Additive-controlled chemoselective inter-/intramolecular hydroamination via electrochemical PCET process

• Kazuhiro Okamoto,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2024, 20, 264–271, doi:10.3762/bjoc.20.27

• this case, intramolecular radical trapping by the uracil nucleobase was preferred, leading to the formation of the cyclized alkyl radical D. Continuous radical recombination furnished dimer 4. Conclusion We observed additive-controlled inter- and intramolecular chemoselectivity in the hydroamination of

Phenanthridine–pyrene conjugates as fluorescent probes for DNA/RNA and an inactive mutant of dipeptidyl peptidase enzyme

• Josipa Matić,
• Tana Tandarić,
• Marijana Radić Stojković,
• Filip Šupljika,
• Zrinka Karačić,
• Ana Tomašić Paić,
• Lucija Horvat,
• Robert Vianello and
• Lidija-Marija Tumir

Beilstein J. Org. Chem. 2023, 19, 550–565, doi:10.3762/bjoc.19.40

• formed an exciplex [15], and conjugates formed of pyrene and an amino acid-fluorescent nucleobase derivative qAN1, differing in length and flexibility between fluorophores [16]. Due to pre-organization, both conjugates strongly interacted with ds-DNA/RNA grooves with similar affinity but opposite

• investigate whether intrinsic dynamical features of studied conjugates both affect and can explain their tendency to undergo mutual association and form stacking interactions. The mentioned approach recently turned out as very useful in interpreting the affinities of several nucleobase – guanidiniocarbonyl

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• can be embedded in complex biosynthetic networks such as in vitro S-adenosylmethionine (SAM)- or carbon dioxide fixation cycles, and de novo nucleobase synthesis [38][39][40][41]. For the biocatalytic synthesis of ATP or derivatives, up to three consecutive phosphorylation reactions are coupled in a

• starting material, and factors such as the necessity to purify the end product. Also, especially PPK2s are described to be very flexible regarding the nucleobase, which is not the case for all other kinases [10][17][61]; depending on the system this might compensate for the not ideal conversion rates

Ferrocenoyl-adenines: substituent effects on regioselective acylation

• Mateja Toma,
• Gabrijel Zubčić,
• Jasmina Lapić,
• Senka Djaković,
• Davor Šakić and
• Valerije Vrček

Beilstein J. Org. Chem. 2022, 18, 1270–1277, doi:10.3762/bjoc.18.133

• ferrocene–nucleobase conjugates [4], which are known to exhibit anticancer [5][6][7], antibacterial [8][9][10], or antitrypanosomal activity [11], but also may serve as electrochemical biosensors [12][13], self-assembled molecular materials [14][15], decorations of carbon tubes and nanomaterials [16][17

• organometallic (metallocene) and heterocyclic (purine) parts. Specifically, adenine and its N6-derivatives, most of which are pharmaceutically attractive and/or biologically relevant [20][21][22], have been selected to study the mechanism underlying the synthesis of the ferrocene–nucleobase conjugates. Several

• procedures for preparing N-ferocenoylated pyrimidines were tested earlier [19][23], and the reaction of nucleobase with (chlorocarbonyl)ferrocene (or ferrocenoyl chloride, FcCOCl) under basic conditions appeared as a simple and optimal method for the synthesis [24]. Herewith, we demonstrate that substituents

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

• Sandeep Kumar,
• Jyotirmoy Maity,
• Banty Kumar,
• Sumit Kumar and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2022, 18, 95–101, doi:10.3762/bjoc.18.10

• ′ proton resonating at δ 4.15 with the C6 proton of the nucleobase resonating at δ 7.67 (see Supporting Information File 1). Based on this analysis of the spatial arrangement of the groups attached at the C5′ chiral centre, the stereochemistry of this carbon centre was assigned to be (R) for both of these

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• . The chemical approaches that were broadly used in the past to access these compounds are separated into two main groups: i) those that modify intact nucleosides by modifying the sugar, nucleobase, or both and ii) those that modify the sugar and introduce a nucleobase to a suitable position of the

• in the presence of levamisole, which gave an improved overall yield of 52 of up to 67%. In this approach, the required stereochemistry of the thioacetal compound was created, so that the coupling with a nucleobase in a further step determines the stereochemistry of the attaching nucleobase at the

• -glycosidic bonds depends on the relative orientation of the anomeric carbon atom and the stereocenter furthest from position C-1 in the sugar. For example, when the nucleobase at C-1 is oriented cis to the hydroxymethyl group of the sugar at C-4, it is a β-glycosidic bond, whereas if it is orientated trans

