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

• data indicate that GuNA[Me] could be a useful modification for therapeutic antisense oligonucleotides. Keywords: artificial nucleic acid; duplex-forming ability; oligonucleotide synthesis; Introduction The efficacy and safety of therapeutic oligonucleotides can be controlled by chemical modifications

• the middle position of 12-mer oligonucleotides (Table 1). The oligonucleotide synthesis was performed using an automated DNA synthesizer following the established synthetic method for GuNA[Me]-T-modified oligonucleotides [20]. 5-(Ethylthio)-1H-tetrazole (ETT) was used as an activator for the coupling

• oligonucleotides. By protecting the guanidine moieties with an acetyl group, we could obtain the oligonucleotides within a 12–25% yield range under the basic conditions (ammonia/methylamine solution) commonly used in oligonucleotide synthesis. The synthesized GuNA[Me]-modified oligonucleotides showed a high

Tuning the stability of alkoxyisopropyl protection groups

• Zehong Liang,
• Henna Koivikko,
• Mikko Oivanen and
• Petri Heinonen

Beilstein J. Org. Chem. 2019, 15, 746–751, doi:10.3762/bjoc.15.70

• only the 2-methoxypropan-2-yl protecting group (MIP) has been adopted in use [2] and the alternative, 2-benzyloxypropan-2-yl, introduced by Mukaiyama in the 1980’s [6] has not gained popularity. The MIP group has been used, e.g., in solution-phase oligonucleotide synthesis for the primary 5’-hydroxy

• . The vinyl ether hydrolysis has earlier shown to be even a subject of general acid catalysis [13][14]. It is useful to compare the stabilities of the acetal protections to those of the 4,4’-dimethoxytrityl protecting group used in oligonucleotide synthesis. Directly comparable data are hard to find

• conditions typically applied in oligonucleotide synthesis, i.e., 3% dichloroacetic acid in acetonitrile or in methanol. In most cass the reactions were complete after a couple of minutes. With the trifluoroethyl acetal derivative 4e the reaction was slow enough that the half-life could be measured, and it

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• bioactivities and/or functions, which has been one of the central topics in the field of chemical biology [16][17][18][19][20][21][22][23][24][25][26]. Since peptide synthesis and oligonucleotide synthesis require different chemistries, such conjugations are typically carried out in the latter stages of the

• supported reactants would be unique alternatives that allow the use of unactivated amino acids or nucleosides. In peptide synthesis, activation of the N-terminus is rather rare, except for some recent encouraging examples [62][63][64][65][66][67][68]; however, this is not the case for oligonucleotide

• synthesis [69][70][71][72][73]. The activation of the 5’-primary alcohol is expected to be even more effective than that of the 3’-secondary alcohols (Figure 2), and the 5’-primary alcohol could then be coupled not only to other nucleosides but also various alcohols via a naturally occurring phosphodiester

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• internucleotide phosphates intact [27]. With both procedures (3'-O-(2-azidomethylbenzoyl) and 3'-O-TBDMS protection), 20 trinucleotides of high purity were prepared and upon phosphitylation used as synthons in oligonucleotide synthesis [27][29]. In general, the reported syntheses of trinucleotides in solution

• the β-cyanoethyl groups at the internucleotide phosphate linkages [27]. For the use in standard oligonucleotide synthesis, trinucleotide phosphoramidites have been dissolved in a mixture of acetonitrile and dichloromethane to a concentration of 0.1–0.15 M. The coupling yields are typically between 70

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• , although it inevitably leads to depurination as a side reaction, in particular on using acyl protections for the amino functions. May be a proper solution to this old problem would open doors for success of oligonucleotide synthesis on a soluble support. Abbreviations General principle of oligonucleotide

• synthesis. Alternative coupling methods used in the synthesis of oligonucleotides. Synthesis of ODNs on a precipitative PEG-support by phosphotriester chemistry using MSNT/NMI activation [37]. Synthesis of ODNs on a precipitative tetrapodal support by phosphotriester chemistry using 1-hydroxybenzotriazole

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

DNA functionalization by dynamic chemistry

• Zeynep Kanlidere,
• Oleg Jochim,
• Marta Cal and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2016, 12, 2136–2144, doi:10.3762/bjoc.12.203

• compound 9 containing two hydroxy groups and the cyanoethyl protected thiol group was converted into the phosphoramidite being compatible with conditions of solid-phase oligonucleotide synthesis. The DMTr protecting group was incorporated and the conversion of the secondary alcohol 10 to phosphoramidite 11

