¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• ][24][25][26][27][28][29]. The labelling enhances the sensitivity of detection and permits the quantitative measurements of JCN and 1H-15N J-coupling constants (JHN) even in a mixture of tautomeric forms [24][25]. Additionally, a method based on amplitude-modulated spin-echo experiments was found to be

Pyrene–nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies

• Artur Jabłoński,
• Yannic Fritz,
• Hans-Achim Wagenknecht,
• Rafał Czerwieniec,
• Tytus Bernaś,
• Damian Trzybiński,
• Krzysztof Woźniak and
• Konrad Kowalski

Beilstein J. Org. Chem. 2017, 13, 2521–2534, doi:10.3762/bjoc.13.249

• pyrenyl–thymine 2 was confirmed by single-crystal X-ray analysis. Crystal structure Crystals of 2 suitable for X-ray diffraction analysis were obtained by slow diffusion of pentane into a chloroform solution of 2. The oak ridge thermal-ellipsoid plot (ORTEP) with the atom labelling scheme is shown in

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• ]. More recently, a global protein glycosylation analysis through chemical labelling and mass finger printing have identified many S-glycosylation sites on different proteins, with a N-acetylglucosamine group bound on cysteines [28]. Other enzymes have been scarcely identified to catalyse the S

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• reaction were addressed by isotopic labelling experiments. Heterologous expression of the diterpene synthase in Nicotiana benthamiana resulted in the production of 18-hydroxydolabella-3,7-diene also in planta, while the results from the heterologous expression in E. coli were shown to be reproducible

• analysis of the obtained terpene products. Incubation of (R)-(1-13C,1-2H)GGPP with HdS resulted in the specific incorporation of the deuterium labelling into the 2α position as indicated by a deminished crosspeak in the HSQC spectrum, while the crosspeak for H2β was strongly enhanced because of the 13C

• labelling of C2 (Figure 2). Consistently, the substrate (S)-(1-13C,1-2H)GGPP gave a product with specific incorporation of the deuterium label into the 2β position. Assuming inversion of configuration at C1 for the cyclisation of GGPP to 3 as reported for several other terpene synthases [13][20][21][22

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

• Ludmila Škorpilová,
• Silvie Rimpelová,
• Michal Jurášek,
• Miloš Buděšínský,
• Jana Lokajová,
• Roman Effenberg,
• Petr Slepička,
• Tomáš Ruml,
• Eva Kmoníčková,
• Pavel B. Drašar and
• Zdeněk Wimmer

Beilstein J. Org. Chem. 2017, 13, 1316–1324, doi:10.3762/bjoc.13.128

• [14][15][16], drugs [17], cell organelle markers, for antibody, peptide and nucleic acid labelling [18][19][20], for pH [21], metal [22][23] and redox potential sensing (well-reviewed in Boens et al. [24]), as well as for the development of photodynamically active agents [25][26]. In this work, we

New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

• Aleksey Yu. Vorob’ev,
• Vyacheslav I. Supranovich,
• Gennady I. Borodkin and
• Vyacheslav G. Shubin

Beilstein J. Org. Chem. 2017, 13, 800–805, doi:10.3762/bjoc.13.80

• could also be extended to tritium labelling of pharmaceutically interesting compounds for medicinal applications. pKa values for N-aminopyridinium cation hydrogen atoms according to DFT M06-2X 6-31+G(d,p) calculations. Relative stability of 3-CO2Et-substituted dihydropyrazolo[1,5-a]pyridines by the M06

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

• Carmen Moreno-Marrodan,
• Francesca Liguori and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• under continuous-flow conditions using supported catalysts. The substrates and the commonly observed products with the labelling adopted in the present review are shown in Scheme 2. Representative data are summarized in Table 1, in which conversions are indicated and catalysts’ efficiencies are

Fluorescent carbon dots from mono- and polysaccharides: synthesis, properties and applications

• Stephen Hill and
• M. Carmen Galan

Beilstein J. Org. Chem. 2017, 13, 675–693, doi:10.3762/bjoc.13.67

• hydrophobic red fluorescent CDs via surface passivation and polymer coating, in which hydrophilic anhydride groups of the polymer can react with PEG-diamine, via a ring-opening to afford a free acid and an amide-linked SPA, lead to water-soluble CDs ready for bio-labelling applications. The CDs were then

• labelled with either TAT (a cell-penetrating peptide), or folate and then incubated with HeLa cells. Fluorescence microscopy images confirmed that incubation times of 3–6 hours were adequate to allow for CD labelling of the cells. Further toxicity assays indicated that concentrations of up to 200 μg/mL

