DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• cycloaddition (CuAAC) [25][26] has naturally inspired the use of this powerful conjugation method to prepare glycan–DNA conjugates. Chevolot and co-workers used this method to conjugate glycans at the 3’-end of DNA [27]. The DNA synthesis was initiated with H-phosphonate that was converted to a phosphoramidate

• co-workers elegantly extended the utility of SELEX [30] to generate aptamers functionalized with glycans through CuAAC [31][32]. Their approach, termed SELMA (selection with modified aptamers), is a multistep procedure that allows screening, selection and amplification of DNA glycoconjugates (Scheme

•  6). At first, a library of single strand DNA with a hairpin is extended with a polymerase replacing dTTP by an alkyne-modified desoxyuridine triphosphate to give a full hairpin with randomized alkyne groups on one strand. Then, CuAAC is performed with a glycosyl azide and the hairpin is released by

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• cycloaddition (CuAAC) was performed for achieving our synthetic goals (Figure 2) [56][57]. With the objective of increasing water solubility and chemical stability in biological medium, triyne 6b, an analogue of F-BODIPY-based scaffold 6a was prepared by replacing the fluoro groups on the boron center with

• our group [11][12], the last stages of the multivalent probe synthesis involved the attachment of peracetylated azido iminosugars 4 on the scaffolds via CuAAC reaction and afterwards O-deacetylation using an anion exchange resin. First attempts to perform CuAAC reactions with triyne substrate 6b

• carefully degassed conditions and the desired protected cluster 12b could be obtained in 56% yield after purification on silica gel (Scheme 2). The major side-product observed which could not be isolated in pure form may correspond to CuAAC reaction of the azido iminosugar 4a with the terminal alkyne

Synthesis and surface grafting of a β-cyclodextrin dimer facilitating cooperative inclusion of 2,6-ANS

• Lars W. Städe,
• Thorbjørn T. Nielsen,
• Laurent Duroux,
• Reinhard Wimmer,
• Kyoko Shimizu and
• Kim L. Larsen

Beilstein J. Org. Chem. 2015, 11, 514–523, doi:10.3762/bjoc.11.58

• −alkyne cycloaddition (CuAAC)) is very attractive [10][11]. CuAAC is known to be selective, proceed fast and produce a high yield under mild conditions. Further, the formed triazole is stable against oxidation, reduction and hydrolysis [10]. Concerning the design of β-CD dimers, it was recently

• was developed in line with the aforementioned strategy of preparation of dimers by CuAAC. In this work, however, 6-monodeoxy-6-monoazido-β-CD (N3β-CD) is coupled with tripropargylamine in a 2 to 1 ratio for synthesis of a β-CD dimer with a free alkyne functionality, allowing for subsequent surface

• quantitative nature of the CuAAC. The formation of a β-CD trimer was not anticipated to be of major concern because of the unfavorable steric interactions upon grafting of a third β-CD onto the β-CD dimer. This was confirmed during purification by flash chromatography by observation of a major peak with a

Formation of nanoparticles by cooperative inclusion between (S)-camptothecin-modified dextrans and β-cyclodextrin polymers

• Thorbjørn Terndrup Nielsen,
• Catherine Amiel,
• Laurent Duroux,
• Kim Lambertsen Larsen,
• Lars Wagner Städe,
• Reinhard Wimmer and
• Véronique Wintgens

Beilstein J. Org. Chem. 2015, 11, 147–154, doi:10.3762/bjoc.11.14

• conversion of the CPT after 24 hours. The N3CPT was purified by automated flash chromatography and obtained in good yields (>80%) and purity (verified by NMR spectroscopy). From the N3CPT two series of novel CPT-dextrans were synthesized by a copper(I)-catalyzed alkyne azide coupling (CuAAC). The dextrans

Articulated rods – a novel class of molecular rods based on oligospiroketals (OSK)

• Pablo Wessig,
• Roswitha Merkel and
• Peter Müller

Beilstein J. Org. Chem. 2015, 11, 74–84, doi:10.3762/bjoc.11.11

• defined a 1,2,3-triazole containing linkage between two piperidine rings as the flexible joint F, which should be easily accessible by copper-catalyzed cycloaddition between an azide G and a terminal alkyne H (CuAAC, “Click” reaction) [16]. Primary alcohols I serve as “protected” azides accessible by

