Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• the C-4 position and/or a combination of both as deposed in Table 3 (A and B), with a selection of amine modifications attached. One of these is the cytosine analogue termed G-clamp (modification 23) which increased the Tm of a DNA duplex by 18 °C when incorporated centrally into a decamer ON (Table

• 38 improved the silencing activity of a siRNA when incorporated into the passenger strand (in the eGFP assay mentioned above). However, a decrease in the silencing activity was observed when incorporated into the guide strand [77]. To design a 2’-O-MOE cationic analogue, the 2'-O-(2-(2-(N,N

• the ONs without disturbing duplex formation, Matsuda and co-workers developed some 2’-deoxyuridine analogues carrying aminoalkyl groups at the 1'-position (Table 7B). These were intended to be used as an attachment point, and the 1’-aminobutane variant of the 2’-deoxyuridine analogue (monomer 67) was

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• ] In 1996, the Banks group reported perfluoro[N-fluoro-N-(4-pyridyl)acetamide] (21-3) as a carboxamide analogue of perfluoro[N-fluoro-N-(4-pyridyl)methanesulfonamide] (11-2, see section 1-11) [82]. Its precursor, 21-2, was prepared from pentafluoropyridine by either one of two methods (Scheme 46

• products in very low yields, varying from 27% to 3% depending on the substrate. The fluorinations were accompanied by tar formation and dimerization. Scheme 57 illustrates some representative examples. 1-26. Perfluoro-(N-fluoro-2,2,6,6-tetramethylpiperidine) and its 2,6-dimethyl analogue In 1999, the Banks

• group reported the syntheses of perfluoro-(N-fluoro-2,2,6,6-tetramethylpiperidine) (26-1) and its 2,6-dimethyl analogue 26-2, reagents which do not have α-fluorine atoms adjacent to the N-F site [89] (Scheme 58). These reagents overcame the drawback of perfluoro-N-fluoropiperidine (1-1) which does

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

• anticonvulsant drug used to treat epilepsy and anxiety disorders [39], and an analogue of pregabalin was transformed to azidated derivative 11a. It is noteworthy that positional selectivity was observed for the α-position of the carbamate functional group due to the stabilization of the carbon radical by the

• adjacent carbamate group. The naturally available substrate 9b was shown to undergo the azidation process at the less sterically hindered position. An analogue of rasagiline (Azilect®), a Parkinson’s disease drug, successfully underwent benzylic azidation, providing product 11c. Other complex molecules

• candidates with tailored physical and biological properties [47]. For example, ampicillin, an analogue of benzylpenicillin (penicillin G), also used as an antibiotic, contains an amine group at the benzylic position [48]. Likewise, other commercially available small-molecule drugs, such as Plavix

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• replaced by an achiral and neutral pseudopeptide backbone having the same number of atoms [2][3]. It is remarkable that this simple design resulted in a nucleic acid analogue that had the right degree of flexibility and favorable conformational properties, enforced by the rotational preferences around

• binding is highly sequence specific as one Watson–Crick base pair mismatch can drop the melting temperature of the complex with PNA by 8–20 °C making PNA an excellent nucleic acid analogue for development of probes and diagnostics. This strong and selective binding has made PNA a key component of assays

• , appears to be the most promising conformationally constrained PNA analogue. Vilaivan and co-workers developed pyrrolidinyl PNA based on an α/β-dipeptide backbone that is one atom longer than the canonical PNA and contains two amide bonds and two cyclic moieties in one monomer (Figure 4) [61]. Cyclobutane

Recent advances in the application of isoindigo derivatives in materials chemistry

• Andrei V. Bogdanov and
• Vladimir F. Mironov

Beilstein J. Org. Chem. 2021, 17, 1533–1564, doi:10.3762/bjoc.17.111

• derivatives is based on the Suzuki reaction. At the same time, pyrene-1-ylboronic acid and 6,6'-dibromoisoindigo were used to introduce a pyrene fragment directly into the isoindigo nucleus, and to obtain a thiophene analogue, pyrenyl-substituted 2-bromothiophene and 6,6'-bis(4,4,5,5-tetramethyl-1,3,2

• PCE of the octyl analogue 25b increases to 6.4% [38]. A slight change in the substituent at the nitrogen atom and the introduction of electron-donor methyl or electron-acceptor cyano groups in the thiophene fragment can lead to a sharp deterioration of all characteristics (structure 26: efficiency

• units was obtained [79]. The study showed that the transition from a less fluorinated analogue (two fluorine atoms on dithiophene) to one containing a larger number of fluorine atoms (two fluorine atoms on dithiophene and two in the 7,7' positions) improves the planarity of the structural units of the

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• overall yield for the route increased from 9 to 21%. To demonstrate capability for anomeric linker attachment and conversion to a biologically relevant analogue of mannuronic acid 1-phosphate, 3-aminopropyl glycoside 20 and glycosyl 1-phosphate 21 were synthesised (Scheme 4). The mixture 18/19 was used

Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

• Ivan P. Mosiagin,
• Olesya A. Tomashenko,
• Dar’ya V. Spiridonova,
• Mikhail S. Novikov,
• Sergey P. Tunik and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2021, 17, 1490–1498, doi:10.3762/bjoc.17.105

• bromide 8, functionalized with an alkoxycarbonyl group at the C1 position, was also synthesized by the developed approach, starting from azirine 4b (Scheme 3). Iodo-substituted salt 2 should be more reactive towards cyclization as compared to its bromo-analogue, and this can be used to control the

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• -hydroxy-4-furyl-tetralin 14af into the PAT analogue 22 (see Figure 1) [26]. The reaction of 14af with p-toluenesulfonyl chloride in pyridine afforded the tosylate 21 in 90% yield, which was then treated with 40% aqueous dimethylamine to produce the tertiary amine containing PAT analogue 22 (cis/trans

• in the side chain. The further manipulation of the hydroxy group affording the PAT analogue demonstrated the synthetic potential for accessing medicinally useful derivatives. Parent structure of 2,4-disubstituted tetralins (1) and selected medicinally useful derivatives 2–4. The speculated

• , b. Conversion of 2-hydroxy-4-(2-furyl)tetralin (14af) into PAT analogue 22. Screening of Lewis acid catalysts.a Dependency of cis/trans ratio of product 14af on conditions and time. Supporting Information The Supporting Information contains experimental procedures, characterization data of all

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• mixture of E/Z isomers. Further, double bond cleavage of nucleoside 120 followed by benzoylation produced the benzoic acid ester of the hemiacetal analogue 121 which was finally converted into double-headed nucleoside 122 via Vorbrüggen coupling reaction followed by deprotection using methanolic ammonia

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• -disubstituted glutarates, and the type-IV Guareschi synthesis is used in the preparation of the conformationally constrained γ-aminobutyric acid (GABA) analogue gabapentin (2) [3], a blockbuster drug for the management of neuropathic pain also used for a range of off-label indications that includes hot flashes

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• DAST [22][25][26][30][35], or reaction of C3/C4 methanesulfonate or trifluoromethanesulfonate esters with a source of nucleophilic fluorine, such as TBAF or KF [22][25][34]. Although these fluorinations usually proceeded with inversion of configuration, the acetylated 3-fluoro-GlcNAc analogue was most

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• ). The LAH reduction of oxazolidine 17 gave N-benzyl-N-methyl analogue 18 which, alternatively, was prepared directly from 2-oxazolidinone 9 via N-benzylation followed by LAH reduction in 2 steps. When compound 13 was reacted with phenylisothiocyanate, thiourea 20 was obtained, which underwent a

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• dibenzofurans 4 were also explored for the treatment of various skin diseases [16]. Furthermore, 2-substituted benzofurobenzofurans 5 with antitubercular activity have been reported [17]. Prado et al. reported the antimycobacterial activity of furo[3,2-f]chromene analogue 6 [18]. The aza analogues of

• aza analogue 9 of previously reported furo[3,2-f]chromene 6 was examined for antimycobacterial activity [28]. This evidence encouraged us to investigate new methodologies for the synthesis of aza analogues of dibenzofuran from commercially available aminochloropyridines. Furthermore, a diverse set of

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• through the neighboring ester type protecting group assistance. At lower temperatures the glycosylation yield was lower, although full conversion of glucosyl fluoride β-9 was still observed. Compared to the analogue mannose derivative α-1a, glucose β-9 turned out to be less stable and more prone to

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• this growing universe of modifications, 2'-modifications, such as the original 2'-OMe, 2'-O-(2-methoxyethyl) (MOE [58][59]), and locked nucleic acid (LNA [44][60]) as well as the FRNA analogue [61][62][63] along with the phosphorothioates, will likely remain critical for the development of new

• nucleic acid Glycol nucleic acid (GNA) with its chiral, acyclic three-carbon backbone linked by phosphate is the simplest phosphodiester-based nucleic acid analogue (Figure 1D). It contains one stereocenter allowing for the synthesis of either (S)-GNA or (R)-GNA where chirality is fixed by use of either

• of NaHMDS in order to selectively alkylate the 2'-OH, followed by TBAF treatment to remove the MDPS protecting group. The 2'-O-MOE soon became the gold standard alkyl modification, owing to its improvement in therapeutically relevant properties. Compared to 2'-OMe RNA, the 2'-O-MOE RNA analogue has

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• -aminophosphonodichloride 92 with phenol and methyl (S)-2-hydroxypentanoate (18). All synthetic phosphonodepsipeptides 99, 102, and 104 were considered as glutathione-analogue phosphonopeptides as mechanism-based inhibitors of γ-glutamyl transpeptidase for probing the cysteinyl-glycine binding site (Scheme 16) [31

• the protected phosphonodepsidipeptide 126 (Scheme 21) [12], that was further converted to the designed hapten 127. The new muramyl dipeptide (MDP) phosphorus analogue 131 related to LK 423 as potential immunomodulator was prepared by the coupling of methyl 1-(N-benzyloxycarbonyl)aminoethylphosphonate

