Alkyne Partners Research Articles

Click approach for the synthesis of 1,4-disubstituted-1,2, 3-triazoles of porphyrin-isatin/sulfa drug conjugates based on m-THPP

New porphyrin-isatin/sulfa drugs conjugates based on symmetrical 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin ([Formula: see text]-THPP) with 1,4-regioisomers of 1,2,3-triazole linker were successfully synthesized. The constructed porphyrin-conjugates 15-19 and 22-24 contained mono-, tri- (unsymmetrical), or tetrafunctionalized units of isatin, sulfanilamide and sulfapyridine with 1,2,3-triazole linker. The synthesis of these conjugates was achieved by nucleophilic functionalization of [Formula: see text]-THPP by propargyl bromide followed by zinc metalation to achieve the mono-/tri-/tetrafunctionalized propargyl[Formula: see text]-THPP zinc-complex derivatives 3-5 (alkyne partners). The formed alkyne partners underwent cycloaddition reaction with isatin azide 8, azidosulfanilamide 13 and azidosulfapyridine 14 (azide partners) using click conditions via applying copper (I) catalyzed azide-alkyne cycloaddition (CuAAC). The utilized protocol succeeded in generating amphiphilic conjugates based on [Formula: see text]-THPP in an easy, simple, and quick manner, with high regioselectivity and high yields for potential medicinal and biological applications. The Zn-porphyrin derivatives’ photonic properties were investigated via photoabsorption and fluorescence. The optical properties were also studied and it is obvious that the Zn-porphyrin complex derivatives are different from those of the free-base porphyrin and could be relied on the number of triazole units and bioconjugate type.

First site-specific conjugation method for native goat IgG antibodies via glycan remodeling at the conserved Fc region.

Despite their triumph in treating human diseases, antibody therapies for animals have gained momentum more slowly. However, the first approvals of animal antibodies for osteoarthritic pain in cats and dogs may herald the dawn of a new era. For example, goats are vital to economies around the world for their milk, meat, and hide products. It is therefore imperative to develop therapies to safeguard goats-with antibodies at the forefront. Goat antibodies will be crucial in the development of therapeutic antibodies, for example, as tracers to study antibody distribution in vivo, reagents to develop other therapeutic antibodies, and therapeutic agents themselves (e.g., antibody-drug conjugates). Hamstringing this effort is a still-burgeoning understanding of goat antibodies and their derivatization. Historically, goat antibody conjugates were generated through stochastic chemical modifications, producing numerous attachment sites and modification ratios, thereby deleteriously impacting antigen binding. Site-specific methods exist but often require substantial engineering and have not been demonstrated with goat antibodies. Nevertheless, we present herein a novel method to site-specifically conjugate native goat antibodies: chemo-enzymatic remodeling of the native Fc N-glycan introduces a reactive azide handle, after which click chemistry with strained alkyne partners affords homogeneous conjugates labeled only on the Fc domain. This process is robust, and resulting conjugates retain their antigen binding and specificity. To our knowledge, our report is the first for site-specific conjugation of native goat antibodies. Furthermore, our approach should be applicable to other animal antibodies-even with limited structural information-with similar success.

Rhodium-Catalyzed [2 + 2 + 2] Cyclotrimerizations of Yndiamides with Alkynes.

Yndiamides offer opportunities for the synthesis of vicinally nitrogen-disubstituted aromatics and azacycles. Here we report the Rh-catalyzed cyclotrimerization of alkynyl yndiamides with alkynes, the regiochemical outcome of which is controlled by the electronic properties of the alkyne partner, enabling the formation of 7-aminoindolines with excellent selectivity (up to >20:1 r.r.). We also report a complementary synthesis of bicyclic 1,2-dianiline derivatives by cyclotrimerization of yndiamides with terminal diynes, where slow addition of the diyne overcomes self-dimerization.

Oxygenated Cyclopentenones via the Pauson-Khand Reaction of Silyl Enol Ether Substrates.

We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson–Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.