• was performed. The base-labile cyanoethyl group [51][52] is known to be resistant under synthesis conditions for the preparation of the phosphoramidite building block and for solid-phase oligonucleotide synthesis [49][53]. Building blocks compatibility with solid-phase synthesis of DNA single strands

• Phosphoramidites 4 and 11 were introduced at position seven of 13mer oligonucleotides ON1 and ON2 applying automated solid-phase synthesis (Table 1 and Supporting Information File 1, Table S1). The last step in the oligonucleotide synthesis involved the deprotection of the amine group using ammonium hydroxide at

TEMPO-derived spin labels linked to the nucleobases adenine and cytosine for probing local structural perturbations in DNA by EPR spectroscopy

• Dnyaneshwar B. Gophane and
• Snorri Th. Sigurdsson

Beilstein J. Org. Chem. 2015, 11, 219–227, doi:10.3762/bjoc.11.24

• . 50% reduction of the nitroxide during oligonucleotide synthesis, which utilized dichloroacetic acid for the removal of the trityl groups. However, in spite of low yields, the spin-labeled oligonucleotides were readily separated from those containing the reduced spin label by denaturing polyacrylamide

Versatile synthesis of amino acid functionalized nucleosides via a domino carboxamidation reaction

• Vicky Gheerardijn,
• Jos Van den Begin and
• Annemieke Madder

Beilstein J. Org. Chem. 2014, 10, 2566–2572, doi:10.3762/bjoc.10.268

• unprotected histidine methyl ester, we decided to protect the imidazole functionality immediately after the reaction with the tert-butyloxycarbonyl (t-Boc) protecting group [53], which is compatible with the reagents used during nucleoside- and oligonucleotide synthesis [45][54]. While the t-Boc group can be

• removed with a 10% TFA solution [54], the acid labile DNA can suffer from depurination after treatment with acid. According to literature, the t-Boc group can also be cleaved during standard deprotection procedures with saturated ammonia after oligonucleotide synthesis [41][55]. In view of all these

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

• systems; solid-phase DNA synthesis; synthetic biology; Introduction It has been nearly 50 years since the first solid-phase synthesis of DNA by Letsinger and Mahadevan [1][2]. This work laid the platform for new strategies in oligonucleotide synthesis, culminating in the development of phosphoramidite

Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support

• Alejandro Gimenez Molina,
• Amit M. Jabgunde,
• Pasi Virta and
• Harri Lönnberg

Beilstein J. Org. Chem. 2014, 10, 2279–2285, doi:10.3762/bjoc.10.237

• this was then used for the 3'-O-acylation of 4a in pyridine in the presence of 4-dimethylaminopyridine. Experimental details for the preparation of all the building blocks and NMR and MS data for their characterization are given in Supporting Information File 1. Oligonucleotide synthesis Previously

• a linear gradient from MeCN 25% at t = 0 min to MeCN 100% at t = 25min (for the HPLC traces, see Supporting Information File 1). Oligonucleotide synthesis. Support 8b (0.151 g; 0.056 mmol) and 6 equiv of the phosphoramidite building block 5a' (200 mg; 0.35 mmol; 1.5 equiv per branch) were dissolved

Second generation silver(I)-mediated imidazole base pairs

• Susanne Hensel,
• Nicole Megger,
• Kristina Schweizer and
• Jens Müller

Beilstein J. Org. Chem. 2014, 10, 2139–2144, doi:10.3762/bjoc.10.221

• the two hydroxy functions with the dimethoxytrityl and the 2-cyanoethyl-N,N-diisopropylphosphoramidite moieties, finally resulting in the formation of 4a/4b suitable for automated solid-phase oligonucleotide synthesis. The pKa values of the free nucleosides 2a/2b were determined by pD-dependent 1H NMR

Structure/affinity studies in the bicyclo-DNA series: Synthesis and properties of oligonucleotides containing bc^en-T and iso-tricyclo-T nucleosides

• Branislav Dugovic,
• Michael Wagner and
• Christian J. Leumann

Beilstein J. Org. Chem. 2014, 10, 1840–1847, doi:10.3762/bjoc.10.194

• arrangement of γ and a somewhat attenuated but clear preference for an S-type furanose conformation. Oligonucleotide synthesis The dodecamers ON1–4, shown in Table 2, containing one to two modifications, were synthesized in order to test the consequences of the two modified bicyclic nucleotides on RNA and DNA