• modified Appel reaction [17]. The alkynes H can be protected by silylation (J) because only primary alkynes react in the CuAAC (Figure 3). The synthesis commences with 4-hydroxypiperidine (1), which was converted to piperidine-4-one 3 bearing a protected alkyne moiety as well as to piperidin-4-one 5 with a

• desilylation (10). The subsequent CuAAC coupling between 9 and 10 turned out to be difficult. Whereas the reaction failed under standard conditions [18] we succeeded after numerous variations of the reaction conditions by applying the Cu/C catalyst [19] in a solvent mixture of DCM and MeOH in the presence of

Synthesis of divalent ligands of β-thio- and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzi trans-sialidase

• María Emilia Cano,
• Rosalía Agusti,
• Alejandro J. Cagnoni,
• María Florencia Tesoriero,
• José Kovensky,
• María Laura Uhrig and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 3073–3086, doi:10.3762/bjoc.10.324

• , and a peak at m/z 988.3291, corresponding to the [M + 2Na]2+ cation, was observed consistent with the proposed structure. Conclusion Mono- and bivalent β-N and β-S-galactopyranosides and lactosides supported on sugar scaffolds were synthesized by a convergent approach using the CuAAC reaction

Sequential decarboxylative azide–alkyne cycloaddition and dehydrogenative coupling reactions: one-pot synthesis of polycyclic fused triazoles

• Kuppusamy Bharathimohan,
• Thanasekaran Ponpandian,
• A. Jafar Ahamed and
• Nattamai Bhuvanesh

Beilstein J. Org. Chem. 2014, 10, 3031–3037, doi:10.3762/bjoc.10.321

• describe a one-pot protocol for the synthesis of a novel series of polycyclic triazole derivatives. Transition metal-catalyzed decarboxylative CuAAC and dehydrogenative cross coupling reactions are combined in a single flask and achieved good yields of the respective triazoles (up to 97% yield). This

• methodology is more convenient to produce the complex polycyclic molecules in a simple way. Keywords: copper(II) acetate; decarboxylative CuAAC; dehydrogenative coupling; fused triazoles; one-pot synthesis; Introduction The copper-catalyzed Huisgen [3 + 2] cycloaddition (or copper-catalyzed azide–alkyne

• cycloaddition, CuAAC) between an organic azide and a terminal alkyne is a well-established strategy for the construction of 1,4-disubstituted 1,2,3-triazoles [1][2][3][4]. In a recent development, this decarboxylative coupling reaction was well documented for the generation of C–C bonds [5]. This method has

A small azide-modified thiazole-based reporter molecule for fluorescence and mass spectrometric detection

• Stefanie Wolfram,
• Hendryk Würfel,
• Stefanie H. Habenicht,
• Christine Lembke,
• Phillipp Richter,
• Eckhard Birckner,
• Rainer Beckert and
• Georg Pohnert

Beilstein J. Org. Chem. 2014, 10, 2470–2479, doi:10.3762/bjoc.10.258

• )-catalyzed azide–alkyne cycloaddition (CuAAC) is often considered as the prototypical transformation [7][8][9]. Due to the mild conditions and the use of aqueous solvents it is an efficient tool for bioorthogonal chemistry even inside of living systems [10]. One application of this concept for functional

• group is usually applied to living organisms and after cell lysis the reporter is introduced by CuAAC [16]. Fluorophore tagged proteins can then be visualized by gel electrophoresis [17]. Besides fluorescence detection, mass spectrometry (MS) is also suited for the monitoring of tagged biological

• compatibility with widely applicable CuAAC approaches, that are, for instance, used in the field of ABPP where fluorescent reporter azides act as part of protein probes. To avoid the need for expensive detection systems for in-gel fluorescence we adjusted the excitation and emission wavelengths of the reporter

Expeditive synthesis of trithiotriazine-cored glycoclusters and inhibition of Pseudomonas aeruginosa biofilm formation

• Meriem Smadhi,
• Sophie de Bentzmann,
• Anne Imberty,
• Marc Gingras,
• Raoudha Abderrahim and
• Peter G. Goekjian

