Terminal Alkynes Research Articles

Total Synthesis of Lobatamides A and C

AbstractThe total synthesis of lobatamides A (1 a) and C (1 c) via a common bislactone intermediate is reported. The allylic aryl moiety including a trisubstituted Z‐olefin was constructed by hydroboration of a 1,1‐disubstituted allene and subsequent Migita‐Kosugi‐Stille coupling. Although the seco acid proved to be highly unstable even in the presence of weak bases, Zhao macrolactonization under acidic conditions via the α‐acyloxyenamide successfully provided the common bislactone intermediate. Hydrozirconation‐iodination of the terminal alkyne and subsequent copper‐mediated coupling with primary amides proceeded successfully in the presence of the sensitive bislactone framework. The developed synthetic route enables the late‐stage installation of enamide side chains, which are crucial structures for V‐ATPase inhibition.

Total Synthesis of Lobatamides A and C.

The total synthesis of lobatamides A (1 a) and C (1 c) via a common bislactone intermediate is reported. The allylic aryl moiety including a trisubstituted Z-olefin was constructed by hydroboration of a 1,1-disubstituted allene and subsequent Migita-Kosugi-Stille coupling. Although the seco acid proved to be highly unstable even in the presence of weak bases, Zhao macrolactonization under acidic conditions via the α-acyloxyenamide successfully provided the common bislactone intermediate. Hydrozirconation-iodination of the terminal alkyne and subsequent copper-mediated coupling with primary amides proceeded successfully in the presence of the sensitive bislactone framework. The developed synthetic route enables the late-stage installation of enamide side chains, which are crucial structures for V-ATPase inhibition.

Palladium-Copper-Catalyzed Oxidative Intermolecular [2 + 2 + 2] Coupling-Annulation: Regioselective Synthesis of Multiaryl-Substituted Benzenes.

A palladium-catalyzed intermolecular [2 + 2 + 2] oxidative coupling-annulation of terminal alkenes and alkynes using copper(II) as the oxidant has been developed through direct C-C bond formation. These reactions provide effective access to multiaryl-substituted benzenes with high regioselectivity in the absence of any ligands. The features of this protocol are broad substrate scope, and high atom and step economy. The aggregation-induced emission properties of selected products were further investigated. These synthesized multiaryl-substituted benzenes may be worth exploring for further applications in the fields of advanced functional materials or drugs.

Metal-organic framework/polyurea composite microreactors prepared in oil-in-oil emulsions

A new technique was developed to create composite microcapsules consisting of metal–organic framework (MOF) and polyurea. This method employs oil-in-oil (O/O) emulsion as a template for forming these microcapsules. It involves emulsifying a polar solvent containing MOF reagents within a nonpolar phase containing a suitable surfactant and an isocyanate monomer. Subsequently, the addition of the amine monomer initiates two simultaneous processes: the formation of MOF crystals in the core of polar droplets and the interfacial polymerization to create polyurea shell. Optimization of the method involved adjusting various parameters affecting the composite microcapsules' structure and morphology. These parameters include the surfactant’s type and concentration, the emulsion phases’ type and concentration, and quantity of the MOF component.This method was applied to create palladium-based MOF/polyurea microreactors by encapsulating sodium tetrachloropalladate and then reducing the palladium salt with hydrogen to generate reactive palladium species. The produced catalysts were utilized in the selective hydrogenation of terminal alkynes. It was observed that the selectivity of the catalyst is influenced by the quantity of encapsulated MOF, the amount of encapsulated palladium, and the solvent type used for the reaction.