• ) [36]. The synthesis of the norleucine-derived phosphonodepsipeptides 135 and 138 was realized by a BOP-activated coupling of N-Cbz-1-aminopentylphosphonic monobenzyl ester (132), a phosphorus analogue of norleucine, with derivatives 133 and 136 of (S)-lactic or glycolic acids followed by

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• auxotrophic E. coli in media with hyperosmotic sodium chloride concentrations [75]. To obtain high in vivo concentrations of the proline analogue, they took advantage of the phenomenon that proline and similar solutes actively accumulate in cells in response to the hyperosmotic shock in bacteria [76]. This

• enabled E. coli to accumulate proline substitutes in hyperosmotic media (e.g., with 0.6 M sodium chloride) and provided a sufficient intracellular concentration of the analogue loaded onto tRNAPro to support protein synthesis. The relevance of this scheme towards the intracellular accumulation of

• once proline is depleted. In general, amino acid analogues are less suitable for natural AARSs than their canonical substrates. Therefore, the intracellular concentration of an analogue should be high enough to promote the misacylation of cognate tRNAPro. Another strategy towards the accumulation of

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• dinucleotide analogue 3j was obtained in 25% isolated yield. We have explored also reactions of 2,6-bistriazolylpurines 2a and 2c with water in buffered and basic medium, respectively (Scheme 5). The buffered conditions (NaOAc/DMSO/H2O) were sufficiently mild to maintain the acetyl protecting groups in product

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• detail by Tidwell et al. [64][65][66] and Richard et al. [67] in solvolysis studies of di(trifluoromethyl)-substituted tosylates 56 in comparison to the monosubstituted analogue 21f (Figure 8). A linear free-energy relationship was found upon plotting the solvolysis rate against YOTs and ρ+ = −10.7 (TFA

• nontrifluoromethylated analogue (δC1 = 206 ppm and δC2 = 251.8 ppm). The authors suggested that “the positive charge is more unevenly localized in the cation” 100, with the resonance form 100’’ contributing significantly more than 100’ (Scheme 28). This unsymmetrical delocalized structure in carbenium compound 100 was

• analogue (dC–O = 1.438 Å) and strongly inhibits the formation of the α-(trifluoromethyl)bisarylcarbenium ion, as illustrated by the higher activation energy needed for the dehydration (ΔECF3 = 21.0 kcal⋅mol−1 vs ΔECH3 = 14.8 kcal⋅mol−1 at the B3LYP/6-31+G(d,p) level). On the other hand, the first arylation

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• ], 4NTC–linker–Fe (12) is almost certainly a better analogue of ferulate linkages found in plant-based structures. Conclusion The use of immobilized Lipozyme® TL IM provides the means to perform the regioselective transesterification of the vinyl ferulate 2 to the primary hydroxy group of benzylic

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• this technique is that the natural amino acid translation process incorporates the specific fluorinated analogue in all the locations where the original amino acid was present, resulting in a “global” labelling of the protein. This can result in a variety of unwanted side effects, including, in some

• -butyloxyproline, with the 4R analogue exhibiting a higher propensity for the polyproline helix structure than the 4S [17]. This differentiated conformational bias observed highlights the potential application of these amino acids as unique probes for molecular recognition studies. The synthesis of unnatural amino

• the γ-butyrobetaine hydroxylase enzyme (hBBOX) (Figure 5a–c). As the fluorine shift of the metabolised product is distinctively different from the shift of the precursor, by producing a novel fluoromethyl analogue of the γ-butyrobetaine substrate (GBBNF) Rydzik et al. were able to monitor carnitine

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• -2-thione species 6a in a high yield (Scheme 1, route 2). The red color of the reaction mixture belonging to the parent o-quinone rapidly turns into a brown color of o-quinone 6a. o-Quinone 6a was isolated as red-brown crystals by cooling the acetone/ether mixture. It is a structural analogue of o

• 6a–d and 7 the dioxolene moiety exhibits structure features which are typical of sterically hindered o-quinones. We conducted some reactions in order to characterize these new species. Recently we reported that 3a, which is the carbonyl analogue of 6a, being treated with more than a triple excess

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• obtained for the 3-(2-(dimethylamino)ethyl)aniline analogue 24j was due to the fact the 2-Cl-Py did not transform to the OAt ether in situ and the subsequent hydrolysis step was very sluggish. We postulate that the presence of the more basic N,N,-dimethylaminoethyl side chain (pKa ≈11) must prevent

Supramolecular polymers with reversed viscosity/temperature profile for application in motor oils

• Jan-Erik Ostwaldt,
• Christoph Hirschhäuser,
• Stefan K. Maier,
• Carsten Schmuck and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2021, 17, 105–114, doi:10.3762/bjoc.17.11

• seen as a neutral analogue of the GCP motif. Due to the missing ionic interactions, the self-association is weaker, but still sufficiently strong, in aprotic solvents such as chloroform (Ka > 106 M−1) [27]. As for the LU, we chose the 1,1’-binaphthyl-2,2’-diamine (BINAM) backbone. The attachment of the