Beilstein J. Org. Chem. 2014, 10, 1981–1990, doi:10.3762/bjoc.10.206

• -triazine (2) as a key precursor [37]. The glycosyl units were incorporated via Cu(I)-catalyzed Huisgen cycloaddition with protected or unprotected glycosyl azides. We first investigated the Cu-catalyzed azide–alkyne cycloaddition (CuAAC) of acetyl protected β-D-galactopyranosyl azide 3 [38], to tris

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

• Silvia Bernardi,
• Paola Fezzardi,
• Gabriele Rispoli,
• Stefania E. Sestito,
• Francesco Peri,
• Francesco Sansone and
• Alessandro Casnati

Beilstein J. Org. Chem. 2014, 10, 1672–1680, doi:10.3762/bjoc.10.175

• Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy 10.3762/bjoc.10.175 Abstract Four novel calix[4]arene-based glycoclusters were synthesized by conjugating the saccharide units to the macrocyclic scaffold using the CuAAC reaction and using long and hydrophilic ethylene glycol spacers

• have been widely studied in their scope and limitations [10][31]. In particular, the Huisgen cycloaddition reaction was first applied to a calixarene in 2000 by Santoyo-González [32]. Later on, Marra et al. [33] demonstrated that the copper-catalyzed azide–alkyne cycloaddition (CuAAC) [34][35] at room

• intramolecular CuAAC reaction with an adjacent azido-arm [37]. Firstly, we decided to evaluate the effectiveness of the two approaches dipolarophile-on-the-calix and dipolarophile-on-the-sugar by using a galactose and cone calixarene scaffolds. This investigation was carried out with the idea to extend the study

Photoswitchable precision glycooligomers and their lectin binding

• Daniela Ponader,
• Sinaida Igde,
• Marko Wehle,
• Katharina Märker,
• Mark Santer,
• David Bléger and
• Laura Hartmann

Beilstein J. Org. Chem. 2014, 10, 1603–1612, doi:10.3762/bjoc.10.166

• block AZO. TDS allows for the conjugation of sugar azide ligands via the copper-catalyzed azide–alkyne cycloaddition (CuAAC). The synthesis and coupling on solid support of TDS and EDS has been previously described [7][10]. AZO was synthesized via Mills coupling adapting literature protocols [20][21][22

• steps, the oligomeric backbone was formed on the solid support. In the next step, the sugar ligands were introduced to the oligomeric backbone via CuAAC. To this end, two sugar azides (2-azidoethyl galactoside and 2-azidoethyl mannoside) were previously synthesized following literature protocols [26]. 8

• solution (8 equiv) together with 0.05 mmol HOBt (4 equiv) and 0.2 mmol (16 equiv) DIPEA in DMF (0.1 mL). This solution was added to the resin. After shaking for one hour the resin was washed from excessive reagent with DMF. General CuAAC protocol: 0.1 mmol (8 equiv) of 2-azidoethyl pyranoside per alkyne

The search for new amphiphiles: synthesis of a modular, high-throughput library

• George C. Feast,
• Thomas Lepitre,
• Xavier Mulet,
• Charlotte E. Conn,
• Oliver E. Hutt,
• G. Paul Savage and
• Calum J. Drummond

Beilstein J. Org. Chem. 2014, 10, 1578–1588, doi:10.3762/bjoc.10.163

• cycloaddition (CuAAC) reaction. The tails were synthesised from two core alkyne-tethered intermediates, which were subsequently functionalised with hydrocarbon chains varying in length and degree of unsaturation and branching, while the five sugar head groups were selected with ranging substitution patterns and

• delivery. Many other fields have utilised the copper-catalysed azide–alkyne cycloaddition (CuAAC) ‘click’ reaction [16][17] to generate libraries of compounds, including enzyme inhibitors [18][19][20], catalysis ligands [21][22][23] and metal frameworks [24][25]. We have recently demonstrated that a

• library of amphiphiles, with ammonium head groups and single-chain saturated tails, can be synthesised in a combinatorial approach, using this chemistry [26]. Amphiphiles and self-assembled nanoparticles have been synthesised using CuAAC chemistry previously [27][28][29], however to our knowledge, this