SYNTHESIS OF 1,2,3-TRIAZOLES BASED ON PHENACYL AZIDE DERIVATIVES VIA CLICK CHEMISTRY

Etherification of n-hexanol, n-heptanol and n-octanol with propargyl bromide in the presence of sodium hydroxide in DMF afforded the terminal alkynes (2) a, b and c. Phenacyl bromide, p-bromophenacyl bromide and p-phenylphenacyl bromide were converted to corresponding azides (4) a, b and c respectively by traditional SN2 reaction of the mentioned bromides and sodium azide in DMF. The cycloaddition of the propargyl ethers (2) with the prepared organic azides (4) using click conditions gave the target 1,4-disubstituted 1,2,3- triazoles (5)-(7) in good yields. All the synthesized triazoles were characterized by FT-IR while the compounds (5) a,b and c were characterized by 1H NMR and 13C NMR in addition to FT-IR technique.

Design and Synthesis of Novel 6,7‐Dihydrobenzo[d]isoxazol‐4(5H)‐one Derivatives Bearing 1,2,3‐Triazole Moiety as Potential Hsp90 Inhibitors and their Evaluation as Antiproliferative Agents

AbstractAn effective approach to 5‐triazolyl‐substituted 6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐ones and 4,5,6,7‐tetrahydrobenzo[d]isoxazoles was developed. The approach included α‐keto bromination of 6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐one followed by nucleophilic substitution of bromine with the azide group. For the preparation of 5‐azido‐6,7‐dihydrobenzo[d]isoxazol‐4(5H)‐one, the carbonyl group at position 4 was reduced to a methylene group under ionic hydrogenation conditions using triethylsilane as a reducing agent. Cu(I)‐catalyzed [2+3] cycloaddition of terminal alkynes to both obtained azides was used for the synthesis of two series of triazolyl derivatives. Compounds, which contain in their structures common for some Hsp90 inhibitors 2,4‐dihydroxy‐5‐isopropylphenyl fragment, were evaluated as antiproliferative agents against two breast cancer cell lines: hormone‐dependent MCF7 and HER2‐positive HCC1954. The lead compound showed half‐maximal inhibitory concentration (IC50) values below 5 μM and induced significant changes in the Hsp90 signaling pathways in HER2‐positive HCC1954 cells. It increased the expression of Hsp70 (used as a pharmacodynamic marker of Hsp90 inhibition) and inhibited the expression of HER2, p‐c‐Met, c‐Met, and p‐AKT. The combination of the selected isoxazole‐triazole hybrid molecule and the earlier described apoptosis inducer LCTA‐3344 demonstrated a significant antiproliferative effect against HCC1954 cells. The lead compound was revealed to be a promising candidate for future anticancer drug design, particularly against aggressive breast cancer positive for HER2.

A heteroleptic Pt-doped Cu-rich hydrides nanocluster

An atomically precise heteroleptic Pt-doped Cu-rich hydride nanocluster [PtH2@Cu14(dtc)6(C2Ph)6] (PtH2Cu14-dtc) has been successfully synthesized. This was achieved by introducing a discrete Pt(II) precursor to the copper hydride nanocluster [Cu28H15(dtc)12](PF6) in the presence of terminal alkynes. The structure of PtH2Cu14 determined by X-ray diffraction reveals a bicapped icosahedral copper(I) cage encapsulating a linear platinum dihydride [PtH2]2- unit. The interstitial hydrides are arranged in a trigonal bipyramidal (tbp) geometry with a five-coordinated hydride as confirmed by 2H NMR and ESI-MS measurements.

Reflections on a Copenhagen-Minneapolis Axis in Bioorganic Chemistry.

The international peptide community rejoiced when one of its most distinguished members, Morten Meldal of Denmark, shared the 2022 Nobel Prize in Chemistry. In fact, the regiospecific solid-phase "copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides" (CuACC) reaction-that formed the specific basis for Meldal's recognition-was reported first at the 17th American Peptide Symposium held in San Diego in June 2001. The present perspective outlines intertwining conceptual and experimental threads pursued concurrently in Copenhagen and Minneapolis, sometimes by the same individuals, that provided context for Meldal's breakthrough discovery. Major topics covered include orthogonality in chemistry; the dithiasuccinoyl (Dts) protecting group for amino groups in α-amino acids, carbohydrates, and monomers for peptide nucleic acids (PNA); and poly(ethylene glycol) (PEG)-based solid supports such as PEG-PS, PEGA, and CLEAR [and variations inspired by them] for solid-phase peptide synthesis (SPPS), solid-phase organic synthesis (SPOS), and combinatorial chemistry that can support biological assays in aqueous media.

