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Current Medicinal Chemistry 2023Sydnones are among the most well-known mesoionic compounds. Since their synthesis in 1935 by Earl and Mecknay, numerous researches have shown that the chemical behavior,...
Sydnones are among the most well-known mesoionic compounds. Since their synthesis in 1935 by Earl and Mecknay, numerous researches have shown that the chemical behavior, physical and biological properties of sydnones make them the most useful compounds in organic chemistry. Sydnones undergo thermal 1,3-dipolar cycloaddition reaction with dipolarophiles (alkynes or alkenes) to give exclusively derivatives containing a pyrazole moiety exhibiting numerous applications, such as pharmaceuticals and agrochemicals. However, the sydnone cycloaddition reaction with alkynes requires harsh conditions, like high temperatures and long reaction times, giving poor regioselectivity to the resulting products. To overcome these constraints, new reactions named CuSAC (Copper- Catalyzed Sydnone-Alkyne Cycloaddition) and SPSAC (Strain-Promoted Sydnone- Alkyne Cycloaddition) have been developed, leading to pyrazoles with interesting constant kinetics.
Topics: Humans; Alkynes; Sydnones; Cycloaddition Reaction; Copper
PubMed: 35726409
DOI: 10.2174/0929867329666220620123050 -
Chemical Reviews Jun 2021Click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on... (Review)
Review
Click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on multiple scientific disciplines, and its implementation within the nucleic acid field has enabled researchers to generate a wide variety of tools with application in biology, biochemistry, and biotechnology. Azide-alkyne cycloadditions (AAC) are still the leading technology among click reactions due to the facile modification and incorporation of azide and alkyne groups within biological scaffolds. Application of AAC chemistry to nucleic acids allows labeling, ligation, and cyclization of oligonucleotides efficiently and cost-effectively relative to previously used chemical and enzymatic techniques. In this review, we provide a guide to inexperienced and knowledgeable researchers approaching the field of click chemistry with nucleic acids. We discuss in detail the chemistry, the available modified-nucleosides, and applications of AAC reactions in nucleic acid chemistry and provide a critical view of the advantages, limitations, and open-questions within the field.
Topics: Alkynes; Azides; Click Chemistry; Cycloaddition Reaction; Nucleic Acids; Thermodynamics
PubMed: 33443411
DOI: 10.1021/acs.chemrev.0c00928 -
Journal of the American Chemical Society Aug 2022Regiodivergent alkyne hydroalkylation to generate different isomers of an alkene from the same alkyne starting material would be beneficial; however, it remains a...
Regiodivergent alkyne hydroalkylation to generate different isomers of an alkene from the same alkyne starting material would be beneficial; however, it remains a challenge. Herein, we report a ligand-controlled cobalt-catalyzed regiodivergent alkyne hydroalkylation. The sensible selection of bisoxazoline () and pyridine-oxazoline () ligands led to reliable and predictable protocols that provided ()-1,2-disubstituted and 1,1-disubstituted alkenes with high / stereoselectivity and regioisomeric ratio starting from identical terminal alkyne and alkyl halide substrates and produced trisubstituted alkenes in the case of internal alkynes. This method exhibits a broad scope for terminal and internal alkynes with a wide range of activated and unactivated alkyl halides and shows excellent functional group compatibility.
