Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• necessary for achieving high reactivity, presumably because it minimizes undesired ligation of the benzoxazole substrates or intermediates. A variety of α-substituted acrylates as well as methacrylonitrile were good substrates. The system is sensitive to sterics, an acetate additive was needed to improve

Learning from the unexpected in life and DNA self-assembly

• Jennifer M. Heemstra

Beilstein J. Org. Chem. 2015, 11, 2713–2720, doi:10.3762/bjoc.11.292

• the sensitivity of split aptamer-based detection assays, and also that by converting the presence of a target molecule into the output of a DNA ligation event, we might be able to use split aptamers in assay formats that were previously inaccessible with these affinity reagents. In our first attempt

• to demonstrate this principle of split aptamer ligation, we functionalized one fragment of the cocaine-binding DNA split aptamer [8] with a cyclooctyne and the other fragment with an azide. Although the cyclooctyne and azide are inherently reactive towards one another [9], we hypothesized that in the

• (Figure 2). In our first experiment, we tested the hypothesis that the untemplated second order reaction would be sufficiently slow to prevent accumulation of the background signal. We were surprised to observe significant ligation between the split aptamer fragments, even in the absence of cocaine. While

Effective ascorbate-free and photolatent click reactions in water using a photoreducible copper(II)-ethylenediamine precatalyst

• Redouane Beniazza,
• Natalia Bayo,
• Florian Molton,
• Carole Duboc,
• Stéphane Massip,
• Nathan McClenaghan,
• Dominique Lastécouères and
• Jean-Marc Vincent

Beilstein J. Org. Chem. 2015, 11, 1950–1959, doi:10.3762/bjoc.11.211

• Gautier and coworkers based on a water-soluble Cu(I)–NHC complex, which could be used under ascorbate-free and open air conditions for the CuAAC ligation of oxidation-sensitive peptides in buffered aqueous media [10]. Recently, we developed the photoreducible copper(II) complexes 2 and 3 incorporating a

Synthesis of γ-hydroxypropyl P-chirogenic (±)-phosphorus oxide derivatives by regioselective ring-opening of oxaphospholane 2-oxide precursors

• Iris Binyamin,
• Shoval Meidan-Shani and
• Nissan Ashkenazi

Beilstein J. Org. Chem. 2015, 11, 1332–1339, doi:10.3762/bjoc.11.143

• fact that the γ-hydroxypropyl substituent, which results directly from the ring opening of the phospholane, could provide a second ligation site upon complexation of the corresponding phosphines to a transition metal catalyst. These P,O bidentate ligands are quite useful in organometallic compounds

Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

• Tobias-Elias Gloe,
• Insa Stamer,
• Cornelia Hojnik,
• Tanja M. Wrodnigg and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 1096–1104, doi:10.3762/bjoc.11.123

• in one step and without the need of protecting group manipulations. This is intriguing in light of biorthogonal ligation methodology as Amadori products are structurally closely related to naturally occurring D-hexopyranosides. In addition, C-glycosyl glycoconjugates are believed to bear great

• ligation method for conjugation of unprotected sugars and amines, when applied to suitable sugar substrates. Herein, we evaluated this synthetic method for the preparation of ligands for the α-D-mannose-specific type 1-fimbrial bacterial lectin FimH. The synthesis of heptopyranose 8 as a starting material

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• ) was selected and synthesized on Rink amide polystyrene resin. For attachment to the polymer carriers the N-cysteinylated peptide CGPPPRGPPPR-NH2 (P2) was prepared, containing a free N-terminus in order to enable the attachment to polymers via native chemical ligation or Michael addition to maleimide

• peptide–polymer conjugates pHPMA-1 and pHPMA-2 via native chemical ligation with the N-cysteinylated peptide CGPPPRGPPPR-NH2 (P2). In contrast, the second carrier molecule, hyperbranched polyglycerol (hPG) was selected as a dendritic polymer. While the backbone of PG is relatively flexible by itself, the

Orthogonal dual-modification of proteins for the engineering of multivalent protein scaffolds

