CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• chemistry” was introduced for the first time by K. B. Sharpless in 1999 at the 217th ACS annual meeting [4]. Most recently, K. B. Sharpless shared the 2022 Nobel Prize in Chemistry with C. R. Bertozzi and M. Meldal for the development of click chemistry and bioorthogonal chemistry. Due to high product

Electrochemical vicinal oxyazidation of α-arylvinyl acetates

• Yi-Lun Li,
• Zhaojiang Shi,
• Tao Shen and
• Ke-Yin Ye

Beilstein J. Org. Chem. 2022, 18, 1026–1031, doi:10.3762/bjoc.18.103

• ; Introduction Organoazides play important roles in pharmaceutical, bioorthogonal chemistry, and many other interdisciplinary research areas [1][2][3]. Among them, azidoketones are also very versatile building blocks in organic synthesis, pharmaceutical, and materials science [4][5][6]. Therefore, the

Synthesis of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines and investigation of their fungistatic activity

• Anna V. Korotina,
• Svetlana G. Tolshchina,
• Rashida I. Ishmetova,
• Natalya P. Evstigneeva,
• Natalya A. Gerasimova,
• Natalya V. Zilberberg,
• Nikolay V. Kungurov,
• Gennady L. Rusinov,
• Oleg N. Chupakhin and
• Valery N. Charushin

Beilstein J. Org. Chem. 2022, 18, 243–250, doi:10.3762/bjoc.18.29

• as high-energy materials [23][24][25], molecules with promising photophysical, electrochemical and coordination properties for use in sensors, OLEDs, semiconductor materials, etc. [26][27][28]. The most important biomedical application of 1,2,4,5-tetrazines are bioorthogonal reactions that allow

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• of biomolecules [35][36][37]. The approaches by Buchwald and Pentelute are suitable for selective, bioorthogonal labelling of cysteine- [38][39][40] and lysine-containing [41][42] peptides and proteins using stochiometric amounts of pre-formed Pd(II)-aryl complexes. They can further be applied for

• ][54][55]. It has been proven that Pd-catalysed cross-couplings are very versatile tools for selective and bioorthogonal modifications of haloindoles, halotryptophans and halotryptophan-containing peptides as well as natural products [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• adjacent directing group (see 31h). This manganese(I)-catalyzed late-stage glycosylation provides hexaglycopeptide conjugate 31m without epimerization. Moreover, the late-stage C–H diversification process enabled bioorthogonal access to glycosylated peptides, such as a fluorescent BODIPY-labeled tryptophan

• assistance. However, application of this protocol for late-stage functionalization remains challenging [96][97][98][99][100][101][102][103]. In 2021, it was revealed by the Ackermann group that manganese(I) catalysis enabled the bioorthogonal late-stage alkenylation of structurally sophisticated peptides

Cyclopropene derivatives of aminosugars for metabolic glycoengineering

• Jessica Hassenrück and
• Valentin Wittmann

Beilstein J. Org. Chem. 2019, 15, 584–601, doi:10.3762/bjoc.15.54

• glycoengineering (MGE). They readily react with tetrazines in an inverse electron-demand Diels–Alder (DAinv) reaction, a prime example of a bioorthogonal ligation reaction, allowing their visualization in biological systems. Here, we present a comparative study of six cyclopropene-modified hexosamine derivatives

• , distinct cell-surface staining after MGE. We further found that the amide-linked Cp-modified glucosamine derivative but not the Cyoc-modified glucosamine is metabolically converted to the corresponding sialic acid. Keywords: bioorthogonal chemistry; carbohydrates; cyclopropenes; inverse electron-demand

• bioorthogonal ligation reaction [5][6]. Mannosamine derivatives are of special interest because they are metabolized to sialic acids and then displayed as terminal structures on the cell surface [7]. Various carbohydrate derivatives with different reporter groups have been applied for MGE [2][3][4]. For example