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• in the biosynthetic pathway of the hypermodified tRNA nucleoside queuosine (Q) (Scheme 1) [5]. The core structure of the nucleobase is 7-aminomethyl-7-deazaguanine, a pyrrolo[2,3-d]pyrimidine also termed prequeuosine base (preQ1) [6][7]. In many bacteria, preQ1 binds to specific mRNA domains and

• nucleobase derivatives [26] required for advanced NMR spectroscopic applications [27], and for the syntheses of azido- or amino-functionalized preQ1 derivatives needed for cellular applications with engineered riboswitches [28]. Finally, we point out that only a single synthetic route has been published to a

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

• strategy that has been employed to optimize the delivery profile of ASOs, is the functionalization of ASOs with cationic amine groups, either by direct conjugation onto the sugar, nucleobase or internucleotide linkage. The introduction of these positively charged groups has improved properties like

• been separated into three sections, nucleobase, sugar and backbone modifications, highlighting what impact the cationic amine groups have on the ONs/ASOs physiochemical and biological properties. Finally, a concluding section has been added, summarizing the important knowledge from the three chapters

• , and examining the future design for ASOs. Keywords: antisense oligonucleotides; backbone modifications; cations; nucleobase modifications; sugar modifications; Introduction Antisense oligonucleotides (ASOs) are single-stranded (ss) oligomers composed of typically 10–25 nucleotides linked by

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

• Rozners and co-workers showed that PNAs as short as hexamers formed strong and sequence specific triplexes at pH 5.5 [27]. Later studies using nucleobase-modified PNA (vide infra) confirmed that PNA had >10-fold higher affinity for dsRNA than for the same sequence of dsDNA [28][29][30][31]. While parallel

• nucleobase stacking pattern similar to that of the A-form RNA [43]. Another crystal structure of a partially self-complementary PNA–PNA duplex revealed PNA’s ability to combine the P-form Watson–Crick duplex with higher order structural features, such as reversed Hoogsteen base pairing, interstrand

• nucleobase with a tertiary amine also destabilized PNA complexes with complementary DNA [49]. The majority of the following studies focused on adding substituents to the original backbone for conformational control and improving PNA’s biophysical properties. Conformationally constrained backbones Nielsen and

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

• of deoxyribonucleic acids (DNA) or ribonucleic acids (RNA), which contain either a purine or pyrimidine nucleobase and a furanosyl moiety of pentose sugars, 2′-deoxyribose or ribose [1][2]. Nucleotides are constituted by addition of a phosphate group at the 5′-position of the nucleosides and these

• monomeric units polymerize to construct nucleic acids (DNA or RNA). These macromolecules preserve and express genetic information in all living cells and viruses. Modified nucleosides are a class of organic compounds which are unnatural and have an altered/substituted nucleobase and/or a modified pentose

• sugar [3][4]. The synthetic accessibility of these organic molecules encouraged researchers to prepare sugar-modified nucleosides [5][6] and nucleobase-modified nucleosides [7][8]. Modified nucleoside monomers comprising more than one nucleobase are called double-headed nucleosides [9][10]. A thorough

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

• necessary protecting groups are present on the nucleobase and sugar moieties [76][77]. Unlike the phosphodiester linkage of natural DNA, the AM1 modification is an example of a non-ionic backbone. The crystal structure of a 13-mer RNA duplex with a single central AM1 modification revealed that this

• target effects [54]. Sugar and nucleobase modifications 2'-O-Alkyl modifications Historically, the 2'-OMe modification (Figure 5A) was the first of its class. The synthesis of each 2'-OMe ribonucleoside required specific considerations [108]. Starting from 3',5'-O-(tetraisopropyldisiloxane-1,3-diyl

• -TIPDS-N4-benzoyl-2'-O-methylcytidine. Next, 3',5'-O-TIPDS-N6-benzoyladenosine suffered from methylation at the nucleobase and thus, 6-chloro-9-β-ᴅ-ribofuranosylpurine was instead used as the starting material. Once TIPDS protected, the 2'-OH could, once again, be selectively methylated with methyl

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• the factors that determines the thermodynamic stability of nucleic acid secondary structures. Neutral or positively charged oligonucleotide analogues should bind more tightly with complementary DNA or RNA. Several studies have focused on the introduction of positively charged groups to a nucleobase

Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

• Naohiro Horie,
• Takao Yamaguchi,
• Shinji Kumagai and
• Satoshi Obika

Beilstein J. Org. Chem. 2021, 17, 622–629, doi:10.3762/bjoc.17.54

• the stability against nucleases, binding affinity to the targets, and efficacy. We previously reported that oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing the thymine (T) nucleobase show excellent biophysical properties for applications in antisense