• polysaccharide-based nanomaterials in other targeted live cell labelling, imaging and drug-delivery applications. In addition to amine containing polysaccharide, other neutral carbohydrate-based polymers have also been reported in the synthesis of CDs. Cyclodextrin is a cyclic glucose polymer that is commonly

Investigation of the action of poly(ADP-ribose)-synthesising enzymes on NAD⁺ analogues

• Sarah Wallrodt,
• Edward L. Simpson and
• Andreas Marx

Beilstein J. Org. Chem. 2017, 13, 495–501, doi:10.3762/bjoc.13.49

• labelling approaches comprising different reporter-modified NAD+ building blocks have stimulated and enriched proteomic studies and imaging applications of ADP-ribosylation processes. Herein, we compare the substrate scope and applicability of different NAD+ analogues for the investigation of the polymer

• allows the selective labelling of poly(ADP-ribose) [17]. As reported, the synthesis of alkyne-modified derivatives 1–4 was previously [16][17][23] accomplished by preparing the respective alkyne-modified nucleosides from common precursors and turning them into their corresponding NAD+ analogues in a two

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• treatment with NaBH4 in 2-propanol by using both basic and nucleophilic properties of the hydride ion. The proposed mechanism involves a double-bond isomerization to the α-aminonitrile intermediate which is then reduced by the hydride ion in a classical way (Scheme 7). Interestingly, deuterium-labelling

• reduction of radical probes (no rearranged products formed from 25d,l,m) and deuterium-labelling experiments (no deuterium incorporation using THF-d8 and quenching with D2O) discard the possibility of a single-electron transfer pathway. Other reductions suggest a hydride addition with formation of an iminyl

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• using sticks and specific helices coloured and labelled; (B) view of the active site of StaF, with residues close to the heme moiety shown as sticks and labelled, with the colour scheme and labelling retained from panel (A); (C) an overlay of the StaF structure (orange) on the Xtei-OxyBtei complex (pale

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• developed a library of cysteine reactive chemical probes with an alkyne handle for fluorescence tagging and report the selective and highly sensitive in vitro labelling of the active site cysteine of this important enzyme. Interestingly, only one type of probe, with a reactive α-chloroacetamide was capable

• of covalently reacting with the active site. We demonstrated the potential of our probes in a competitive labelling platform where we screened a library of synthetic HHQ and PQS analogues with heteroatom replacements and found several inhibitors of probe binding that may represent promising scaffolds

• for the development of customized PqsD inhibitors as well as a chemical toolbox to investigate the activity and active site specificity of the enzyme. Keywords: activity-based probes; PqsD; protein labelling; Pseudomonas aeruginosa; quinolones; Introduction The emergence of multi-drug resistant

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• of enduracididine In 1984, a radio-labelling study was carried out to determine the biosynthesis of enduracididine (1) [48]. Arginine (18) and its precursors ornithine and citrulline, were found to be incorporated into enduracididine (1), but not histidine (19) [48]. Between the enduracidin and

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• in both cases a syn addition, as could be shown by incubation of (2-13C)geranyl diphosphate in deuterium oxide. Keywords: biosynthesis; enzyme mechanisms; isotopic labelling; stereochemistry; terpenes; Introduction Among all classes of natural products the climax of structural diversity and

• either enantiomer of the α-terpinyl cation (6, Scheme 1). Isotopic labelling experiments currently experience a revival [15] and are a very powerful method to follow the enzyme mechanisms of terpene cyclases [16][17][18][19][20][21][22][23][24] including the stereochemical courses of the cyclisation

• labelling experiments that gave insights into the cyclisation mechanism of the bacterial 1,8-cineol synthase. Results The absolute configuration of the intermediate terpinyl cation While the two possible cyclisation pathways via (R)- and (S)-6 to 1 cannot be distinguished with unlabelled GPP, its two

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

• 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

• ligations such as the site-specific labelling/immobilisation of proteins 4. Reported synthetic routes to ACBT 8: A) Original route reported by Takakura et al. [14] and Wang et al. [15]. B) The improved route reported by McCutcheon et al. [7]. Scale-up of ACBT synthesis. DABCO-catalysed cyanation of 6

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• cyclases, purification and full structure elucidation of their products by NMR and determination of optical rotary powers. Furthermore, the enzyme mechanisms of the investigated terpene cyclases were studied by isotopic labelling experiments [34] similar to recently reported investigations on other

• isotopic labelling experiments. The proposed biosynthesis of 7-epi-α-eudesmol (4) starts with a 1,10-cyclisation of FPP to the (E,E)-germacradienyl cation (B) which is attacked by water to form hedycaryol (4a). Its reprotonation at C-1 initiates a second cyclisation to cation C that undergoes deprotonation