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• ][24]. Water is inexpensive, non-flammable, non-toxic and environmentally friendly, all characteristics that make it an ideal solvent. Furthermore, water is the media of biochemical reactions, and metathesis is a bioorthogonal reaction that can be exploited in a biological setting. Figure 1 illustrates

• rounds of mutation and screening the performances of genetically-encoded enzymes. Hypothesizing that this tool may be applicable to the optimization of artificial metalloenzymes (ArMs) for olefin metathesis, a new-to-nature bioorthogonal reaction might be introduced in a biological system. ArMs result

• from the incorporation of a catalytically active organometallic moiety within a protein scaffold. Such biohybrid catalysts enable a chemogenetic optimization of their catalytic performances. As olefin metathesis is bioorthogonal, it offers attractive features for the manipulation of biological systems

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• dyes which could be applied as FRET pair. In this case, labeling was achieved in two bioorthogonal reactions, an iEDDA and a SPAAC reaction. Furthermore, dual modification with an azido and an alkyne function enabled fluorophore/biotin labeling using a combination of SPAAC and CuAAC reaction. Efficient

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• additionally increase the acidity of the α-proton. Nevertheless, glycine derivatives with electron-withdrawing substituents like formylglycine [58][59], phenylglycine [60][61] and fluorinated alanine [62][63][64] have attracted great attention as peptidomimetics, drugs or in the bioorthogonal functionalization

Correction: Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2017, 13, 301–302, doi:10.3762/bjoc.13.32

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• development of new building blocks for specific and bioorthogonal labeling of biologically active compounds is of high importance. Depending on their size and composition, building blocks can influence (bio-)chemical parameters such as the lipophilicity (log P) affecting the solubility and the biological

• connection to the label (e.g., fluorescence dye, radionuclide) and the second is used for the introduction of a (bioorthogonal) functional group (e.g., azide, alkyne, phosphane, tetrazine) to later connect to the biomolecule via bioorthogonal ligation. Our aim was the development of novel, N,N

• ’-unsymmetrically functionalized piperazine derivatives using a high-yielding, simple synthesis with either a bioorthogonal alkyne or azide functionality for future labeling purposes. Furthermore, characterization of these piperazine derivatives was performed with emphasis on their particular NMR behavior. In order

Economical and scalable synthesis of 6-amino-2-cyanobenzothiazole

• Jacob R. Hauser,
• Hester A. Beard,
• Mary E. Bayana,
• Katherine E. Jolley,
• Stuart L. Warriner and
• Robin S. Bon

Beilstein J. Org. Chem. 2016, 12, 2019–2025, doi:10.3762/bjoc.12.189

• Laboratories, University of Leeds, Leeds LS2 9JT, UK 10.3762/bjoc.12.189 Abstract 2-Cyanobenzothiazoles (CBTs) are useful building blocks for: 1) luciferin derivatives for bioluminescent imaging; and 2) handles for bioorthogonal ligations. A particularly versatile CBT is 6-amino-2-cyanobenzothiazole (ACBT

• luciferin scaffolds [2][5][8]. Even in the presence of other thiols and amines, CBTs react rapidly and selectively with 1,2-aminothiols under physiological conditions. This selective and bioorthogonal reactivity of CBTs has been exploited in the development of the CBT ligation as a useful and fast

• bioorthogonal reaction (k ≈ 10 M−1s−1) [9] for site-specific labelling or immobilisation of proteins 4, either at an N-terminal cysteine residue or at a 1,2-aminothiol group incorporated into a non-natural amino acid (Scheme 1) [10][11]. In addition, CBT derivatives have been used for the synthesis of polymeric

Organic chemistry meets polymers, nanoscience, therapeutics and diagnostics

• Vincent M. Rotello

Beilstein J. Org. Chem. 2016, 12, 1638–1646, doi:10.3762/bjoc.12.161

• -resistant bacteria such as MRSA [90] and nanocapsule systems work against the biofilms [91] made by these nasties [92]. We have also made a foray into bioorthogonal chemistry, using nanoparticles to encapsulate transition metal catalysts, generating “nanozymes” that can catalyze processes in cells that even