• , which is a common approach to partially neutralize the polyanionic property of oligonucleotides [15][16][17][18]. In our previous study, a guanidine-bridged nucleic acid (GuNA[H]; Figure 1) bearing a thymine (T) nucleobase was synthesized as a novel artificial nucleic acid for antisense applications [19

• immunologically unfavorable cytosine (C), is needed. The preparation of all four phosphoramidites (A, G, mC, and T) is generally not easy because each nucleobase differs in the sensitivity to reactions, and appropriate protecting groups need to be selected [8][21][22][23]. We recently achieved the synthesis of

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• building blocks of the purine nucleosides with functionalities suitable for post-synthetic conjugation at the nucleobase are basically missing, and also in the pyrimidine series, the few existing derivatives of uridine do not offer much variety. Motivated by this lack of functional building blocks, we have

• of the linker L at C8 in derivative 7 changes the J1’-2’ coupling constant only slightly (4.8 Hz J1’-2’), however, brings in a strong steric effect and most likely induces a preferential syn-conformation of the nucleobase relative to the sugar residue. These effects together can be accounted for the

• the iodination of a purine nucleobase, which is achieved under harsher conditions. Thus, the 3′,5′-O-di-tert-butylsilyl protecting group was introduced, followed by reaction of the 2’-OH group with TBDMS chloride to generate intermediate 10 (Scheme 2). Subsequently, the iodination was carried out

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• – binding to several different DNA or RNA structures but for each of them giving a different spectrophotometric response [17][18][19][20][21][22]. Until now we have studied aryl systems which behaved as ds-DNA/RNA intercalators, DNA/RNA groove binders, or nucleobase derivatives. In this work we focused our

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

• Annike Weißenstein,
• Myroslav O. Vysotsky,
• Ivo Piantanida and
• Frank Würthner

Beilstein J. Org. Chem. 2020, 16, 2032–2045, doi:10.3762/bjoc.16.170

• stronger quenching for GC-DNA and the weaker for AT(U)-polynucleotides (Figure 5a and b). Because guanine is the most electron-rich nucleobase, this behaviour points at a fluorescence quenching mechanism by charge transfer from the electron-rich purine bases to the electron-poor NDI molecular probes

• commonly attributed to nucleobase pairs. However, since it is not likely that the chirality of the double helix will strongly increase upon binding of a small molecule, the most prominent changes at 300 nm and above are most likely attributable to ICD bands of the NDI core bound to the polynucleotide in a

Extension of the 5-alkynyluridine side chain via C–C-bond formation in modified organometallic nucleosides using the Nicholas reaction

• Renata Kaczmarek,
• Dariusz Korczyński,
• James R. Green and
• Roman Dembinski

Beilstein J. Org. Chem. 2020, 16, 1–8, doi:10.3762/bjoc.16.1

• hexacarbonyl complexes; Nicholas reaction; nucleosides; propargyl cation; Introduction Nucleoside analogs are molecules of high pharmacological interest for the treatment of various conditions, especially cancer and viral diseases [1][2][3][4][5]. The substitution at C-5 of the uracil nucleobase provides a

• common framework for materials with potent biological properties [6][7][8][9][10]. Modification on this site of the nucleobase usually does not interfere with Watson–Crick base pairing. For example, C-5-modified pyrimidines are well tolerated by commercial polymerases [11][12]. Alkynyl modifications not

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• [35][36][37][38]. In the literature, there are also examples using post-synthesis modifications to introduce sensitive groups to ODNs [12]. However, these methods are case-specific, and their procedures are usually complicated. The ODN synthesis method without nucleobase protection could be considered

• using large excess is not ideal for a technology aimed to be practically and universally useful. In this paper, we report the use of dimethyl-Dmoc (dM-Dmoc), which we previously studied for alkyl- and arylamine protections [44], in place of Dmoc for nucleobase protection for ODN synthesis (Scheme 1

• , which was phosphitylated to give 3b. The dG phosphoramidite monomer 3c had to be synthesized using a slightly different procedure (Scheme 2). The amide function in the nucleobase in the silyl protected nucleoside 19 [45] was temporarily protected with TBSCl to give 20 [49]. This intermediate was not

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting

• , constituting an attractive alternative to current literature methods for accessing 6. To explore the utility of iodide 14 in the synthesis of novel antivirals, we examined its reactivity towards other 6-substituted purine nucleobase analogues (Scheme 6). Alkylation of both 6-chloropurine (22) and N6