• Michaela Mühlberg,
• Michael G. Hoesl,
• Christian Kuehne,
• Jens Dernedde,
• Nediljko Budisa and
• Christian P. R. Hackenberger

Beilstein J. Org. Chem. 2015, 11, 784–791, doi:10.3762/bjoc.11.88

• (CuAAC) and oxime ligation. This method was applied to the conjugation of biotin and β-linked galactose residues to yield an enzymatically active thermophilic lipase, which revealed specific binding to Erythrina cristagalli lectin by SPR binding studies. Keywords: chemoselectivity; dual protein

• ligation [34][35] as the second orthogonal conjugation reaction in addition to CuAAC for the attachment of functional moieties to Aha residues installed by auxotroph expression. In order to install a second unnatural functionality in the protein, in addition to SPI, we utilized the well-established

• conjugated with biotin using oxime ligation, by which the protein scaffold was immobilized on a streptavidin gold chip to monitor carbohydrate–protein binding studies by surface plasmon resonance (SPR). This immobilization strategy allowed easy handling and reproducible orientation, which are notable

Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency

• Anna K. Ciuk and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 668–674, doi:10.3762/bjoc.11.75

• install both branches on a carbohydrate scaffold. This would allow to favour the intramolecular [2 + 2] cycloaddition over an intermolecular reaction and moreover, a multifunctional carbohydrate scaffold facilitates further ligation or immobilization, respectively, of the final molecular construct. After

• scaffold (blue), an appropriate ligation chemistry is required. Additional ligation of sugar ligands (pink) leads to the analogous divalent glycothymine glycoconjugate (B). As building blocks for this molecular architecture a mannoside scaffold (blue), thymine (green), and α-D-mannosyl ligands (pink) were

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

• give 36 (Scheme 8). Besides the widely used CuAAC ligation the Staudinger ligation [22] is also an important tool for coupling molecules. To verify that the diazide 34 is also suitable for this reaction we first prepared the cinnamoyl substituted phosphane 38 from (2-hydroxyphenyl)diphenylphosphane (37

• ). By heating 34 and 38 in DMF for 3 h the AR 39 was obtained as result of a traceless Staudinger ligation, albeit with low yield (Scheme 9). As already mentioned, we were interested in articulated rods whose folded-stretched equilibrium could be influenced by external stimuli. In order to realize this

Autonomous assembly of synthetic oligonucleotides built from an expanded DNA alphabet. Total synthesis of a gene encoding kanamycin resistance

• Kristen K. Merritt,
• Kevin M. Bradley,
• Daniel Hutter,
• Mariko F. Matsuura,
• Diane J. Rowold and
• Steven A. Benner

Beilstein J. Org. Chem. 2014, 10, 2348–2360, doi:10.3762/bjoc.10.245

• requisite single-stranded oligonucleotides followed by annealing, primer extension to fill in any gaps, and ligation. Unfortunately, DNA is not this ideal. With just four nucleotides, the information density of standard DNA is too low to allow (without explicit design) even a dozen or so single strands to

• self-assembly was successful was the electrophoretic detection of the full-length non-amplified product (Figure 5). A gel resolving crude, non-amplified products obtained from the “one-pot” annealing, extension, and ligation process showed a major band at ~863 base pairs, the size of the expected

• were defective, smaller constructs were self-assembled. Figure 8 shows the results of stepwise assembly of subsets of the fragments, after the target ligation products were rescued from the mixture by PCR (30 cycles). As is evident by the intensity of the bands arising from the amplicons four, eight

Expanding the scope of cyclopropene reporters for the detection of metabolically engineered glycoproteins by Diels–Alder reactions

• Anne-Katrin Späte,
• Verena F. Schart,
• Julia Häfner,
• Andrea Niederwieser,
• Thomas U. Mayer and
• Valentin Wittmann

Beilstein J. Org. Chem. 2014, 10, 2235–2242, doi:10.3762/bjoc.10.232

• Diels–Alder reaction between methylcyclopropene tags and tetrazines has become a popular ligation reaction due to the small size and high reactivity of cyclopropene tags. Attaching the cyclopropene tag to mannosamine via a carbamate linkage has made the reaction even more efficient. Here, we expand the

