDescribed herein is a dirhodium(II)‐catalyzed silylation of propargyl esters with hydrosilanes, using tertiary amines as axial ligands. By adopting this strategy, a range of versatile and useful allenylsilanes can be achieved with good yields. This reaction not only represents a SN2′‐type silylation of the propargyl derivatives bearing a terminal alkyne moiety to synthesize allenylsilanes from simple hydrosilanes, but also represents a new application of dirhodium(II) complexes in catalytic transformation of carbon‐carbon triple bond. The highly functionalized allenylsilanes that are produced can be transformed into a series of synthetically useful organic molecules. In this reaction, an intriguing ON‐OFF effect of the amine ligand was observed. The reaction almost did not occur (OFF) without addition of Lewis base amine ligand. However, the reaction took place smoothly (ON) after addition of only catalytic amount of amine ligand. Detailed mechanistic studies and density functional theory (DFT) calculations indicate that the reactivity can be delicately improved by the use of tertiary amine. The fine‐tuning effect of the tertiary amine is crucial in the formation of the Rh−Si species via a concerted metalation deprotonation (CMD) mechanism and facilitating β‐oxygen elimination.

Rapid Access to Divergent Fused Polycycles Via One-Pot A3 Coupling and Intramolecular Diels-Alder Reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Constructing Pd and Cu Crowding Single Atoms by Protein Confinement to Promote Sonogashira Reaction.

For multicenter-catalyzed reactions, it is important to accurately construct heterogeneous catalysts containing multiple active centers with high activity and low cost, whichis more challenging compared to homogeneous catalysts because of the low activity and spatial confinement of active centers in the loaded state. Herein, a convenient protein confinement strategy is reported to locate Pd and Cu single atoms in crowding state on carbon coated alumina for promoting Sonogashira reaction, the most powerful method for constructing the acetylenic moiety in molecules. The single-atomic Pd and Cu centers take advantage in not only the maximized atomic utilization for low cost, but also the much-enhanced performance by facilitating the activation of aryl halides and alkynes. Their locally crowded dispersion brings them closer to each other, which facilitates the transmetallation process of acetylide intermediates between them. Thus, the Sonogashira reaction is drove smoothly by the obtained catalyst with a turnover frequency value of 313 h-1, much more efficiently than that by commercial Pd/C and CuI catalyst, conventional Pd and Cu nanocatalysts, and mixed Pd and Cu single-atom catalyst. The obtained catalyst also exhibits the outstanding durability in the recycling test.

Migration of Condensed Aromatic Hydrocarbons During Alkyne-Vinylidene Rearrangements.

Diarylacetylenes ArC≡CAr featuring condensed aromatic hydrocarbon fragments (Ar) such as naphthalene, anthracene, phenanthrene and pyrene were converted into vinylidene ligands by 1,2-migration reactions within the coordination sphere of half-sandwich complexes [MII(dppe)Cp]+ (MII = RuII, FeII). Comparison of the extent of conversion of the alkyne substrates to the vinylidene complexes [Ru{=C=CAr2}(dppe)Cp]+ with those obtained from acetylenes functionalized by smaller groups (H, CH3, Ph) show that the molecular volume (VM) of the migrating group and relief of steric congestion plays a role during the rearrangement process. Conversely, the H-atoms from the larger condensed ring aryl groups that are in close proximity to the migrating sites also have a significant influence on the efficacy and extent of the reaction by restricting access of the alkyne to the metal center, resulting in a less effective migration reaction. This combination of competing steric factors (acceleration due to relief of steric congestion and restricted access of the alkyne moiety to the reaction site) is exemplified by the facile migration of 1-pyryl entities and the low yields of vinylidene products formed from 1,2-bis(9-anthryl)acetylene.

A β-Glucosyl Sterol Probe for in situ Fluorescent Labelling in Neuronal Cells to Investigate Neurodegenerative Diseases.