Intramolecular Nitrone Interrupted Click Reaction.

We document the intramolecular interception of a Cu-catalyzed azidoalkyne cycloaddition employing a suitably placed nitrone group, providing a simple route to the unprecedented spiro-polyheterocyclic scaffold. The reaction is comprised of a Cu-catalyzed [3 + 2]-cycloaddition of (2-azidoaryl)isatogen with a terminal alkyne and the intramolecular trapping of the transient Cu-triazolide intermediate with the isatogen, with a net formation of one C-C and two C-N bonds and the new heterocyclic ring being spiro-annulated.

Clicked BODIPY-Fullerene-Peptide Assemblies: Studies of Electron Transfer Processes in Self-Assembled Monolayers on Gold Surfaces.

Two BODIPY-C60-peptide assemblies were synthesized by CuAAC reactions of BODIPY-C60 dyads and a helical peptide functionalized with a terminal alkyne group and an azide group, respectively. The helical peptide within these assemblies was functionalized at its other end by a disulfide group, allowing formation of self-assembled monolayers (SAMs) on gold surfaces. Characterizations of these SAMs, as well as those of reference molecules (BODIPY-C60-alkyl, C60-peptide and BODIPY-peptide), were carried out by PM-IRRAS and cyclic voltammetry. BODIPY-C60-peptide SAMs are more densely packed than BODIPY-C60-alkyl and BODIPY-peptide based SAMs. These findings were attributed to the rigid peptide helical conformation along with peptide-peptide and C60-C60 interactions within the monolayers. However, less dense monolayers were obtained with the target assemblies compared to the C60-peptide, as the BODIPY entity likely disrupts organization within the monolayers. Finally, electron transfer kinetics measurements by ultra-fast electrochemistry experiments demonstrated that the helical peptide is a better electron mediator in comparison to alkyl chains. This property was exploited along with those of the BODIPY-C60 dyads in a photo-current generation experiment by converting the resulting excited and/or charge separated states from photo-illumination of the dyad into electrical energy.

Chemical Probes to Interrogate the Extreme Environment of Mosquito Larval Guts.

Mosquito control methods are vital to curtail the spread of life-threatening illnesses, such as dengue fever, malaria, and yellow fever. Vector control technologies must be selective to minimize deleterious effects on our ecosystem. Successful methods that control mosquito larva populations utilize the uniquely high alkaline nature of the midgut. Here, we present novel protected triazabutadienes (pTBD) that are deprotected under basic conditions of the larval midgut, releasing an aryl diazonium ion (ADI) that results in protein modification. The probes contain a bioorthogonal terminal alkyne handle, enabling a selective Cu-click reaction with an azidofluorophore for quantification by SDS PAGE and visualization using fluorescence microscopy. A control TBD, unable to release an ADI, did not label the midgut. We envision our chemical probes will aid in the development of new selective mosquito control methods, thus preventing the spread of mosquito-borne illnesses with minimal impact on other organisms in the ecosystem.

Cobalt catalyzed practical hydroboration of terminal alkynes with time-dependent stereoselectivity

Stereodefined vinylboron compounds are important organic synthons. The synthesis of E−1-vinylboron compounds typically involves the addition of a B-H bond to terminal alkynes. The selective generation of the thermodynamically unfavorable Z-isomers remains challenging, necessitating improved methods. Here, such a proficient and cost-effective catalytic system is introduced, comprising a cobalt salt and a readily accessible air-stable CNC pincer ligand. This system enables the transformation of terminal alkynes, even in the presence of bulky substituents, with excellent Z-selectivity. High turnover numbers (>1,600) and turnover frequencies (>132,000 h−1) are achieved at room temperature, and the reaction can be scaled up to 30 mmol smoothly. Kinetic studies reveal a formal second-order dependence on cobalt concentration. Mechanistic investigations indicate that the alkynes exhibit a higher affinity for the catalyst than the alkene products, resulting in exceptional Z-selective performance. Furthermore, a rare time-dependent stereoselectivity is observed, allowing for quantitative conversion of Z-vinylboronate esters to the E-isomers.