Topics: Alkenes; Alkynes; Catalysis; Cobalt; Ligands
PubMed: 35866845
DOI: 10.1021/jacs.2c06279 -
Chemical Reviews Aug 2022Reaction discovery and catalyst screening lie at the heart of synthetic organic chemistry. While there are efforts at catalyst design using computation/artificial... (Review)
Review
Reaction discovery and catalyst screening lie at the heart of synthetic organic chemistry. While there are efforts at catalyst design using computation/artificial intelligence, at its core, synthetic chemistry is an experimental science. This review overviews biomacromolecule-assisted screening methods and the follow-on elaboration of chemistry so discovered. All three types of biomacromolecules discussed─enzymes, antibodies, and nucleic acids─have been used as "sensors" to provide a readout on product chirality exploiting their native chirality. Enzymatic sensing methods yield both UV-spectrophotometric and visible, colorimetric readouts. Antibody sensors provide direct fluorescent readout upon analyte binding in some cases or provide for cat-ELISA (Enzyme-Linked ImmunoSorbent Assay)-type readouts. DNA biomacromolecule-assisted screening allows for templation to facilitate reaction discovery, bimolecular reactions into a pseudo-unimolecular format. In addition, the ability to use DNA-encoded libraries permits the barcoding of reactants. All three types of biomacromolecule-based screens afford high sensitivity and selectivity. Among the chemical transformations discovered by enzymatic screening methods are the first Ni(0)-mediated asymmetric allylic amination and a new thiocyanopalladation/carbocyclization transformation in which both C-SCN and C-C bonds are fashioned sequentially. Cat-ELISA screening has identified new classes of sydnone-alkyne cycloadditions, and DNA-encoded screening has been exploited to uncover interesting oxidative Pd-mediated amido-alkyne/alkene coupling reactions.
Topics: Alkynes; Amination; Artificial Intelligence; Catalysis; DNA
PubMed: 35904776
DOI: 10.1021/acs.chemrev.2c00213 -
Accounts of Chemical Research Apr 2020Organic azides are involved in a variety of useful transformations, including nitrene chemistry, reactions with nucleophiles and electrophiles, and cycloadditions. The... (Review)
Review
Organic azides are involved in a variety of useful transformations, including nitrene chemistry, reactions with nucleophiles and electrophiles, and cycloadditions. The 1,3-dipolar cycloadditions of azides constitute a major class of highly reliable and versatile reactions, as shown by the development and rapid adoption of click chemistry and bioorthogonal chemistry. Metal-catalyzed azide-alkyne cycloaddition (Cu/RuAAC), the prototypical click reaction, has found wide utility in pharmaceutical, biomedical, and materials sciences. The strain-promoted, or distortion-accelerated, azide-alkyne cycloaddition eliminates the need for a metal catalyst.In the azide-mediated 1,3-dipolar cycloaddition reactions, azides are ambiphilic, i.e., HOMO-LUMO-controlled dipoles where both the HOMO and LUMO interact strongly with the dipolarophile. Azide-alkyne cycloaddition proceeds primarily through the HOMO-LUMO interaction, and electron-deficient dipolarophiles react more readily. The inverse-electron-demand reaction, involving the LUMO-HOMO interaction, is less common because of the low stability of electron-deficient azides such as acyl, sulfonyl, and phosphoryl azides. Nevertheless, there have been reports since the 1960s showing enhanced reaction kinetics between electron-poor azides and electron-rich dipolarophiles. Our laboratory has developed the use of perfluoroaryl azides (PFAAs), a class of stable electron-deficient azides, as nitrene precursors and for reactions with nucleophiles and electron-rich dipolarophiles. Perfluorination on the aryl ring also facilitates the synthesis of PFAAs and quantitative analysis of the products by F NMR spectroscopy.In this Account, we summarize key reactions involving electrophilic azides and applications of these reactions in materials synthesis and chemical biology. These electron-deficient azides exhibit unique reactivity toward nucleophiles and electron-rich or strained dipolarophiles, in some cases leading to new transformations that do not require any catalysts or products that are impossible to obtain from the nonelectrophilic azides. We highlight work from our laboratories on reactions of PFAAs with enamines, enolates, thioacids, and phosphines. In the reactions of PFAAs with enamines or enolates, the triazole or triazoline cycloaddition products undergo further rearrangement to give amidines or amides as the final products at rates of up to 10 times faster than their non-fluorinated anlogues. Computational investigations by the distortion/interaction activation strain model reveal that perfluorination lowers the LUMO of the aryl azide as well as the overall activation energy of the reaction by decreasing the distortion energies of the reactants to reach the transition states. The PFAA-enamine reaction can be carried out in a one-pot fashion using readily available starting materials of aldehyde and amine, making the reaction especially attractive, for example, in the functionalization of nanomaterials and derivatization of antibiotics for the preparation of theranostic nanodrugs. Similar fast kinetics was also observed for the PPAA-mediated Staudinger reaction, which proceeds at 10 times higher rate than the classic Staudinger ligation, giving stable phosphoimines in high yields. The reaction is biorthogonal, allowing cell-surface labeling with minimal background noise.