Ceric Ammonium Nitrate Promoted Oxidative Coupling of Terminal Alkynes and 1,3-Keto Esters: A Synthesis of Unsymmetrical 1,1,2-Triacylalkenes

AbstractUnsymmetrical 1,1,2-triacylalkenes were conveniently prepared by the oxidative coupling of 1,3-keto esters with terminal alkynes by employing 4.0 equivalents of inexpensive ceric ammonium nitrate (CAN) as the oxidant in acetonitrile as the solvent at 0 °C. The method is milder than previously reported methods and can be conducted under air, thereby demonstrating its practicality and versatility for preparing these useful building blocks. The reaction is believed to occur by a single-electron-transfer process of the 1,3-keto ester substrate initiated by CAN to generate an α-radical species that quickly adds to the terminal alkyne partner in the reaction. Subsequent oxidation of the resulting vinyl radical by air and CAN then leads to the formation of the triacylalkene product as a mixture of E- and Z-isomers. The reaction was shown to be general, with 27 illustrative examples of the formation of the desired products in up to quantitative yield and with moderate to excellent alkene geometrical selectivities.

Synthesis and Biological Evaluation of Novel 1,4-Disubstituted 1,2,3-Triazoles and Bis 1,2,3-Triazoles as Anti-Bacterial Agents

A library of novel 1,4-disbustituted 1,2,3-triazoles 3a-3k was prepared by using Click-chemistry concept. In this 1,3-dipolar cycloaddition, the 3-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde (1) was used as alkyne partner which was synthesized from vanillin and propargyl bromide and was reacted with differently substituted arylpropoxy azides to furnish series of mono and bis 1,4-disubstituted-1,2,3-triazoles. All the synthesized compounds were characterized spectroscopically and were evaluated for their antimicrobial activity. Preliminary results of antibacterial screening revealed that various synthesized compounds have the highest inhibitory effects then the control ciprofloxacin against the growth of a wide range of both gram positive and gram negative bacterial strains. Compounds 3g and 3b were found to be the most active against various strains of gram-positive and gram-negative bacteria.

Synthesis, antibacterial activity and molecular docking study of vanillin derived 1,4-disubstituted 1,2,3-triazoles as inhibitors of bacterial DNA synthesis

Antimicrobial resistance (AMR) compelled scientists in general while pharmacists, chemists and biologists in specific to believe that we could always remain ahead of the pathogens. The pipeline of new drugs is running gasping and the inducements to develop new antimicrobials to address the global problems of drug resistance are weak. In this pursuit, effective endeavours to prepare new anti-bacterial entities is highly wished. The present study demonstrates successful synthesis of a library of 1,4-disbustituted 1,2,3-triazoles (3a-3k) using Click-chemistry concept and anti-their bacterial potential. In this 1,3-dipolar cycloaddition, the 3-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde (1) was used as alkyne partner which was synthesized from vanillin and propargyl bromide and further reacted with differently substituted arylpropoxy azides (2a-k) to furnish series of mono and bis1,4-disubstituted-1,2,3-triazoles. All the synthesized compounds were characterized spectroscopically and were evaluated for their initial antimicrobial activity. Preliminary results of antibacterial screening revealed that the synthesized compounds have the highest inhibitory effects compare to the control ciprofloxacin. The compounds 3b and 3g were found to be the most active (MIC: 5 μg/mL, MIC: 10 μg/mL respectively) against various strains of gram-positive and gram-negative bacteria. The molecular docking study against 4GQQ protein with synthesized ligands was performed to see the necessary interactions responsible for anti-bacterial activity. The docking analysis of the most potent compound 3g supported the antibacterial activity exhibiting high inhibition constant and binding energy.

Linear and Convergent Syntheses of Bifunctional Hydroxy-Bisphosphonic Compounds as Potential Bone-Targeting Prodrugs

The synthesis of two bifunctional compounds bearing a terminal hydroxy-bisphosphonic function (HBP) was achieved following a linear and a convergent strategy. In the linear approach, the free hydroxy-bisphosphonic function was introduced in the last step of the synthesis, under neutral conditions using an Arbuzov reaction with tris(trimethylsilyl) phosphite and a carboxylic acid precursor activated in situ with catecholborane. In the convergent approach, Huisgen type cycloaddition was studied starting from an HBP-functionalized alkyne partner to obtain the targeted bifunctional molecule. These complementary approaches allow for the preparation of complex bone-targeting molecules as potential prodrug candidates.

Preparation of stimulus‐responsive, polyfluorene‐wrapped carbon nanotubes via palladium cross coupling

ABSTRACTDecoration of carbon nanotube surfaces without damaging nanotube optoelectronic properties is an ongoing challenge. Here, we utilize Sonogashira coupling chemistry to decorate the nanotube surface without perturbing optoelectronic properties. Reactive, noncovalently functionalized polymer–nanotube complexes were prepared using a polyfluorene with aryl iodide groups in its side chains. The aryl iodides enable Pd cross coupling between polymer–nanotube complexes and small molecules or polymers derivatized with an alkyne. Modestly efficient coupling was found to occur under dilute conditions at elevated temperatures. Successful coupling between aryl iodide and alkyne partners was observed using infrared spectroscopy via the appearance of carbonyl stretches that originate from covalently linked, carbonyl‐containing alkynes, and thermogravimetric analysis was used to measure reaction conversion under various conditions. Grafting of the hydrophobic polymer–nanotube complex with poly(ethylene glycol) enabled the dispersion to be transferred from organic to aqueous solution. This chemistry resulted in no damage to the nanotube sidewall, as evidenced by Raman spectroscopy. The aryl iodide‐containing polyfluorene–nanotube complex was also coupled to a photoswitchable alkyne‐containing spiropyran moiety and it was found that the photoswitch retained its functionality after coupling to the polymer–nanotube complex. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 2723–2729

Design and Synthesis of Iminosydnones for Fast Click and Release Reactions with Cycloalkynes.

Emerging applications in the field of chemical biology are currently limited by the lack of bioorthogonal reactions allowing both removal and linkage of chemical entities on complex biomolecules. We recently discovered a novel reaction between iminosydnones and strained alkynes leading to two products resulting from ligation and fragmentation of iminosydnones under physiological conditions. We now report the synthesis of a panel of substituted iminosydnones and the structure reactivity relationship between these compounds and strained alkyne partners. This study identified the most relevant substituents, which allow to increase the rate of the transformation and to develop a bifunctional cleavable linker with improved kinetics.

Ruthenium-Catalyzed [2+2+2] Cycloaddition of 1,6-Enynes and Unactivated Alkynes: Access to Ring-Fused Cyclohexadienes.

The [2+2+2] intermolecular carbocyclization reactions between 1,6-enynes and alkynes catalyzed by [RuCl(cod)(Cp*)] (cod=1,5-cyclooctadiene, Cp*=pentamethylcyclopentadienyl) are reported to provide bicyclohexa-1,3-dienes. The presented reaction conditions are compatible with internal and terminal alkynes and the chemo- and regioselectivity issues are controlled by the presence of substituents at the propargyl carbon center of the alkyne(s) partner(s).

Rhodium-Catalyzed Intermolecular Carbonylative [2 + 2 + 1] Cycloaddition of Alkynes Using Alcohol as the Carbon Monoxide Source for the Formation of Cyclopentenones.

A highly regioselective rhodium-catalyzed intermolecular carbonylative [2 + 2 + 1] cycloaddition of alkynes using alcohol as a CO surrogate to access 4-methylene-2-cyclopenten-1-ones has been developed. In this transformation, the alcohol performs multiple roles, including generating the Rh-H intermediate, functioning as the CO source, and assisting in the isomerization of the alkyne. Alkynes can act as both the olefin and the alkyne partner in the cyclopentenone core.

Ag(I)‐Catalyzed Cyclizative Hydration of Alkynes and Propargylic Alcohols. A Mild Approach to 2‐Acylfuran Derivatives

AbstractWe developed a mild strategy for the synthesis of 2‐acylfuran derivatives via cyclizative hydration of propargylic alcohols and alkynes, under Ag(I) catalysis. This is the first report employing the propargylic alcohols and their derivatives as alkyne partners in the cyclizative hydration process. This process found very broad scope for propargylic alcohols, alkynes and tethers. The highly chemo‐selective cyclizative hydration of 6‐acetoxy‐hex‐2‐en‐4‐ynal substrates suggests that, the acetoxy directed hydration of alkyne is not operable under Ag‐catalysis conditions and hence propargylic acetates can also be conveniently employed for the synthesis of 2‐(acetoxyacyl)furans.

Water-Promoted Regiospecific Azidolysis and Copper-Catalyzed Azide-Alkyne Cycloaddition: One-Pot Synthesis of 3-Hydroxy-1-alkyl-3-[(4-aryl/alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-ones.

An efficient, eco-friendly, base free, one-pot, sequential protocol was developed for epoxide azidolysis and copper-catalyzed azide-alkyne cycloaddition using water as the solvent for the synthesis of 3-hydroxy-1-alkyl-3-[(4-aryl/alkyl-1H-1,2,3-triazol-1-yl)methyl]indolin-2-ones. The optimized reaction conditions have been generalized in the case of aromatic as well as aliphatic alkyne partners to afford good yields and high regioselectivity.