Upper Rim-Bridged Calix[4]arenes via Cyclization of meta Alkynyl Intermediates with Diphenyl Diselenide.

A Sonogashira coupling of meta-iodocalix[4]arene with various terminal acetylenes confirmed that the meta position of calixarene is well addressable, and that both thermal and microwave protocols led to good yields of alkynylcalixarenes. Alkynes thus obtained were subjected to the ferric chloride and diphenyl diselenide-promoted electrophilic closure. It turns out that the calix[4]arenes give completely different bridging products than those described for the non-macrocyclic starting compounds. This can be demonstrated not only by the isolation of products with a six-membered ring (6-exo-dig), but mainly by the smooth formation of the 5-endo-dig cyclization, which has never been observed in the aliphatic series. An attempt at electrocyclization led to a high yield of the 1,2-diketone (oxidation of the starting alkyne), again in contrast to the reaction described for the acyclic derivatives. The structures of the unexpected products were unequivocally established by X-ray analysis and clearly demonstrate how the preorganized macrocyclic skeleton favors a completely different regioselectivity of cyclization reactions compared to common aliphatic compounds.

Air Induced Phosphoryl Radical Mediated Stereoselective Hydrosulfonylation of Alkynes via Halogen Atom Transfer: Ingress of Z-Vinyl Sulfones.

The phosphoryl radical is well-known to participate in addition reactions with alkenes/alkynes. Here, we report a novel reaction mode of the phosphoryl radical where it participates in halogen atom transfer (XAT) with electron deficient vinyl halides instead of a facile addition reaction. Nevertheless, in comparison with aryl and alkyl halides, the exploitation of vinyl halides into a carbon radical via XAT is quite rare. This protocol provides an opportunity for direct hydrosulfonylation of numerous internal as well as terminal alkynes to get various Z-vinyl sulfones under environmentally benign conditions. Generation of the phosphoryl radical in the open air, water as a solvent, excellent functional group compatibility, and exceptional chemoselectivity are the attractive features of the present methodology.

Bioinspired Photoactive Cu-Halide Coordination Polymers for Reduction Activation and Oxygen Conversion.

Natural copper oxygenases provide fundamental principles for catalytic oxidation with kinetically inert molecular oxygen, but it remains a marked challenge to mimic both their structure and function in an entity. Inspired by the CuA enzymatic sites, herein we report two new photoactive binuclear copper-iodine- and bisbenzimidazole-comodified coordination polymers to reproduce the natural oxo-functionalization repertoire in a unique photocatalytic pathway. Under light irradiation, the Cu-halide coordination polymers effectively reduce NHP esters and complete oxygen reduction activation via photoinduced electron transfer for the aerobic oxidative coupling of hydroquinone with terminal alkynes, affording hydroxyl-functionalized ketones with high efficiency and selectivity. This supramolecular approach to developing bioinspired artificial oxygenases that merge transition metal- and photocatalysis supplies a new way to fabricate distinctive photocatalysts with desirable catalytic performances and controllable precise active sites.

Copper-Mediated Cyclization of Terminal Alkynes with CF3-Imidoyl Sulfoxonium Ylides To Construct 5-Trifluoromethylpyrroles.

A copper-mediated [3 + 2] cyclization of CF3-imidoyl sulfoxonium ylides and terminal alkynes has been demonstrated. This work provides a practical approach for assembling 5-trifluoromethylpyrroles with the merits of a broad substrate scope, good functional tolerance, and mild reaction conditions. Control experiments and DFT studies indicate that this reaction may involve the addition of π-bonds of terminal alkynes by copper-carbene radicals and hydrogen migration.