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals

• Sonia L. Repetto,
• James F. Costello,
• Craig P. Butts,
• Joseph K. W. Lam and
• Norman M. Ratcliffe

Beilstein J. Org. Chem. 2016, 12, 1467–1475, doi:10.3762/bjoc.12.143

• geminal ethers arranged according to their hydroxonium catalytic coefficients for hydrolysis, providing for the first time a framework for the development of FDII. A combination of 1H NMR, labelling and computational studies was used to assess the effects that may govern the observed relative rates of

• -induced O(1/3)–C(5/4) cleavage pathway for the systems under study here. Though the products of hydrolytic attack at C(2) or C(4/5) are constitutionally indistinguishable, the participation of a C(4/5) pathway brought about through intramolecular strain may be detected using H218O labelling (Scheme 2

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• EIMS fragmentation mechanisms of the two sesquiterpene ethers corvol ethers A and B, and the sesquiterpene alcohols epi-cubebol and isodauc-8-en-11-ol. Keywords: bacteria; isotopic labelling; mass spectrometry; reaction mechanisms; terpenes; Introduction Gas chromatography coupled to electron impact

• , introduction of labelling into the various positions of the compound of interest may require a different synthetic strategy for each individual target isotopomer. Most of these studies made use of deuterium labellings that can frequently be introduced into reactive positions of a (functionalised) terpene

• isolated from the producing organism. Deuterium labellings also allow to follow hydrogen rearrangements, but non-specific hydrogen migrations during the fragmentation process and kinetic isotope effects can make data interpretation difficult. In contrast, the introduction of 13C-labelling into a terpene

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

• and its target dsDNA sequence fragment used in our previous work are shown on Figure 5. In addition to the terminal alkyne group, an amine group was introduced into the α-position of the γ-aminobutyric acid linker (Figure 5B). This provides versatility for labelling of MGBs. For example, the terminal

• alkyne can be used for labelling of MGB with a fluorophore using "click chemistry" and the amino group can be used to conjugate the probe to TFO or to another polyamide [15] and vice versa. Synthesis of modified polyamides, containing an azide or alkyne group The following polyamides (11–14, Figure 6

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• phosphate. This points to an adenylation-type mechanism, and the authors also proposed a hemiorthoamide mechanism to account for the absence of wasted ATP hydrolysis (Figure 3B, pathway a). An alternative mechanism that would also account for the [18O]-labelling results involves direct activation of the

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

• : deuterium labelling; nanomedicine; Raman spectroscopy; Shapiro reaction; squalene; Introduction Application of nanotechnology to medicine holds promises to profoundly impact healthcare especially to treat severe diseases such as cancer, intracellular infections, neurodegenerative diseases, etc. Indeed, the

Natural products in synthesis and biosynthesis II

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 413–414, doi:10.3762/bjoc.12.44

• methods such as isotopic labelling experiments [8] continue to be important. I thank all contributors that participated in this third Thematic Series on natural product chemistry in the Beilstein Journal of Organic Chemistry and also the whole team at the Beilstein-Institut for their professional work. I

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• -assisted click cluster synthesis. An example of the MW-promoted ‘cooperative’ click reaction of azido-CDs has recently been reported and offers useful synthetic insights into a specific labelling strategy [54]. The aforementioned reaction afforded a new series of antimicrobial γ-CD derivatives that

Tandem processes promoted by a hydrogen shift in 6-arylfulvenes bearing acetalic units at ortho position: a combined experimental and computational study

• Mateo Alajarin,
• Marta Marin-Luna,
• Pilar Sanchez-Andrada and
• Angel Vidal

Beilstein J. Org. Chem. 2016, 12, 260–270, doi:10.3762/bjoc.12.28

• are conceivable for explaining these conversions. Deuterium labelling experiments exclude the [1,4]-hydride shift as the first step. A computational study scrutinized the reaction channels of these tandem conversions starting by [1,5]-, [1,7]- and [1,9]-H shifts, revealing that this first step is the

• from those starting by [1,5]-, [1,7]- or [1,9]-H shifts, represented in Scheme 4, by deuterium labelling experiments. Thus, if the conversion of the deuterated acetal-fulvene 14, in which deuterium replaces the proton at the acetalic carbon of 3a, was actually initiated by a [1,4]-deuteride shift, the

• (Scheme 6). 1H NMR analyses showed that only protons, not deuteriums, were linked to the C4 atom of 18 and to C9 of 19. Instead, one deuterium atom is found at the methylene group of each regioisomer. Moreover, we carried out a second labelling experiment by using now as starting material the