A β-glucosyl sterol probe bearing a terminal alkyne moiety for fluorescent tagging enables the investigation of the neuronal and intracellular localization of this class of compounds involved in neurodegenerative diseases. The compound showed localization in the neuronal cells, with marked differences in the uptake and metabolism leading to enhanced persistence with respect to the un-glycosylated sterol analogue. In addition, a different impact was observed towards lysosomes, with the simple sterol probe showing the enlargement of the lysosome structures, while the β-glucosyl sterol was less capable to alter the morphology of this specific organelle.

Synthesis of mannose conjugated biodegradable polyester-based nanocarriers and their binding study with Concanavalin A

In this paper, we aim to create fully biodegradable glyconanoparticles formed via self-assembly of glycopolymers, comprising of biodegradable aliphatic polyester conjugated with mannose moiety. To accomplish the goal, a series of random copolymers comprised of poly(propargyl glycolide-co-lactide) were synthesized. Alkyne moiety of the poly (propargyl glycolide) component was then clicked with mannose ethyl azide to produce amphiphilic glycopolymers in good yield (60–75 %). The glycopolymers were then self-assembled to form glyconanoparticles of 15–23 nm size in dry state and 78–88 nm size in hydrated state (hydrodynamic diameter). The copolymers were characterized by NMR and FTIR, whereas the nanoparticles were thoroughly characterized by DLS, FESEM, and HR-TEM and explored for their lectin binding efficiency. Isothermal calorimetry (ITC) experiments suggest a stronger binding efficiency of glyconanoparticles towards mannose-specific lectin such as Concanavalin A, as compared to its corresponding glycopolymers (∼2 fold) and monomeric mannose unit (∼7-fold) as well. Moreover, curcumin was selected as the model drug to be encapsulated (∼76 % encapsulation efficiency) and released (74 % in 24 h) from the glyconanoparticles. Apart from these, excellent haemocompatibility, cell viability, and cellular uptake of the nanoparticles (more than 80 % cells showed uptake of the nanoparticles), further supported their potential as drug carriers having sugar as a targeting moiety.

Optical Fiber-Assisted Printing: A Platform Technology for Straightforward Photopolymer Resins Patterning and Freeform 3D Printing.

Light-based 3D printing techniques represent powerful tools, enabling the precise fabrication of intricate objects with high resolution and control. An innovative addition to this set of printing techniques is Optical Fiber-Assisted Printing (OFAP) introduced in this article. OFAP is a platform utilizing an LED-coupled optical fiber (LOF) that selectively crosslinks photopolymer resins. It allows change of parameters like light intensity and LOF velocity during fabrication, facilitating the creation of structures with progressive features and multi-material constructs layer-by-layer. An optimized formulation based on allyl-modified gelatin (gelAGE) with food dyes as photoabsorbers is introduced. Additionally, a novel gelatin-based biomaterial, alkyne-modified gelatin (gelGPE), featuring alkyne moieties, demonstrates near-visible light absorption thus fitting OFAP needs, paving the way for multifunctional hydrogels through thiol-yne click chemistry. Besides 2D patterning, OFAP is transferred to embedded 3D printing within a resin bath demonstrating the proof-of-concept as a novel printing technology with potential applications in tissue engineering and biomimetic scaffold fabrication, offering rapid and precise freeform printing capabilities.

Ytterbium(II) Complex-Catalyzed Selective Single and Double Hydrophosphination of 1,3-Enynes.

1,3-Enynes with conjugated alkene and alkyne moieties are attractive building blocks in synthetic chemistry. However, neither 4,1-hydrophosphination nor dihydrophosphination of 1,3-enynes has been reported. In this paper, the divalent ytterbium and calcium amide complexes supported by silaimine-functionalized cyclopentadienyl ligands (C5Me4-Si(L)=NR) were developed, which successfully catalyzed the efficient single and double hydrophosphination of 1,3-enynes with diarylphosphines. The hydrophosphination reactions selectively produced homoallenyl phosphines and (E)-propenylene diphosphines, respectively. This work demonstrated the potential of hemilabile silaimine-Cp ligands in the supporting the efficient and selective rare- and alkaline-earth catalysts.