Topics: Alkynes; Azides; Chemistry Techniques, Synthetic; Cycloaddition Reaction; Electron Transport
PubMed: 32207916
DOI: 10.1021/acs.accounts.0c00046 -
Advanced Materials (Deerfield Beach,... Feb 2023Bioorthogonal chemistry, referring to the rapid and selective synthesis of imaging and/or therapeutic molecules in live animals via transition metal-mediated non-natural...
Bioorthogonal chemistry, referring to the rapid and selective synthesis of imaging and/or therapeutic molecules in live animals via transition metal-mediated non-natural chemical transformation without disrupting endogenous reactions, has greatly expanded the tools and techniques for biomedicine. However, owing to safety concerns associated with metal toxicity, selectivity, sensitivity and stability, efficient bioorthogonal reactions that can be reliably executed in complex biological environments remain challenging. In this study, an intelligent, versatile bioorthogonal catalyst based on ultrasmall poly(acrylic acid)-modified copper nanocomplexes (Cu@PAA NCs) to achieve high spatiotemporal catalytic efficacy is established. The catalytic activity of the Cu@PAA NCs can be reversibly regulated via valence state interconversion between Cu(II) and Cu(I) under exogenous ultrasound irradiation, promoting off-target prodrug activation in lesion sites through the Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Moreover, ultrasound-triggered electron-hole separation endows the Cu@PAA NCs with robust sonosensitizing ability for sonodynamic therapy. Furthermore, the Cu@PAA NCs exhibit enhanced contrast in magnetic resonance and photoacoustic imaging. Notably, the renal-clearable Cu@PAA NCs exhibit intrinsically benign biocompatibility. This spatiotemporally ultrasound-mediated bioorthogonal catalysis not only expands the repertoire of in situ therapeutic agents but also provides a new avenue for disease theranostics.
Topics: Animals; Transition Elements; Copper; Catalysis; Alkynes; Azides
PubMed: 36529698
DOI: 10.1002/adma.202209179 -
Nature Communications Aug 2022Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological...
Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological research. However, the efficient preparation of macrocycles remains an ongoing research challenge in organic synthesis because of the high entropic penalty involved in the ring-closing process. Herein we report a photocatalyzed thiol-yne click reaction to forge diverse sulfur-containing macrocycles (up to 35-membered ring) and linear C2-linked 1,2-(S-S/S-P/S-N) functionalized molecules, starting from the simplest alkyne, acetylene. Preliminary mechanistic experiments support a visible light-mediated radical-polar crossover dihydrothiolation process. This operationally straightforward reaction is also amenable to the synthesis of organometallic complexes, bis-sulfoxide ligand and a pleuromutilin antibiotic drug Tiamulin, which provides a practical route to synthesize highly valued compounds from the feedstock acetylene gas.
Topics: Acetylene; Alkynes; Click Chemistry; Sulfhydryl Compounds
PubMed: 36008444
DOI: 10.1038/s41467-022-32723-0 -
Molecules (Basel, Switzerland) Dec 2020Popular and readily available alkenes and alkynes are good substrates for the preparation of functionalized molecules through radical and/or ionic addition reactions.... (Review)
Review
Popular and readily available alkenes and alkynes are good substrates for the preparation of functionalized molecules through radical and/or ionic addition reactions. Difunctionalization is a topic of current interest due to its high efficiency, substrate versatility, and operational simplicity. Presented in this article are radical addition followed by oxidation and nucleophilic addition reactions for difunctionalization of alkenes or alkynes. The difunctionalization could be accomplished through 1,2-addition (vicinal) and 1,n-addition (distal or remote) if H-atom or group-transfer is involved in the reaction process. A wide range of moieties, such as alkyl (R), perfluoroalkyl (R), aryl (Ar), hydroxy (OH), alkoxy (OR), acetatic (OCR), halogenic (X), amino (NR), azido (N), cyano (CN), as well as sulfur- and phosphorous-containing groups can be incorporated through the difunctionalization reactions. Radicals generated from peroxides or single electron transfer (SET) agents, under photoredox or electrochemical reactions are employed for the reactions.
