This paper describes the synthesis of precursors with a benzo[b]furan skeleton for the intramolecular 1,3-dipolar cycloaddition of azomethine ylides prepared from N-substituted 3-allyl-aminobenzo[b]furan-2-aldehydes and secondary amines derived from α-amino acid esters. Reactions were initiated by heating. The products consisted of four fused rings with three stereogenic centers. Their structure and stereochemistry were determined by NMR spectra and X-ray measurements.

• Keywords
• 1,3-dipolar cycloaddition, 3-amino-benzo[b]furan-2-carbaldehyde, fused heterocycles, thermal initiation,
• MeSH
• Aldehydes chemical synthesis   MeSH
• Azo Compounds chemistry   MeSH
• Cycloaddition Reaction MeSH
• Furans chemical synthesis   MeSH
• Molecular Conformation MeSH
• Thiosemicarbazones chemistry   MeSH
• Hot Temperature MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehydes MeSH
• azomethine MeSH Browser
• Azo Compounds MeSH
• Furans MeSH
• Thiosemicarbazones MeSH

Nonproteinogenic amino acids are prepared by an unprecedented domino aza-Michael addition-1,3-dipolar cycloaddition, leading to enantiopure highly substituted pyrrolidinopyrazolines. Nonaflyl azide serves as highly effective diazo transfer reagent, forming the link between the conjugate addition and cycloaddition steps. The resulting pyrrolidinopyrazolines can be rapidly transformed to either α,β,γ-triamino acids or 3,4-methano-β-prolines. Peptide coupling can be regioselectively conducted at each of the amino groups.

• MeSH
• Amino Acids chemical synthesis   chemistry   MeSH
• Cycloaddition Reaction MeSH
• Molecular Structure MeSH
• Peptides chemistry   MeSH
• Proline analogs & derivatives   chemical synthesis   chemistry   MeSH
• Pyrazoles chemistry   MeSH
• Pyrroles chemistry   MeSH
• Stereoisomerism MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amino Acids MeSH
• beta-proline MeSH Browser
• Peptides MeSH
• Proline MeSH
• Pyrazoles MeSH
• Pyrroles MeSH

Fluorogenic bioorthogonal reactions enable visualization of biomolecules with excellent signal-to-noise ratio. A bicyclononyne-tetrazine ligation that produces fluorescent pyridazine products has been developed. In stark contrast to previous approaches, the formation of the dye is an inherent result of the chemical reaction and no additional fluorophores are needed in the reagents. The crucial structural elements that determine dye formation are electron-donating groups present in the starting tetrazine unit. The newly formed pyridazine fluorophores show interesting photophysical properties the fluorescence intensity increase in the reaction can reach an excellent 900-fold. Model imaging experiments demonstrate the application potential of this new fluorogenic bioorthogonal reaction.

• Keywords
• Diels-Alder reactions, cyclic alkynes, cycloaddition reactions, fluorogenic probes, tetrazines,
• MeSH
• Cycloaddition Reaction MeSH
• Fluorescent Dyes chemistry   MeSH
• Heterocyclic Compounds, 1-Ring chemistry   MeSH
• Microscopy, Confocal MeSH
• Humans MeSH
• Bridged Bicyclo Compounds chemistry   MeSH
• Cell Line, Tumor MeSH
• Pyridazines chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Fluorescent Dyes MeSH
• Heterocyclic Compounds, 1-Ring MeSH
• Bridged Bicyclo Compounds MeSH
• Pyridazines MeSH

This review covers all known examples of [3 + 2]-cycloaddition between sydnones and both terminal as well as internal alkynes/cycloalkynes taken from literature since its discovery by Huisgen in 1962 up to the current date. Except enumeration of synthetic applications it also covers mechanistic studies, catalysis, effects of substituents and reaction conditions influencing reaction rate and regioselectivity.

• Keywords
• Cu(I) catalysis, [3 + 2]-cycloaddition, alkynes, mechanism, regioselectivity, sydnones,
• Publication type
• Journal Article MeSH
• Review MeSH

In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.

• MeSH
• Benzaldehydes chemistry   MeSH
• Cell Cycle drug effects   MeSH
• Cycloaddition Reaction MeSH
• Betulinic Acid MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Pentacyclic Triterpenes MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Triazoles chemistry   MeSH
• Triterpenes chemistry   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• benzaldehyde MeSH Browser
• Benzaldehydes MeSH
• Betulinic Acid MeSH
• Pentacyclic Triterpenes MeSH
• Antineoplastic Agents MeSH
• Triazoles MeSH
• Triterpenes MeSH

Two alternative flexible alkyne-linked thymine nucleosides (propargyl-diethylene glycol- or undecyn-linked 5-hydroxymethyluracil derivatives), as well as their phosphoramidites and triphosphates, were designed and synthesized. The nucleoside 3'- O-phosphoramidites were successfully incorporated into oligonucleotides on a solid support, whereas the nucleoside triphosphates served as good substrates for polymerase synthesis of modified DNA, which underwent fast and efficient copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reactions.