Orthogonal dual thiol–chloroacetyl and thiol–ene couplings for the sequential one-pot assembly of heteroglycoclusters

• Michele Fiore,
• Gour Chand Daskhan,
• Baptiste Thomas and
• Olivier Renaudet

Beilstein J. Org. Chem. 2014, 10, 1557–1563, doi:10.3762/bjoc.10.160

• alkyne–azide cycloaddition (CuAAC) [18] or SN2 reaction [19]. In addition, orthogonal chemoselective ligations were proved more attractive strategies to prepare hGCs in high yields, in part because they require less synthetic and purification steps. For example, oxime and CuAAC ligations have been used

• in our group to prepare tetravalent structures displaying two sugars either in 2:2 or 3:1 relative proportions [20]. In the meanwhile, the group of A. Dondoni has developed a sequential orthogonal TEC in combination with CuAAC for grafting two different sugar motifs on calix[4]arene scaffold [21

Synthesis and solvodynamic diameter measurements of closely related mannodendrimers for the study of multivalent carbohydrate–protein interactions

• Yoann M. Chabre,
• Alex Papadopoulos,
• Alexandre A. Arnold and
• René Roy

Beilstein J. Org. Chem. 2014, 10, 1524–1535, doi:10.3762/bjoc.10.157

• separating the anomeric and the core carbons, were synthesized using azide–alkyne cycloaddition (CuAAc). Compound 23 was prepared by an efficient convergent strategy. The sugar precursors consisted of either a 2-azidoethyl (3) or a prop-2-ynyl α-D-mannopyranoside (7) derivative. The solvodynamic diameters of

• -azidoethyl α-D-mannopyranoside 3 [34] under classical copper-catalyzed dipolar cycloaddition (CuAAc) to afford 4 in 56% yield. Structure 4 was readily characterized by the absence of acetylenic protons at δ 3.16 ppm, the appearance of identical triazole protons (3H) at δ 7.74 ppm relative to the anomeric

• follow a conceptually identical strategy to the one described above for trimers 5 and 9. Toward this goal, propargylated 9-mer scaffold 10 [17] was treated under the same CuAAc conditions with azide 3 to provide peracetylated 11 in 83% yield which upon Zemplén de-O-acetylation gave 12 in essentially

Multichromophoric sugar for fluorescence photoswitching

• Stéphane Maisonneuve,
• Rémi Métivier,
• Pei Yu,
• Keitaro Nakatani and
• Juan Xie

Beilstein J. Org. Chem. 2014, 10, 1471–1481, doi:10.3762/bjoc.10.151

• because sophisticated multistep experimental procedures are often implicated. Recently, the Cu(I)-catalyzed alkyne–azide cycloaddition reaction (CuAAC, an excellent example of click chemistry) has been demonstrated as a robust and highly efficient ligation tool to conjugate various azido- and alkyne

• systems [17]. In order to introduce three DCM fluorophores and one photochromic species into the glycopyranoside scaffold, methyl 6-O-trityl-α-D-glucopyranoside 3 was chosen as starting material (Scheme 1). O-Propargylation followed by microwave-assisted CuAAC with azido-functionalized DCM fluorophore 5

Microwave-assisted Cu(I)-catalyzed, three-component synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles

• Yogesh Kumar,
• Vijay Bahadur,
• Anil K. Singh,
• Virinder S. Parmar,
• Erik V. Van der Eycken and
• Brajendra K. Singh

Beilstein J. Org. Chem. 2014, 10, 1413–1420, doi:10.3762/bjoc.10.145

• were used. In general, good to excellent yields were obtained for the desired cyclized products. Plausible mechanism The desired product could be obtained by the two mechanistic pathways A and B as described in Scheme 2. The CuAAC could take place prior to or after benzimidazole formation and we do not

• first, followed by the formation of triazole by CuAAC reaction to give the desired product 4a. Conclusion We developed a novel microwave-assisted, Cu(I)-catalyzed, three-component reaction for the synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles in good to

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores

• Mathieu L. Lepage,
• Alessandra Meli,
• Anne Bodlenner,
• Céline Tarnus,
• Francesco De Riccardis,
• Irene Izzo and
• Philippe Compain