• . Using the standard phosphoramidite protocol, the oligonucleotide synthesis failed completely at the site of modification and not even traces of a full length oligonucleotide could be observed after chain assembly and deprotection. Only 5’-phosphorylated, truncated oligonucleotide fragments could be

• for oligonucleotide synthesis [36]. Under these conditions, full length oligonucleotide ON4 could be isolated in 80% as determined by trityl assay. Due to limited availability of the phosphoramidite building block 10, only this particular oligonucleotide could be obtained in sufficient quantities for

Influence of perylenediimide–pyrene supramolecular interactions on the stability of DNA-based hybrids: Importance of electrostatic complementarity

• Christian B. Winiger,
• Simon M. Langenegger,
• Oleg Khorev and
• Robert Häner

Beilstein J. Org. Chem. 2014, 10, 1589–1595, doi:10.3762/bjoc.10.164

• total of four PDIs (blue) and/or pyrenes (green). Oligomers 1–7 consisting of varying numbers of pyrene or PDI moieties covalently linked to complementary DNA strands were prepared by automated oligonucleotide synthesis using the previously described phosphoramidite pyrene [53] and PDI [55] building

A new building block for DNA network formation by self-assembly and polymerase chain reaction

• Holger Bußkamp,
• Sascha Keller,
• Marta Robotta,
• Malte Drescher and
• Andreas Marx

Beilstein J. Org. Chem. 2014, 10, 1037–1046, doi:10.3762/bjoc.10.104

• 4 [42] yielding 5 in acceptable yields (Scheme 1). Finally, compound 5 was transformed into 6 by phosphitylation resulting in a building block that bears protection groups and reactive groups that are standard in solid phase DNA oligonucleotide synthesis. Synthesis of branched oligonucleotides. DNA

• oligonucleotide synthesis was performed at 0.2 µmol scale (trityl-on mode) employing the standard phosphoramidites and 6 which was diluted in a mixture containing 10% CH2Cl2 in CH3CN to a final concentration of 0.12 M. 3000 Å LCAA-CPG support was used, derivatized with the respective 3'-nucleotide of the

• data for all new compounds, materials and general procedures are given. Oligonucleotide synthesis and characterization of oligonucleotides, original melting curves of oligonucleotides and CD spectra of double stranded Y-motif are also shown. Further AFM studies, DLS spectra and EPR related experiments

Synthesis of nucleotide–amino acid conjugates designed for photo-CIDNP experiments by a phosphotriester approach

• Tatyana V. Abramova,
• Olga B. Morozova,
• Vladimir N. Silnikov and
• Alexandra V. Yurkovskaya

Beilstein J. Org. Chem. 2013, 9, 2898–2909, doi:10.3762/bjoc.9.326

• phosphotriester block liquid phase synthesis. The phosphotriester approach to the oligonucleotide synthesis was shown to be a versatile and economic strategy for preparing the required amount of high quality samples of nucleotide–amino acid conjugates. Keywords: CIDNP; nucleotide–amino acid conjugates

• ; oligonucleotide synthesis; phosphotriester approach; Introduction Maintaining the integrity of the genome is of paramount biological importance, since the damage of DNA is considered to cause aging and various degenerative diseases. To prevent the pathological DNA damage, cells evolve the DNA repair machinery

• derivative [27], we used the LPS strategy in combination with the phosphotriester approach for the oligonucleotide synthesis to obtain target conjugates 1–8. The phosphoramidite condensation in LPS usually leads to the lower yields in these reactions due to insufficient stability of active phosphoramidites

Camera-enabled techniques for organic synthesis

• Steven V. Ley,
• Richard J. Ingham,
• Matthew O’Brien and
• Duncan L. Browne

Beilstein J. Org. Chem. 2013, 9, 1051–1072, doi:10.3762/bjoc.9.118

• plurality of chemical reactions in an array format (Figure 17). This system is specifically targeted at oligonucleotide synthesis where multiple reactions may frequently be performed in parallel, and so this invention included the development of optical analysis software to process the vast amount of data

Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

• Lucie Brulikova and
• Jan Hlavac

Beilstein J. Org. Chem. 2011, 7, 678–698, doi:10.3762/bjoc.7.80

• interaction between the above noted proteins and modified oligonucleotides, in which thymidine is replaced by a 5-formyl derivative. A phosphoramidite 145 for oligonucleotide synthesis was prepared from O2-2'-cyclouridine (135) by a multistep synthesis (Scheme 24). In a first step, O2-2'-cyclouridine (135