• bioorthogonal labeling reactions that allow visualization [5][6]. Whereas in the first report on glycan labeling by this approach the ketone–hydrazide ligation was employed [7], later investigations mainly relied on the Staudinger ligation [8] and azide–alkyne [3 + 2] cycloaddition (copper-catalyzed [9][10] or

• strain-promoted [11][12]). Since the initial reports from 2008 [13][14][15], more and more laboratories successfully employ the inverse-electron-demand Diels–Alder (DAinv) reaction as a bioorthogonal ligation reaction for different applications [16][17][18]. In the meantime, the DAinv reaction has also

Bifunctional dendrons for multiple carbohydrate presentation via carbonyl chemistry

• Davide Bini,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2014, 10, 1686–1691, doi:10.3762/bjoc.10.177

• of the glycoconjugation to the G0 dendron and G1 dendron by reductive amination, we decided to evaluate the possibility to obtain better conjugation yields by oxime ligation. Thus, G0, G1 and G2 dendrons 1–3 were reacted with α-O-L-fucopyranosyloxyamine (5) in citrate buffer at pH 3.5 [20] (Scheme 4

• quantitative yields. Conclusion In conclusion, novel G0, G1 and G2 dendrons suitable for glycoconjugation by carbonyl chemistry were synthesized. The conjugation of the saccharide by reductive amination was characterized by a low efficiency. On the other hand, the oxime ligation afforded the glycoconjugated

• : a) 4, 3 M Na2SO4, AcOH, NaCNBH3, EtOH, 80 °C, 6 h. Dendron conjugation to fucose via oxime ligation (buffer = citrate buffer). Supporting Information Supporting Information File 546: Experimental part. Acknowledgements This research was financially supported by the Cariplo Fundation under the

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

• binary combinations of α-D-Man or β-D-GlcNAc, thus providing rapid access to attractive heteroglycosylated platforms for diverse biological applications. Keywords: chemoselective ligation; heteroglycocluster; multivalency; multivalent glycosystems; one-pot synthesis; Introduction Multivalent

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

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• conjugates 2–5 produce amounts of IL-12 that are close to background level. In agreement with the results of the NOD2 transfected HEK cells conjugates 4 and especially 5 are more active than 2 and 3 indicating that the MDP ligation locus affects the activity of the constructs. Notably, reference Pam3Cys

• -terminal ligation of the MDP to the antigenic SIINFEKL peptide via either the L-isoglutamine function or the C-1 of MDP. During the synthesis the glycosidic bond of MDP turned out to be sensitive to acidic deprotection conditions, resulting in partial hydrolysis of the aglycon. Nevertheless, pure MDP

• derivatives and conjugates could be isolated. The NOD2 stimulatory potential critically depended on the mode of ligation. Where the constructs that were conjugated via the anomeric center of MDP showed good NOD2 activation, the conjugates linked to the antigenic peptide through the L-isoglutamine residue were

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• of the human growth hormone was PEGylated using a two-step strategy in which a linker was first incorporated by a carboxypeptidase-catalyzed transpeptidation and then used for the ligation of the PEG moiety [29]. A more specific and irreversible attachment of a single PEG molecule has been achieved

• periodate oxidation A small glycan may be also introduced by chemical ligation to an inaccessible aminoacid in a natural protein, like Cys34 in human serum albumin. The glycan may be oxidized by periodate to afford aldehyde groups for selective multiple coupling with a PEG hydrazide (PEG-Hz), as shown in

Design and synthesis of multivalent neoglycoconjugates by click conjugations

• Feiqing Ding,
• Li Ji,
• Ronny William,
• Hua Chai and
• Xue-Wei Liu

Beilstein J. Org. Chem. 2014, 10, 1325–1332, doi:10.3762/bjoc.10.134

• construction of a 1,4-disubstituted-1,2,3-triazole unit via a copper(I)-catalyzed modern version of the Huisgen-type azide–alkyne cycloaddition [6][7][8][9][10] has been considered to be a powerful ligation method for glycoconjugation [11][12][13][14][15][16]. In addition to the simplicity of this reaction and