Application of Cu(I)-catalyzed azide–alkyne cycloaddition for the design and synthesis of sequence specific probes targeting double-stranded DNA

• Svetlana V. Vasilyeva,
• Vyacheslav V. Filichev and
• Alexandre S. Boutorine

Beilstein J. Org. Chem. 2016, 12, 1348–1360, doi:10.3762/bjoc.12.128

• oligonucleotides and polyamide MGBs. A simple and effective method of bioorthogonal conjugation using CuAAC was applied to the synthesis of conjugates between various TFOs and MGBs. Synthesized products were purified, isolated and characterized. Functionalized polyamides were applied for the synthesis of

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

• Eric Buchy,
• Branko Vukosavljevic,
• Maike Windbergs,
• Dunja Sobot,
• Camille Dejean,
• Simona Mura,
• Patrick Couvreur and
• Didier Desmaële

Beilstein J. Org. Chem. 2016, 12, 1127–1135, doi:10.3762/bjoc.12.109

• physicochemical properties and thus does not perturb the structure of the described NAs. Consequently, deuterated squalenic acid is expected to be excellent as bioorthogonal Raman tag for squalene-based NAs. Since the Raman signal intensity is expected to increase with the number of deuterium atoms in the same

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

• profiling (ABPP); bioorthogonal; click chemistry; mass defect; molecular probe; Introduction Fluorescent dyes are widely used for detection and monitoring in the fields of chemistry, biochemistry, molecular biology, medicine and material sciences. Due to sensitive and selective detection methods and

• )-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

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

• higher fluorescence staining of cell-surface glycoconjugates, the glucosamine derivative gave higher labeling efficiency with protein preparations containing also intracellular proteins. Keywords: bioorthogonal chemistry; carbohydrates; cyclopropenes; inverse-electron-demand Diels-Alder reactions

• 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

Triazol-substituted titanocenes by strain-driven 1,3-dipolar cycloadditions

• Andreas Gansäuer,
• Andreas Okkel,
• Lukas Schwach,
• Laura Wagner,
• Anja Selig and
• Aram Prokop

Beilstein J. Org. Chem. 2014, 10, 1630–1637, doi:10.3762/bjoc.10.169

• molecules. Since no metal complexes are required to catalyze the 1,3-dipolar cycloaddition [41][42][43], the reaction can be even used for the functionalization of biomolecules in living systems and has therefore been called bioorthogonal [34][35]. To the best of our knowledge, no examples of the Ti

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

• ]. The intermediate, a phosphaza ylide (1, Scheme 1a) is readily formed with loss of nitrogen gas, while subsequent hydrolysis yields the corresponding amine and phosphine oxide. A variant of this reaction is the Staudinger ligation [4], a bioorthogonal reaction that has become an important tool of

Bioorthogonal metabolic glycoengineering of human larynx carcinoma (HEp-2) cells targeting sialic acid

• Arne Homann,
• Riaz-ul Qamar,
• Sevnur Serim,
• Petra Dersch and
• Jürgen Seibel

Beilstein J. Org. Chem. 2010, 6, No. 24, doi:10.3762/bjoc.6.24

• at the termini of mammalian cell-surface glycostructures, which participate in essential interaction processes including adhesion of pathogens prior to infection and immunogenicity. Here we present the synthesis and bioorthogonal metabolic incorporation of the sialic acid analogue N-(1-oxohex-5-ynyl

• )neuraminic acid (Neu5Hex) into the cell-surface glycocalyx of a human larynx carcinoma cell line (HEp-2) and its fluorescence labelling by click chemistry. Keywords: bioorthogonal metabolic glycoengineering; click chemistry; sialic acid; Introduction The surface of eukaryotic cells is heavily covered with

• processes involved in infection, inflammation or tumor formation [1]. Recent studies have shown that the surface of a T-cell line (Jurkat), Chinese hamster ovary (CHO) cells, cervical adenocarcinoma (HeLa) cells as well as many other cell types can be labelled with bioorthogonal, that is metabolically inert