• MeSH
• Alkynes chemistry   MeSH
• Azides MeSH
• Cycloaddition Reaction MeSH
• DNA MeSH
• Catalysis MeSH
• Copper MeSH
• Molecular Structure MeSH
• Organophosphorus Compounds MeSH
• Polyphosphates MeSH
• Thymidine MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alkynes MeSH
• Azides MeSH
• DNA MeSH
• Copper MeSH
• Organophosphorus Compounds MeSH
• phosphoramidite MeSH Browser
• Polyphosphates MeSH
• Thymidine MeSH
• triphosphoric acid MeSH Browser

The synthesis and chromatographic evaluation of a series of new Cinchona derived chiral weak anion exchangers is presented. Huisgen Cu(I) mediated alkyne-azide cycloaddition, so-called click chemistry, was used as an immobilization strategy. In this way it was possible to immobilize about 90% of offered selector via 1,2,3-triazole linker, which displays a more efficient way of binding the selector to modified silica compared to common radical mediated thiol-ene addition. Problems associated with potential radical scavenging properties of chiral selectors thereby could be circumvented. The evaluation of the synthesized chiral stationary phases regarding chromatographic behavior was carried out using polar organic mode mobile phase composition and a set of representative chiral organic acids. Different loading densities revealed an optimum selector density of about 310μmol/g chiral stationary phase with respect to resolution and selectivity. A decrease of performance was observed for higher loading, indicating mutual spatial influence of selector units leading to sterical hindrance. In addition, we observed that the effect of free azide groups on retention is negligible and the overall chromatographic behavior is comparable to other Cinchona derived chiral stationary phases.

• Keywords
• Chiral anion exchange chromatography, Cinchona alkaloids, Click chemistry, Copper-catalysis, Enantiomer separation, Liquid chromatography,
• MeSH
• Alkynes chemistry   MeSH
• Amino Acids chemistry   MeSH
• Azides chemistry   MeSH
• Quinidine analogs & derivatives   chemical synthesis   chemistry   MeSH
• Quinine analogs & derivatives   chemical synthesis   chemistry   MeSH
• Chromatography MeSH
• Click Chemistry MeSH
• Cycloaddition Reaction MeSH
• Ion Exchange MeSH
• Carbamates chemical synthesis   chemistry   MeSH
• Silicon Dioxide MeSH
• Stereoisomerism MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkynes MeSH
• Amino Acids MeSH
• Azides MeSH
• Quinidine MeSH
• Quinine MeSH
• Carbamates MeSH
• Silicon Dioxide MeSH

Altering the reactivity model of a molecule can potentially eliminate limitations existing in its current paradigm. When it comes to the activation of Donor-Acceptor Cyclopropanes (DACs), Lewis acids have been the state-of-the-art. Although a variety of polarized 2π components have been successfully coupled with DACs for [3+2] cycloaddition, unpolarized alkenes prove to be a roadblock due to an inherent polarity mismatch with the Lewis acid-mediated 1,3-zwitterionic intermediate. Hereby, harnessing the distonic radical cation mode of cleavage by photoredox catalysis overcomes this mismatched reactivity of the zwitterionic intermediate, providing a unique route to highly substituted cyclopentanes and cyclopentenes. Expansion of this strategy to bicyclo[1.1.0]butanes enables access to bicyclo[3.1.1]heptanes (BCHs) through a facile [3σ+2σ] cycloaddition. Detailed mechanistic insights are also provided using dispersion-corrected density functional theory.

• Keywords
• bicyclic structures, cycloaddition, cyclopentanes, photochemistry, radicals,
• Publication type
• Journal Article MeSH

The development of fluorogenic reactions which lead to the formation of fluorescent products from two nonfluorescent starting materials is highly desirable, but challenging. Reported herein is a new concept of fluorescent product formation upon the inverse electron-demand Diels-Alder reaction of 1,2,4,5-tetrazines with particular trans-cyclooctene (TCO) isomers. In sharp contrast to known fluorogenic reagents the presented chemistry leads to the rapid formation of unprecedented fluorescent 1,4-dihydropyridazines so that the fluorophore is built directly upon the chemical reaction. Attachment of an extra fluorophore moiety is therefore not needed. The photochemical properties of the resulting dyes can be easily tuned by changing the substitution pattern of the starting 1,2,4,5-tetrazine. We support the claim with NMR measurements and rationalize the data by computational study. Cell-labeling experiments were performed to demonstrate the potential of the fluorogenic reaction for bioimaging.

• Keywords
• bioorthogonal chemistry, click reactions, cycloaddition, heterocycles, imaging agents,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Inverse-electron-demand Diels-Alder (iEDDA) cycloaddition between 1,2,4,5-tetrazines and strained dienophiles belongs among the most popular bioconjugation reactions. In addition to its fast kinetics, this cycloaddition can be tailored to produce fluorescent products from non-fluorescent starting materials. Here we show that even the reaction intermediates formed in iEDDA cycloaddition can lead to the formation of new types of fluorophores. The influence of various substituents on their photophysical properties and the generality of the approach with use of various trans-cyclooctene derivatives were studied. Model bioimaging experiments demonstrate the application potential of fluorogenic iEDDA cycloaddition.

• Keywords
• bioorthogonal chemistry, click chemistry, cycloaddition, heterocycles, tetrazines,
• MeSH
• Cycloaddition Reaction MeSH
• Cyclooctanes chemistry   MeSH
• Fluorescent Dyes chemical synthesis   chemistry   MeSH
• Microscopy, Fluorescence methods   MeSH
• HeLa Cells MeSH
• Heterocyclic Compounds, 2-Ring chemical synthesis   chemistry   MeSH
• Heterocyclic Compounds, 1-Ring chemistry   MeSH
• Microscopy, Confocal methods   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cyclooctanes MeSH
• Fluorescent Dyes MeSH
• Heterocyclic Compounds, 2-Ring MeSH
• Heterocyclic Compounds, 1-Ring MeSH