Beilstein J. Org. Chem. 2014, 10, 1406–1412, doi:10.3762/bjoc.10.144

• iminosugars 5 onto polyalkyne “clickable” scaffolds 2–4 by Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reactions [40][41] (Figure 1). N-alkyl derivatives of DNJ were logically chosen as the peripheral ligands because of the therapeutic relevance of these compounds [42]. In addition, most of the

• microwave-assisted CuAAC reaction (Scheme 2). The multiconjugation reaction proceeded smoothly to afford the six desired DNJ clusters 9 in 69–95% yields. With the exception of octavalent iminosugars 9c (n = 6) and 9d (n = 9), these compounds showed complex 1H NMR spectra at room temperature as exemplified

Human dendritic cell activation induced by a permannosylated dendron containing an antigenic GM₃-lactone mimetic

• Renato Ribeiro-Viana,
• Elena Bonechi,
• Javier Rojo,
• Clara Ballerini,
• Giuseppina Comito,
• Barbara Richichi and
• Cristina Nativi

Beilstein J. Org. Chem. 2014, 10, 1317–1324, doi:10.3762/bjoc.10.133

• functionalized with an alkyne group by a Cu(I) azide–alkyne cycloaddition (CuAAC) reaction. Then, the mimetic 6 with a butyne group at the anomeric position, which is required for the conjugation to the glycodendron 7 (Scheme 1), was also prepared as already reported [33]. The synthesis of the tricyclic spiro

• purification the resulting syrup was conjugated with the glycodendron 7 by a CuAAC reaction with CuSO4 as a copper source, sodium ascorbate to reduce Cu(II) to Cu(I) in situ, and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) to stabilize Cu(I). The solution was treated with a resin (Quadrasil MP) to

Tandem Cu-catalyzed ketenimine formation and intramolecular nucleophile capture: Synthesis of 1,2-dihydro-2-iminoquinolines from 1-(o-acetamidophenyl)propargyl alcohols

• Gadi Ranjith Kumar,
• Yalla Kiran Kumar,
• Ruchir Kant and
• Maddi Sridhar Reddy

Beilstein J. Org. Chem. 2014, 10, 1255–1260, doi:10.3762/bjoc.10.125

• compounds in moderate to good yields under mild reaction conditions. Keywords: alkyne; azide; cycloaddition; cyclization; quinoline; Introduction The synthesis of N-sulfonylketenimines via CuAAC (copper-catalyzed azide–alkyne cycloaddition) between terminal alkynes and sulfonyl azides has staged for a

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

• Malamatenia D. Manouilidou,
• Yannis G. Lazarou,
• Irene M. Mavridis and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 774–783, doi:10.3762/bjoc.10.73

• . These include the well-known copper-catalyzed azide–alkyne cyclization (CuAAC, “click” reaction) between an azido-CD derivative and an alkyne linker [19][22][23][24] [22], or vice versa, the metal catalyzed reactions between propargyl-CDs and aryl dihalides such as the Sonogashira and Glaser–Hay

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• ]. Multicomponent reactions towards amide isosteres often involve an Ugi reaction followed by a Click reaction, in which two of the Ugi-inputs either contain an alkyne or an azide moiety. A well-known example of the latter reaction is the Copper(I) catalyzed azide–alkyne cycloaddition (CuAAC) between acetylenes and

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• -ansamitocin derivative 6, folate-ansamitocin P-3 conjugate 7 and thiol 8. Strategies for introducing linker-based thiol groups to the aromatic moiety of ansamitocin P-3 for accessing tumor targeting conjugates (CuAAC; Cu-mediated azide–alkyne cycloaddition). Mutasynthetic transformation of aminobenzoic acid

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• between isoquinolinium-2-ylamide 43 and keteneimine 57 [79], silver salt plays the usual role of a π-philic catalyst, whereas ketene imine 57 is generated by a well-known procedure involving a copper(I)-catalyzed azide–alkyne [3 + 2] cycloaddition (CuAAC) giving rise to 5-cuprated triazole intermediate 56

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

• Regina Berg Bernd F. Straub Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany 10.3762/bjoc.9.308 Abstract The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle

• reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species

• itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies