Alkyne Functionality Research Articles

Tetranuclear Dicationic Aurophilic Gold(I) Catalysts in Enyne Cycloisomerization: Cooperativity for a Dramatic Shift in Selectivity.

In comparison to mononuclear gold Lewis acid catalysts, digold complexes and dual-gold catalysis have illustrated a distinct and powerful potential for the activation of carbon-carbon multiple bonds. Herein, this concept is pushed further by designing novel tetranuclear gold(I) dicationic complexes structurally supported by strongly stabilizing constraint diphosphinoferrocenyl ligands and attractive closed-shell Au⋅⋅⋅Au aurophilic interactions. The use of a molecularly-defined tetranuclear dicationic aurophilic gold(I) precatalyst for the selectivity-challenging cycloisomerization of low-substituted 1,6-enynes favors the formation with high selectivity of strained azabicyclo[4.1.0]hept-4-enes - even in the complete absence of activating/orienting substituents on alkyne and olefin reactive functions. This selectivity is not achieved by the reported phosphine- and carbene-stabilized mono- and dinuclear cationic gold(I) complexes, including the ones formed from the same ligands. More importantly this selectivity differs also from nanoparticles and heterogeneous gold catalysts reported to date. DFT studies correlated to experimental mechanistic investigations support an unprecedented "cluster-like" reactivity from polynuclear cooperation at the origin of this peculiar selectivity where the aurophilic interactions preexist, and pre-organize, gold cluster reactive intermediates.

Synthesis and cellular evaluation of click-chemistry probes to study the biological effects of alpha, beta-unsaturated carbonyls

Humans are commonly exposed to α,β-unsaturated carbonyls as both environmental toxins (e.g. acrolein) and therapeutic drugs (e.g. dimethylfumarate, DMFU, a front-line drug for the treatment of multiple sclerosis and psoriasis). These compounds undergo rapid Michael addition reactions with amine, imidazole and thiol groups on biological targets, with reaction at protein Cys residues being a major reaction pathway. However, the cellular targets of these species (the ‘adductome’) are poorly understood due to the absence of readily identifiable tags or reporter groups (chromophores/fluorophores or antigens) on many α,β-unsaturated carbonyls. Here we report a ‘proof of concept’ study in which we synthesize novel α,β-unsaturated carbonyls containing an alkyne function introduced at remote sites on the α,β-unsaturated carbonyl compounds (e.g. one of the methyl groups of dimethylfumarate). The presence of this tag allows ‘click-chemistry’ to be used to visualize, isolate, enrich and characterize the cellular targets of such compounds. The probes show similar selectivity and reactivity to the parent compounds, and compete for cellular targets, yielding long-lived (stable) adducts that can be visualized in intact cells (such as primary human coronary artery smooth muscle cells), and extracted and enriched for subsequent target analysis. It is shown using this approach that dimethylfumarate forms adducts with multiple intracellular targets including cytoskeletal, organelle and nuclear species, with these including the rate-limiting glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This approach should be amenable to use with multiple α,β-unsaturated carbonyls and a wide variety of targets containing nucleophilic sites.

Recent Advances in the Functionalization of Terminal and Internal Alkynes

AbstractAlkynes are one of the most fundamental and diverse functional groups utilized in organic synthesis. Over the past few years, the development of efficient synthetic methodologies for the functionalization of alkynes has been an active area of research. A plethora of alkyne functionalization reactions have been reported in the literature to construct functionalized alkynes and alkene scaffolds, which are important building blocks in many natural products, pharmaceuticals, and key intermediates in various synthetic transformations. In this review, we describe the most recent advances in the functionalization of alkynes with an emphasis on substrate scope, limitations, regioselectivity control and applications of these reactions. This review covers the literature from 2016 to 2021.

Biosynthesis of Isonitrile- and Alkyne-Containing Natural Products.

Natural products are a diverse class of biologically produced compounds that participate in fundamental biological processes such as cell signaling, nutrient acquisition, and interference competition. Unique triple-bond functionalities like isonitriles and alkynes often drive bioactivity and may serve as indicators of novel chemical logic and enzymatic machinery. Yet, the biosynthetic underpinnings of these groups remain only partially understood, constraining the opportunity to rationally engineer biomolecules with these functionalities for applications in pharmaceuticals, bioorthogonal chemistry, and other value-added chemical processes. Here, we focus our review on characterized biosynthetic pathways for isonitrile and alkyne functionalities, their bioorthogonal transformations, and prospects for engineering their biosynthetic machinery for biotechnological applications.

Recent Advances in the Smiles Rearrangement: New Opportunities for Arylation

AbstractThe Smiles rearrangement has undergone a renaissance in recent years providing new avenues for non-canonical arylation techniques in both the radical and polar regimes. This short review will discuss recent applications of the reaction (from 2017 to late 2021), including its relevance to areas such as heterocycle synthesis and the functionalization of alkenes and alkynes as well as glimpses at new directions for the field.1 Introduction2 Polar Smiles Rearrangements3 Radical Smiles: Alkene and Alkyne Functionalization4 Radical Smiles: Rearrangements via C–X Bond Cleavage5 Radical Smiles: Miscellaneous Rearrangements6 Conclusions

Efficient synthesis of chitosan derivatives as clickable tools

An efficient method for the synthesis of a series of alkynoyl-chitosan derivatives having different properties is presented. Utilizing this method, we could introduce alkyne functionalities on the amino group of chitosan without the use of protection groups. We prepared two series of chitosan derivatives, one containing alkyl spacers which are soluble in organic medium while the other contains PEG spacers which have aqueous solubility. Furthermore, we could produce derivatives having varying degree of substitution on the chitosan backbone. This series of alkynoyl-chitosan derivatives would serve as a useful tool for linking other molecules through click chemistry and we have confirmed this by successfully performing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction with small and large azide molecules to produce four series of conjugates.

Chemical Synthesis of a Functional Fluorescent-Tagged α-Bungarotoxin.

α-bungarotoxin is a large, 74 amino acid toxin containing five disulphide bridges, initially identified in the venom of Bungarus multicinctus snake. Like most large toxins, chemical synthesis of α-bungarotoxin is challenging, explaining why all previous reports use purified or recombinant α-bungarotoxin. However, only chemical synthesis allows easy insertion of non-natural amino acids or new chemical functionalities. Herein, we describe a procedure for the chemical synthesis of a fluorescent-tagged α-bungarotoxin. The full-length peptide was designed to include an alkyne function at the amino-terminus through the addition of a pentynoic acid linker. Chemical synthesis of α-bungarotoxin requires hydrazide-based coupling of three peptide fragments in successive steps. After completion of the oxidative folding, an azide-modified Cy5 fluorophore was coupled by click chemistry onto the toxin. Next, we determined the efficacy of the fluorescent-tagged α-bungarotoxin to block acetylcholine (ACh)-mediated currents in response to muscle nicotinic receptor activation in TE671 cells. Using automated patch-clamp recordings, we demonstrate that fluorescent synthetic α-bungarotoxin has the expected nanomolar affinity for the nicotinic receptor. The blocking effect of fluorescent α-bungarotoxin could be displaced by incubation with a 20-mer peptide mimicking the α-bungarotoxin binding site. In addition, TE671 cells could be labelled with fluorescent toxin, as witnessed by confocal microscopy, and this labelling was partially displaced by the 20-mer competitive peptide. We thus demonstrate that synthetic fluorescent-tagged α-bungarotoxin preserves excellent properties for binding onto muscle nicotinic receptors.

Recent advances in visible-light-mediated functionalization of olefins and alkynes using copper catalysts.

Over the past decade, visible-light photoredox catalysis has blossomed as a powerful strategy and offers a discrete activation mode complementary to thermal controlled reactions. Visible-light-mediated photoredox catalysis also offers exciting opportunities to achieve challenging carbon-carbon and carbon-heteroatom bond formations with excellent chemo-, regio-, or stereoselectivity under mild and ecologically benign conditions. The greater part of photoredox reactions depends on heavy metals like ruthenium(II) or iridium(III) based complexes as photoredox catalysts owing to their strong absorption, long-lived excited-state lifetimes and high oxidation or redox potentials. However, these transition metal complexes are expensive and pose severe drawbacks with respect to large scale application and sustainability. Organic dyes are also commonly used as a low-cost alternative to Ru- or Ir-based complexes. However, they have inferior photostability. Thus, further development of alternative photocatalysts based on copper salts or copper complexes is widely investigated because of their economic and environmental benefits. In recent years, visible-light-mediated direct functionalization of olefins or alkynes to afford a diverse range of organic compounds has received extensive interest from synthetic chemists due to their easy availability and reactivity towards a large number of reactants. In this review, we have highlighted the most recent significant advances that have been made in the use of copper-based photocatalysts for the functionalization of olefins and alkynes with an emphasis on substrate scope, limitations, mechanistic understanding and applications of these reactions. This review covers the literature from 2015 to 2021.

Through structural isomerism: positional effect of alkyne functionality on molecular optical properties.

Literature studies on the effects of alkyne functionality in manipulating the optical properties of donor-π-acceptor-type molecular scaffolds have been scarce compared to those on the alkene functional group. Here, two structurally isomeric donor-acceptor (D-A) dyes were synthesized to study the positional effect of alkyne functionality (triple bond) on their optical, electrochemical and charge generation properties in order to design efficient dyes for possible application in dye sensitized solar cells (DSSCs). These dyes, named CAPC and PACC, contain carbazole and cyanoacrylic acid as the donor and acceptor units, respectively, and the π-conjugation length within the molecules was controlled by the introduction of an alkyne group. The D-π-A design was followed in designing CAPC with the alkyne serving as the π-spacer, while in PACC, alkyne was placed on the donor, which was directly in conjugation with the acceptor. This rendered equal conjugation lengths within the designed dyes. With the help of photophysical characterizations, it was concluded that CAPC featured better characteristics for a DSSC dye than PACC. Our conclusions were further supported by the results of transient absorption spectroscopy, electrochemical analysis, fluorescence lifetime studies and density functional theory.

Regio- and Stereoselective Synthesis of Enol Carboxylate, Phosphate, and Sulfonate Esters via Iodo(III)functionalization of Alkynes.

β-Iodo(III)enol carboxylates, phosphates, and tosylates can be efficiently synthesized through regio- and stereoselective iodo(III)functionalization of alkynes. The combination of chlorobenziodoxole and silver salt has proven to generate a versatile cationic iodine(III) electrophile to activate alkynes and engage various carboxylic acids, triethyl phosphate, and p-toluenesulfonic acid as nucleophiles. The β-iodo(III)enol esters serve as starting materials for the synthesis of multisubstituted alkenes through sequential cross-coupling of the C-I(III) and C-O bonds.

Covalent-linked porphyrin-based polymer/multi-walled carbon nanotube nanohybrids: Synthesis and enhanced nonlinear optical performance

In this paper, a series of novel porphyrin-based polymers named poly(6-(5'-(4′-phenoxyl)-10′,15′,20′-triphenylporphyrin) methacrylate)n with different molecular weights and functional alkyne end-groups (PPorx-C≡CH) were successfully synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. Furthermore, the corresponding multi-walled carbon nanotube (MWCNT) nanohybrids PPorx-MWCNTs were prepared by reacting PPorx-C≡CH with MWCNT-N3 through click reaction. PPorx-MWCNT exhibited obvious fluorescence quenching at 652 and 725 nm compared to PPorx-C≡CH, demonstrating the photo-induced electron transfer (PET) process between PPorx and MWCNT, which was proved by photo-electrochemical experiments. After covalent-linked with MWCNT, PPorx-MWCNT show an enhanced NLO performance (the third order optical susceptibility (Im[χ(3)]) = 4.93 × 10−11 esu) compared to PPorx-C≡CH in N,N-dimethylformamide (DMF) solution, causing by the PET process. In order to enhance the practicality of PPorx-MWCNT, the PPorx-MWCNT/polymethyl methacrylate (PPorx-MWCNT/PMMA) composites were prepared. Among them, PPor3-MWCNT/PMMA showed the best NLO performance (Im[χ(3)] = 5.58 × 10−11), with a limiting threshold of 0.98 J/cm2. Compared with methyl methacrylate (MMA) system, the weaker aggregation effect in PMMA matrix contributes to enhance the NLO properties of PPorx-MWCNT. Our study has opened a new path for the development of high performance NLO materials for practical applications.

Cover Feature: Electrochemical Proton Reduction over Nickel Foam for Z‐Stereoselective Semihydrogenation/deuteration of Functionalized Alkynes (ChemSusChem 1/2022)

The Cover Feature shows an alternative approach to the use of noble metals and flammable hydrogen gas for the semireduction of alkynes. Water electrolysis on the surface of commercially available nickel foam can deliver adsorbed hydrogen species that are chemo- and stereoselectively transferred to alkynes under ambient conditions. More information can be found in the Research Article by A. Valiente et al.

Chemistry on the Complex: Derivatization of TiO4 N2 -Based Complexes and Application to Multi-Step Synthesis.

The chemistry on octahedral TiO4 N2 -complexes is described. The Ti(IV)-based precursors are composed of two 3,3'-diphenyl-2,2'-biphenolato ligands (1) and one substituted 1,10-phenanthroline ligand (2-5). The application of imine condensation, palladium-catalyzed C-C bond formation or copper-catalysed azide-alkyne cycloaddition allowed the grafting of various new groups onto these species. In particular Sonogashira reactions permitted to observe an excellent conversion of the starting complexes. This systematic study enabled to compile the factors required to preserve the framework of the complexes in the course of a chemical transformation. Thanks to this chemistry realized on the complex, the Ti(1)2 fragment was used as a protecting group to develop a multi-step synthesis of a bis-phenanthroline compound (12), for which the synthesis without this protection failed. Thus, a dinuclear complex [Ti2 (1)4 (12)] was first prepared starting from complex precursor bearing an acetylenic function via a Hay coupling reaction. This was followed by a deprotection step affording 12. Overall, this work illustrates how the Ti(1)2 fragment could be an useful tool for the preparation of unprecedented diimine compounds.

Visible-light-mediated copper photocatalysis for organic syntheses.

Photoredox catalysis has been applied to renewable energy and green chemistry for many years. Ruthenium and iridium, which can be used as photoredox catalysts, are expensive and scarce in nature. Thus, the further development of catalysts based on these transition metals is discouraged. Alternative photocatalysts based on copper complexes are widely investigated, because they are abundant and less expensive. This review discusses the scope and application of photoinduced copper-based catalysis along with recent progress in this field. The special features and mechanisms of copper photocatalysis and highlights of the applications of the copper complexes to photocatalysis are reported. Copper-photocatalyzed reactions, including alkene and alkyne functionalization, organic halide functionalization, and alkyl C–H functionalization that have been reported over the past 5 years, are included.

Formulation of silica‐based corn oil transformed polyester acryl amide‐phenol formaldehyde corrosion resistant coating material

AbstractIt is important to check the economic losses due to spontaneous metallic corrosion of major infrastructures, precious equipment's, and ensure the sustainable growth. Fabrication of environmentally benign functional polymeric material by transforming agricultural waste and products into value added polymeric products is of great importance in recent times. Here, we report the formulation of functional hybrid polymeric material using corn oil (CO) as our starting material. The functionality of CO was improved by green route, to produce corn diol fatty amide (HECA). Functionalization of CO was achieved in systematic manner by following green chemistry approach. First, diol fatty amide (HECA) was prepared followed by conversion of terminal OH groups of HECA into acrylic ester using condensation reaction with acrylic acid (AA). The base polymeric moiety was further modified to include phenyl acetylene functionality and SiO2 nanoparticle entities. The formulation of hydrophobic stable polymeric structure is important to sustain highly corrosive environment and long‐lasting performance of the material. The inclusion of different functionality and hydrophobic groups were confirmed by Fourier‐transform infrared and proton nuclear magnetic resonance spectroscopies. The baked coating was finalized by addition of phenol formaldehyde polymeric resin in different phr (part per hundred part of resin). The transmission electron microscopy, scanning electron microscope, energy dispersive X‐ray spectroscopy, and elemental mapping of the coating material confirms the formation of a hybrid material with uniform distribution of inorganic and organic components. The potentiodynamic polarization and electrochemical impedance spectroscopic analysis verified the better resistive performance of inorganic hybrid over the counter organic coatings. The enhanced thermal stability, hydrophobic character, and corrosion resistance performance of CO based coating material indicates the potential of the synthesized green route materials.

A chemical labeling of N6-formyl adenosine (f6A) RNA

N6-methyl adenosine (m6A) is an eminent epigenetic mark in mRNAs that affects a broad range of biological functions in diverse species. However, the chemically inert methyl group prevents a direct labeling of this modification for subsequent detection and sequencing. Therefore, most current approaches for the labeling of m6A still have limitations of relying on the utilization of corresponding methyltransferases, which resulted in the lacking of efficiency. Here we present an approach which selectively alkylated the N6-formyl adenosine (f6A), the key intermediate during chemical oxidation of m6A, with an alkyne functionality that can be further labeled with click reactions. This covalent labeling approach will be able to facilitate in the affinity purification, detection and genome-wide profiling studies.

Enantioselective Oxidative Multi-Functionalization of Terminal Alkynes with Nitrones and Alcohols for Expeditious Assembly of Chiral α-Alkoxy-β-amino-ketones.

Catalytic oxidative functionalization of alkynes has emerged as an effective method in synthetic chemistry in recent decades. However, enantioselective transformations via metal carbene intermediates are quite rare due to the lack of robust chiral catalysts, especially in the intermolecular versions. Herein, we report the first asymmetric three-component reaction of commercially available alkynes with nitrones and alcohols, which affords α-alkoxy-β-amino-ketones in good yields with high to excellent enantioselectivity using combined catalysis by an achiral gold complex and a chiral spiro phosphoric acid (CPA). Mechanistically, this atom-economic reaction involves a catalytic alkyne oxidation/ylide formation/Mannich-type addition sequence that uses nitrone as the oxidant and the leaving fragment imine as the electrophile, providing a novel method for multi-functionalization of commercially available terminal alkynes.

Total synthesis of the proposed structure of metacridamide B

The first asymmetric total synthesis of the proposed structure of metacridamide B, a 17-membered macrolide with anticancer activity, has been accomplished in a highly convergent and flexible manner. The key features of our synthesis involved hydroxyl directed ruthenium catalyzed alkyne functionalization, Stille coupling, asymmetric Corey-Bakshi-Shibata reduction, Micalizio coupling and Yamaguchi macrolactonization. Careful comparison of the 1H and 13C NMR spectroscopic data confirmed that the natural metacridamide B had been erroneously represented as its C9-epimer.

Dual Functionalization of Alkynes Utilizing the Redox Characteristics of Transition Metal Catalysts

AbstractTri‐ and tetrasubstituted alkene scaffolds are prominent building blocks in many bioactive natural products, drug molecules, and key intermediates in various synthetic transformations. The dual functionalization of alkynes promises an easy introduction of functional groups across the triple bond with a high step and atom economy, exemplifying a class of reactions to construct tri‐ and tetrasubstituted alkene scaffolds. This review discusses the versatility and advances in the transition metal‐catalyzed redox dual functionalization of alkynes, their unique mechanistic features, and the synthetic applications of the methodology. This collection focuses on the formation of simultaneous C−C/C−X bonds involving various oxidation states of the metals in the catalytic cycle. Apart from the classical redox reactivity, radical‐mediated functionalizations are also discussed in detail.

An E. coli-Based Biosynthetic Platform Expands the Structural Diversity of Natural Benzoxazoles.

Benzoxazoles are frequently found in synthetic pharmaceuticals and medicinally active natural products. To facilitate benzoxazole-based drug development, an eco-friendly and rapid platform for benzoxazole production is required. In this study, we have completed the biosynthesis of benzoxazoles in E. coli by coexpressing the minimal set of enzymes required for their biosynthesis. Moreover, by coupling this E. coli-based platform with precursor-directed biosynthesis, we have shown that the benzoxazole biosynthetic system is highly promiscuous in incorporating fluorine, chlorine, nitrile, picolinic, and alkyne functionalities into the scaffold. Our E. coli-based system thus paves the way for straightforward generation of novel benzoxazole analogues through future protein engineering and combinatorial biosynthesis.