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• ’-fluorinated hexitol nucleic acids FHNA and Ara-FHNA (Figure 1) with the fluorine in axial or equatorial orientation, respectively. Both modifications preferentially adopt a chair conformation with the nucleobase in axial orientation which mimics the C3’-endo conformation of the furanose ring. Thermal

• mechanism came from the outcome of the reaction where a tricyclic sugar was first treated with NIS and then with Bu3SnH resulting as expected in a gem-difluorinated bicyclic sugar (Scheme S1, Supporting Information File 1). This reaction also ruled out the involvement of the nucleobase or the iodine at the

• pseudorotation phase angle P adopting values of 175° (6a) and 181° (6b), respectively. The maximum puckering amplitude νmax was 43° (6a) and 40° (6b). Furthermore, the nucleobase displayed an anti orientation. The carbocyclic ring adopted a chair conformation. As a consequence, the angle γ was aligned in the

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• spectra (Supporting Information File 1). The plan for the pyrimidine nucleoside synthesis comprised the use of the meanwhile well-established β-selective N-iodosuccinimide (NIS)-mediated addition of a persilylated nucleobase to a tricyclic glycal [43][45][53][54]. Therefore, the gem-difluorinated

• the nucleobase was conducted by 1H,1H-ROESY experiments (Supporting Information File 1). The β-anomer 7β then was subjected to Luche reduction [55][56] producing selectively the desired S-configuration at the C(5’) position due to hydride delivery from the less hindered exo-side of the carbonyl group

• of the nucleobase was partially removed. As a consequence an additional benzoylation step was needed to obtain the allylic alcohol 14 in high yields. Verification of the configuration at C(5’) was again accomplished by 1H,1H-ROESY experiments (Supporting Information File 1). Tritylation of the

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• functionalized at the 5-position of the nucleobase with octadiynyl side chains and with azido groups at the 5’-position of the sugar moieties were synthesized. The macrocycles display freely accessible Watson–Crick recognition sites. The conformation of the 16-membered macrocycle was deduced from X-ray analysis

• . Monomeric purine and pyrimidine nucleosides form smaller ring systems known as cyclonucleosides incorporating O, N or S-bridges within the sugar moiety or between the nucleobase and the sugar residue [6]. Macrocycles can be obtained by a variety of chemical reactions [7][8][9][10]. Often, several protection

• derivative 4 the dU macrocycle 8 could be isolated in 46% yield even in the absence of TBTA. However, the yield of cyclization was significantly improved when TBTA was added (69%). This demonstrates the influence of the nucleobase on the intramolecular cyclization reaction. All compounds were characterized

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• were obtained in moderate yields [104]. Aiming at an improved procedure to synthesize nucleosides with glycosylation of the nucleobase, De Napoli et al. used the Bu3P-ADDP system to connect inosine and uridine derivatives with D-ribofurano and D-glucopyrano moieties [105]. Hocek’s group in 2015

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• , Tokushima, 770-8505, Japan 10.3762/bjoc.14.137 Abstract To synthesize nucleoside and oligosaccharide derivatives, we often use a glycosylation reaction to form a glycoside bond. Coupling reactions between a nucleobase and a sugar donor in the former case, and the reaction between an acceptor and a sugar

• well. The extension of hypervalent iodine-mediated glycosylation allowed us to couple a nucleobase with cyclic allylsilanes and glycal derivatives to yield carbocyclic nucleosides and 2’,3’-unsaturated nucleosides, respectively. In addition, the combination of hypervalent iodine and Lewis acid could be

• glycoside bond. In the case of nucleoside synthesis, a coupling reaction between a persilylated nucleobase and a sugar donor is typically used [15][16][17]. On the other hand, the reaction between an acceptor and sugar donor is carried out in the presence of an appropriate activator for oligosaccharide

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• Reactions of nucleoside sugar and nucleobase moieties An early example of the application of mechanochemistry for nucleoside derivatisation was reported by Khalafi-Nezhad and Mokhtari who effected regioselective 5′-protection of ribonucleosides and thymidine using a mortar and pestle with trityl

• and carboxylic acid Boc protection using an improvised attritor-type mill. Nucleobase Boc protection via transient silylation using an improvised attritor-type mill. Chemoselective N-acylation of an aminonucleoside using LAG in a MBM. Azide–alkyne cycloaddition reactions performed in a copper vessel

• in a MBM. Thiolate displacement reactions of nucleoside derivatives in a MBM. Selenocyanate displacement reactions of nucleoside derivatives in a MBM. Nucleobase glycosidation reactions and subsequent deacetylation performed in a MBM. Regioselective phosphorylation of nicotinamide riboside in a MBM