ChemInform Abstract: Synthesis of 5,6‐Dihydrodibenzo[b,h][1,6]naphthyridines via Copper Bromide Catalyzed Intramolecular [4 + 2] Hetero‐Diels—Alder Reactions.

AbstractCompounds (VII) and (IX) are also successfully obtained by using this strategy.

A Study on the Photoreaction of 2(5H)-Furanones with Substituted Acetylenes: Evidence for a Mechanistic Reformulation.

The photoreaction of 2(5H)-furanones with alkynes has been investigated. The complexity of this process is evidenced by the variety of isolated products, which have allowed disclosing interesting mechanistic aspects. When the reaction is performed in acetonitrile under direct excitation, in addition to the primary [2+2] cycloadducts, products derived from an 1,3-acyl shift rearrangement are also formed. For unsymmetrical alkynes, the rearrangement of the head-to-tail primary adducts produces new regioisomers and, when the starting furanone is chiral, this rearrangement inverts the relative anti/syn geometry of the primary cycloadducts. In the reactions performed in acetone under photosensitized conditions, rearranged products were never detected, supporting that the 1,3-acyl shift takes place from the singlet excited state S1 of the β,γ-unsaturated lactone. When bis(trimethylsilyl)acetylene is used as the alkyne partner, the major photoproducts are monocyclic bis(trimethylsilyl)lactones.

Synthesis of 5,6-Dihydrodibenzo[b,h][1,6]naphthyridines via Copper Bromide Catalyzed Intramolecular [4 + 2] Hetero-Diels-Alder Reactions.

A highly efficient synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines was achieved by reaction between 2-(N-propargylamino)benzaldehydes and arylamines in the presence of CuBr2. The in situ generated electron-deficient heterodienes bearing a tethered alkyne partner underwent an intramolecular inverse electron-demand hetero-Diels-Alder reaction followed by air oxidation to furnish the products in high yields. This reaction tolerated a large number of substituents to afford diverse products under mild conditions. This strategy was also successfully extended to the synthesis of 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones starting from 3-amino-2H-chromen-2-one, again in high yields.

Thermally controlled silicone functionalization using selective Huisgen reactions

The thermal azide–alkyne cycloaddition using electron deficient alkynes has previously been applied to the room temperature crosslinking of polysiloxanes. However, only propiolates were used as the alkyne partner to functionalize polysiloxanes under metal-free conditions. Herein, we extend the methodology to alkynes with differing electronic demands and therefore different reactivities, which opens the possibility for selective silicone functionalization using sequential reactions simply by changing temperatures. To obtain a more thorough understanding of the effect of the alkyne electron density on the cycloaddition, differential scanning calorimetry was used to determine the temperature at which triazole formation is initiated for a variety of alkynes. The study showed acetylene dicarboxylates to have the lowest onset cycloaddition temperature of those studied, 37°C. By contrast, propargyl esters only began to react at 101°C, with other carbonyl-modified alkynes showing intermediate reactivity. Benzyl azide was used to demonstrate that the silicone copolymers bearing pendant propiolate alkynes could be reacted preferentially at lower temperatures, but only just, over the more electron rich terminal propiolamide alkynes. By contrast, the reaction of silicone propiolates with benzyl azide occurred nearly specifically in the presence of terminal propargyl alkynes on a polysiloxane copolymer containing both groups.

ChemInform Abstract: Toward the Synthesis of Amphidinolide P: Optimization of a Model Ene—Yne Metathesis Fragment Coupling.

Abstract Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

Cross-metathesis of terminal alkynes.

Terminal acetylenes are amongst the most problematic substrates for alkyne metathesis because they tend to undergo rapid polymerization on contact with a metal alkylidyne. The molybdenum complex 3 endowed with triphenylsilanolate ligands, however, is capable of inducing surprisingly effective cross-metathesis reactions of terminal alkyl acetylenes with propynyl(trimethyl)silane to give products of type R(1)-C≡CSiMe. This unconventional way of introducing a silyl substituent onto an alkyne terminus complements the conventional tactics of deprotonation/silylation and excels as an orthogonal way of alkyne protecting group chemistry for substrates bearing base-sensitive functionalities. Moreover, it is shown that even terminal aryl acetylenes can be cross-metathesized with internal alkyne partners. These unprecedented transformations are compatible with various functional groups. The need to suppress acetylene formation, which seems to be a particularly effective catalyst poison, is also discussed.