Flash vacuum pyrolysis of steroid propargyl ethers

Owing to its unique rearrangement and cyclization processes via flash vacuum pyrolysis (FVP), the acetylenic moiety has attracted considerable attention by organic chemists as a key building block in the construction of innovative organic architects. Herein, a series of seven steroid propargyl ether precursors have been successfully synthesized and pyrolyzed. Analysis and characterization of the FVP products revealed that the propargyl ethers of phenolic steroids undergo Claisen-rearrangement to give 2-indanone and benzo cyclobutene derivatives, while propargyl ethers of non-aromatic steroids resulted in the corresponding α, β-unsaturated ketones.

Synthesis of Dihydrobenzosiloles and Silacyclopentanes by Double Hydroalumination of Terminal Alkynes

AbstractWe have developed an efficient method for the synthesis of 2,3-dihydro-1H-1-benzosiloles in 19% to 90% isolated yield from 1-hydrosilyl-2-ethynylbenzenes by using two equivalents of diisobutylaluminum hydride. The reaction mechanism involves regioselective double hydroalumination of the alkyne moiety followed by cyclization to a 2-alanyldihydrobenzosilole. A silacyclopentane (silolane) was also synthesized in 97% isolated yield from the corresponding 4-silylbut-1-yne under the same reaction conditions. Although the substrate-scope study was conducted on a 0.5-mmol scale, a gram-scale reaction of (2-ethynylphenyl)(diphenyl)silane under the optimized reaction conditions successfully afforded the desired product in 94% isolated yield without loss of reactivity.

Novel Zinc-porphyrin dyes for dye-sensitized solar cells that enables light capture in the near-ultraviolet and visible range

Two novel Zinc-porphyrin central dyes (T-5 and T-6) containing acetylene moiety have been designed and synthesized for application in dye-sensitized solar cells (DSSCs). The light-harvesting capabilities and photovoltaic performance of these dyes were investigated systematically through comparison of different donor (D) unit. Devices fabricated from phenoxazine (POZ)-based molecule T-5 showed higher short-circuit current (JSC, 11.32 mA cm-2) compared to T-6 which based on phenothiazine (PTZ) (10.1 mA cm-2) under standard global AM 1.5 G solar condition. This is due to the fact that the POZ unit has a greater electron supply capacity than the PTZ unit. The introduction of the acetylene moieties into the molecular structure broadens the light absorption range of the dye molecule to the entire visible range and the near-ultraviolet region. The conclusions of this paper demonstrate that incorporating strong electron donor groups in dye molecules, in synergy with conjugated groups, broadens the spectral range of light absorption, thereby enhancing the performance of the dye device.

Boryl Radical as a Catalyst in Enabling Intra- and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules.

Cascade radical cyclization constitutes an atom- and step-economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox-active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium-based N-heterocyclic carbene (NHC)-boryl radical is capable of catalyzing cascade cyclization reactions in both intra- and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo- and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β-elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Boryl Radical as a Catalyst in Enabling Intra‐ and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules

AbstractCascade radical cyclization constitutes an atom‐ and step‐economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox‐active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium‐based N‐heterocyclic carbene (NHC)‐boryl radical is capable of catalyzing cascade cyclization reactions in both intra‐ and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo‐ and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β‐elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Synthesis of a Side Chain Alkyne Analogue of Sitosterol as a Chemical Probe for Imaging in Plant Cells.

Clickable chemical tools are essential for studying the localization and role of biomolecules in living cells. For this purpose, alkyne-based close analogs of the respective biomolecules are of outstanding interest. Here, in the field of phytosterols, we present the first alkyne derivative of sitosterol, which fulfills the crucial requirements for such a chemical tool as follows: very similar in size and lipophilicity to the plant phytosterols, and correct absolute configuration at C-24. The alkyne sitosterol FB-DJ-1 was synthesized, starting from stigmasterol, which comprised nine steps, utilizing a novel alkyne activation method, a Johnson-Claisen rearrangement for the stereoselective construction of a branched sterol side chain, and a Bestmann-Ohira reaction for the generation of the alkyne moiety.