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• obtain the desired polypeptide. The condensation can occur via chemoselective ligation techniques such as native chemical ligation (NCL), expressed protein ligation (EPL), Staudinger ligation or click reaction [8][79]. Recently, peptide drugs as the pharmaceuticals Enfuvirtide, Eptifibitide and

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• for carbohydrate and peptide chemistry. Therefore, sugar units are introduced by side-chain ligation and labeling strategies on the peptide scaffold or were established by incorporation of sugar-β-amino acids by solid-phase peptide synthesis (SPPS) [36][37]. Sugar amino acid building blocks have

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

• , 15310 Greece. Tel. +30210 6503796, Fax: +30 210 6511766 10.3762/bjoc.10.73 Abstract β-Cyclodextrin (β-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2-(diphenylphosphanyl)terephthalate, a doubly active linker was

• conformations which bring the phenyl groups either inside the β-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii

• ) satisfactory aqueous solubility and independent binding capacity of the cavities. Keywords: calculations; conformations; cyclodextrin; dimer; inclusion; PM3; Staudinger ligation; Introduction The Staudinger reaction [1] is a classical method for the preparation of amines from phosphines and azides [2][3

Methylidynetrisphosphonates: Promising C₁ building block for the design of phosphate mimetics

• Vadim D. Romanenko and
• Valery P. Kukhar

Beilstein J. Org. Chem. 2013, 9, 991–1001, doi:10.3762/bjoc.9.114

• interest is also associated with the use of trisphosphonic acids as ligands for calcium ligation and as potential bone affinity agents. Finally, there is no doubt that organometallic and coordination chemistry will benefit from future innovative application of these compounds. Bond angles and bond

Design and synthesis of tag-free photoprobes for the identification of the molecular target for CCG-1423, a novel inhibitor of the Rho/MKL1/SRF signaling pathway

• Jessica L. Bell,
• Andrew J. Haak,
• Susan M. Wade,
• Yihan Sun,
• Richard R. Neubig and
• Scott D. Larsen

Beilstein J. Org. Chem. 2013, 9, 966–973, doi:10.3762/bjoc.9.111

• , click ligation of a fluorescent dye, and gel electrophoresis revealed specific labeling of a single 24 kDa band that could be blocked with an active competitor. Future work will focus on identifying the labeled protein(s). Keywords: CCG-1423; click ligation; photoaffinity labeling; Rho pathway

• group in performing activity-based protein profiling (ABPP) [19][20]. This entails the incorporation of a ligand for recognition by the target, a reactive functionality for covalently bonding to the target, and either an azide or acetylene moiety as a latent linker for subsequent ligation of a tag for

Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptide

• Lena Möller,
• Christian Hess,
• Jiří Paleček,
• Yi Su,
• Axel Haverich,
• Andreas Kirschning and
• Gerald Dräger

Beilstein J. Org. Chem. 2013, 9, 270–277, doi:10.3762/bjoc.9.33

• required for these kinds of 1,3-dipolar cycloadditions, but their potential cytotoxic properties limit the usability in biomedical applications [16][17]. For overcoming this problem, several copper-free ligation methods were developed. In this work we pursue both options, i.e., the copper-mediated as well

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• conjugation methods such as the Staudinger ligation [1] or the copper-catalyzed alkyne azide cycloaddition (CuAAC) [2][3], a large number of versatile and functional bioconjugates are accessible for various applications in chemical biology [4]. To date, many therapeutically active molecules are synthetic

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• ]. This is an attractive concept, because it can be combined with solid-phase peptide synthesis (SPPS) [4][5], as well as with native chemical ligation (NCL) utilizing an S→N acyl shift [3][6][7][8][9][10]. In addition, glycocysteine derivatives can be easily converted into the corresponding dimers by

• mannopyranside 4 can be prepared by Staudinger ligation of O-acetyl-protected 2-azidoethyl α-D-mannopyranoside [11] and the cysteine derivative Fmoc-Cys(Trt)-OH as described earlier [1]. Then, a sequence of Fmoc-deprotection, leading to 5 and acidic removal of the trityl group by using TFA and triethylsilane