Topics: Alkenes; Alkynes; Free Radicals; Oxidation-Reduction; Peroxides
PubMed: 33379397
DOI: 10.3390/molecules26010105 -
Accounts of Chemical Research Dec 2022The formation and study of molecules that model the sp-hybridized carbon allotrope, carbyne, is a challenging field of synthetic physical organic chemistry. The target...
The formation and study of molecules that model the sp-hybridized carbon allotrope, carbyne, is a challenging field of synthetic physical organic chemistry. The target molecules, oligo- and polyynes, are often the preferred candidates as models for carbyne because they can be formed with monodisperse lengths as well as defined structures. Despite a simple linear structure, the synthesis of polyynes is often far from straightforward, due in large part to a highly conjugated framework that can render both precursors and products highly reactive, i.e., kinetically unstable. The vast majority of polyynes are formed as symmetrical products from terminal alkynes as precursors via an oxidative, acetylenic homocoupling reaction based on the Glaser, Eglinton-Galbraith, and Hay reactions. These reactions are very efficient for the synthesis of shorter polyynes (e.g., hexaynes and octaynes), but yields often drop dramatically as a function of length for longer derivatives, usually starting with the formation of decaynes. The most effective approach to circumvent unstable precursors and products has been through the incorporation of sterically demanding end groups that serve to "protect" the polyyne skeleton. This approach was arguably identified in the early 1950s by Bohlmann and co-workers with the synthesis of Bu-end-capped polyynes. During the next 50 years, a polyyne with 14 contiguous alkyne units remained the longest isolated derivative until 2010, when the record was extended to 22 alkyne units. The record length was broken again in 2020, when a polyyne consisting of 24 alkynes was isolated and characterized. Beyond polyynes, there have been several reports describing the potential synthesis of carbyne, but conclusive characterization and proof of structure have been tenuous. The sole example of synthetic carbyne arises from synthesis within carbon nanotubes, when chains of thousands of sp carbon atoms have been linked to form polydisperse samples of carbyne. Thus, model compounds for carbyne, the polyynes, remain the best means to examine and predict the experimental structure and properties of this carbon allotrope.This Account will discuss the general synthesis of polyynes using homologous series of polyynes with up to 10 alkyne units as examples (decaynes). The limited number of specific syntheses of series with longer polyynes will then be presented and discussed in more detail based on end groups. The monodisperse polyynes produced from these synthetic efforts are then examined toward providing our best extrapolations for the expected characteristics for carbyne based on C NMR spectroscopy, UV-vis spectroscopy, X-ray crystallography, and Raman spectroscopy.
Topics: Humans; Polyynes; Nanotubes, Carbon; Alkynes; Carbamates
PubMed: 36484500
DOI: 10.1021/acs.accounts.2c00662 -
Nature Chemistry Aug 2021Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's...
Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's lipophilicity, but the role of the membrane's rich and uniform stereochemistry as a permeability determinant is largely ignored in empirical and computational measurements. Here, we describe a new approach to measuring permeation using continuously generated microfluidic droplet interface bilayers (DIBs, generated at a rate of 480 per minute) and benchmark this system by monitoring fluorescent dye DIB permeation over time. Enantioselective permeation of alkyne-labelled amino acids (Ala, Val, Phe, Pro) and dipeptides through a chiral phospholipid bilayer was demonstrated using DIB transport measurements; the biological L enantiomers permeated faster than the D enantiomers (from 1.2-fold to 6-fold for Ala to Pro). Enantioselective permeation both poses a potentially unanticipated criterion for drug design and offers a kinetic mechanism for the abiotic emergence of homochirality via chiral transfer between sugars, amino acids and lipids.
Topics: Alkynes; Amino Acids; Cholesterol; Fluorescent Dyes; Lipid Bilayers; Permeability; Phosphatidylcholines; Stereoisomerism
PubMed: 34112989
DOI: 10.1038/s41557-021-00708-z