Carboxylate-Catalyzed C-Silylation of Terminal Alkynes.

A carboxylate-catalyzed, metal-free C-silylation protocol for terminal alkynes is reported using a quaternary ammonium pivalate as the catalyst and commercially available N,O-bis(silyl)acetamides as silylating agents. The reaction proceeds under mild conditions, tolerates a range of functionalities, and enables concomitant O- or N-silylation of acidic OH or NH groups. A Hammett ρ value of +1.4 ± 0.1 obtained for para-substituted 2-arylalkynes is consistent with the proposed catalytic cycle involving a turnover-determining deprotonation step.

Sulfonamide tethered 1,4-disubstituted 1,2,3-triazoles: Synthesis and antibacterial evaluation

A series of twenty one sulfonamide tethered 1,4-disubstituted 1,2,3-triazoles was synthesized in good yields through a facile expeditious click synthetic protocol involving Cu(I) mediated cyclization between terminal alkynes containing ester linkage and 4-azidobenzenesulfonamide. All the synthesized triazoles were characterized using FTIR,1H NMR,13C NMR and HRMS techniques. Synthesized compounds were also evaluated for in vitro antibacterial activity against two Gram positive bacteria (Staphylococcus aureus, Bacillus subtilis) and two Gram negative bacteria (Klebsiella pneumoniae, Escherichia coli) by serial dilution method. In the series, compound 6 l, 3-(1-(4-sulfamoylphenyl)-1H-1,2,3-triazol-4-yl)propyl 4-bromobenzoate with Minimum Inhibitory Concentration (MIC) 0.0134 µmol/mL exhibited appreciable antibacterial activity against all bacterial strains comparable with standard drug Ciprofloxacin (MIC 0.0189 µmol/mL). Further, molecular docking study was also performed to gain insight for binding interactions with dihydropteroate synthase enzyme.

Photoredox‐Enabled Manganese‐Catalyzed [2+2+2] Cycloaddition of Alkynes

AbstractManganese (Mn) is the third most abundant transition metal on Earth and is known for its exceptional biocompatibility. The development of novel catalytic mode for Mn is of great significance to advancing organic synthesis. In this study, the first manganese (Mn)‐catalyzed [2+2+2] cycloaddition of alkynes is achieved with the aid of visible‐light photoredox catalysis. Photoredox catalysis is proposed to promote the transformation by in situ reduction of high‐valent Mn(II) complex to Mn(0) species, thereby initiating the reaction. Additionally, a photooxidation‐induced reductive ellimination step is also suggested. This system is further distinguished by its notable tolerance towards both terminal and internal alkynes as counterparts of diynes.

Divergent Reactivity of a Cyclic Bis-Hydridostannylene: A Masked Sn(I) Diradicaloid.

Herein, reactivity studies of a cyclic bis-hydridostannylene [(ADC)SnH]2 (1-H2) (ADC=PhC{(NDipp)C}2; Dipp=2,6-iPr2C6H3) with various unsaturated organic substrates are reported. Reactions of terminal alkynes (RC≡CH) with 1-H2 afford mixed acetylide-vinyl-functionalized bis-stannylenes via dehydrogenation and hydrostannylation. Treatment of 1-H2 with PhC≡CCH3 gives a unique distannabarrelene via dehydrogenative C(sp3)-H stannylation and hydrostannylation of the C≡CCH3 moiety. 1-H2 undergoes dehydrogenative [2+2]-cycloaddition reactions with diphenylacetylene, azobenzene, acetone, benzophenone, and benzaldehyde to form the 1,4-distannabarrelene derivatives. The elimination of H2 in these reactions suggests the masked-diradical property of 1-H2. In fact, these [2+2]-cycloaddition products are also accessible on treatments of the Sn(I) diradicaloid [(ADC)Sn]2 (1) with appropriate reagents. All compounds have been characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction. Moreover, the catalytic activity of 1-H2 has been shown for the hydroboration of unsaturated substrates.