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

• , functionalized phosphoramidite building blocks of all four nucleosides are highly desired. The number of commercially available RNA phosphoramidites that carry a suitable functionality for post-synthetic attachment of dyes, reporter groups or other conjugates is still rather limited. In particular, monomer

• 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

• with the 3’-OH group, due its higher acidity [29]. For modified nucleosides, the preference of 2’-O-TBDMS formation in the presence of AgNO3 may not be given [29], and indeed, as already mentioned above, the C8-linker conjugated nucleoside derivative 7 (Scheme 1) shows the opposite behavior: the 3’-O

Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases

• Julia N. Artsemyeva,
• Ekaterina A. Remeeva,
• Tatiana N. Buravskaya,
• Irina D. Konstantinova,
• Roman S. Esipov,
• Anatoly I. Miroshnikov,
• Natalia M. Litvinko and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2020, 16, 2607–2622, doi:10.3762/bjoc.16.212

• substrates of the phosphorolysis of uridine, thymidine, and 1-(β-ᴅ-arabinofuranosyl)uracil (Ara-U) catalyzed by recombinant E. coli uridine (UP) and thymidine (TP) phosphorylases. α-ᴅ-Pentofuranose-1-phosphates (PF-1Pis) obtained by phosphorolysis were used in the enzymatic synthesis of nucleosides. It was

• PF-1Pis can be used in three routes: (1) preparation of barium salts of PF-1Pis, (2) synthesis of nucleosides by reacting the crude PF-1Pi with an heterocyclic base, and (3) synthesis of nucleosides by reacting the ionically bound PF-1Pi to the resin with an heterocyclic base. These three approaches

• were tested in the synthesis of nelarabine, kinetin riboside, and cladribine with good to excellent yields (52–93%). Keywords: anion exchange resins; N6-benzyladenosine; cladribine; enzymatic glycosylation; kinetin riboside; nelarabine; α-ᴅ-pentofuranose-1-phosphates; phosphorolysis of nucleosides

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

• Patrizia Andreozzi,
• Lorenza Tamberi,
• Elisamaria Tasca,
• Gina Elena Giacomazzo,
• Marta Martinez,
• Mirko Severi,
• Marco Marradi,
• Stefano Cicchi,
• Sergio Moya,
• Giacomo Biagiotti and
• Barbara Richichi

Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

• range of biomolecules: amino acids [8], peptides [9], glycosides [10], nucleosides/nucleotides [11], and lipids [12]. Also, protein-based nano-bio-conjugates [13] have been prepared by ball milling, retaining the native properties of the proteins after mechanochemical synthesis. Boronic acids and their

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• N-heterocyclic compounds such as phenanthridine, carbazole, and dibenzo[b,d]azepine. Simultaneously, Guo’s group published the arylation of nucleosides bearing a purine moiety. The transformation was regioselective and tolerated various substituents at the N9 position of the purine, including sugar

• features when working with biological systems. Thus, a variety of functionalized purines nucleosides that are potentially of great importance in medicinal chemistry were obtained in good yields. In contrast to C(sp2)–H bonds, C(sp3)–H bond activation is much more challenging. Inspired by the potential of

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• of anal gland secretions of the stoat [1] and the ferret [2]. Some pharmaceutical and biological thietane-containing compounds include thiaanalogue thietanose nucleosides 1 and 2 [3][4], and the spiroannulated glyco-thietane nucleoside 3 [5] of the antiviral (anti-HIV and HSV) drug oxetanocin A, the

• 1966 [32]. They treated 3,5-dichloropentan-2-ol (9) with K2S to produce 1-(thietan-2-yl)ethan-1-ol (10) in 65% yield (Scheme 1). In 2007, Nishizono and co-workers used 2,2-bis(bromomethyl)propane-1,3-diol (11) as starting material to prepare thietanose nucleosides 2 and 14. They first carried out a

• double displacement with sodium sulfide to obtain thietane-3,3-diyldimethanol (13), which was further converted into two different thietanose nucleosides 2 and 14 [33] (Scheme 2). In the synthesis of sesquiterpene thioalkaloids, the method also was utilized. A double-aldol condensation of methyl

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• ., glycals, nucleosides and nucleobases) [80]. In 2018, Hu and co-workers reported a complementary approach for the pentafluoroethylation of aryl iodides using TMSCF3 for the formation of CuCF2CF3 [81]. They suggested that in the presence of CuCl, KF and TMSCF3, the corresponding CuCF3 species will be formed

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• previously reported methods required high temperatures [118][119][120]. A library of compounds was reported by that group using this approach, and a plausible mechanism is shown in Figure 13. Arylation of purines: Purine bases and purine nucleosides, which are common structural motifs in DNA and RNA, have an

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

• confirmed that the Nicholas reaction can be carried out in a nucleoside presence, leading to a divergent synthesis of novel metallo-nucleosides enriched with alkene, arene, arylketo, and heterocyclic functions, in the deoxy and ribo series. Keywords: alkynes; 5-alkynyluridines; C–C-bond formation; dicobalt

• 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

• carbon monoxide-releasing properties [27][28] of dicobalt hexacarbonyl alkyne complexes have been noted, and their medicinal potential has been summarized [29][30][31]. Despite developments, the collection of metallo-nucleosides is limited. Hybridization of alkyl and aryl-substituted alkyne cobalt

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• peptidyl nucleosides with primarily antifungal properties. The stereoselective synthesis of (+)-polyoxamic acid ((2S,3S,4S)-144) was successfully carried out starting with Horner–Wadsworth–Emmons olefination of the aziridine aldehyde (2R,1'R)-6 which provided a 98:2 mixture of trans- and cis-acrylates 69b

Robust perfluorophenylboronic acid-catalyzed stereoselective synthesis of 2,3-unsaturated O-, C-, N- and S-linked glycosides

• Madhu Babu Tatina,
• Xia Mengxin,
• Rao Peilin and
• Zaher M. A. Judeh

Beilstein J. Org. Chem. 2019, 15, 1275–1280, doi:10.3762/bjoc.15.125

• molecular recognition, cell–cell interaction, immunological recognition and transmission of biological information [4][5][6]. They are easily transformed into important bioactive compounds such as oligosaccharides, glycopeptides, nucleosides, antibiotics, uronic acids and other natural products [1][2][3

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

• removed with an acid in each synthetic cycle. The exo-amino groups of nucleosides dA, dC and dG are protected with acyl groups, the nascent ODN is anchored to a solid support via a base- or nucleophile-cleavable linker, and in the most widely used phosphoramidite technology the phosphate groups are

Synthesis of acylglycerol derivatives by mechanochemistry

• Karen J. Ardila-Fierro,
• Andrij Pich,
• Marc Spehr,
• José G. Hernández and
• Carsten Bolm

Beilstein J. Org. Chem. 2019, 15, 811–817, doi:10.3762/bjoc.15.78

• Chemosensation, Institute for Biology II, RWTH Aachen University, D-52074 Aachen, Germany 10.3762/bjoc.15.78 Abstract In recent times, many biologically relevant building blocks such as amino acids, peptides, saccharides, nucleotides and nucleosides, etc. have been prepared by mechanochemical synthesis. However

• transformations. Additionally, synthesizing lipid structures mechanochemically would complement the preparation of biologically relevant building blocks (amino acids, peptides, saccharides, nucleosides, etc.) by mechanochemistry, thereby highlighting the importance of mechanical forces in the chemistry of life

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

• place practically instantaneous at room temperature with reagents 1a–d. In order to avoid formation of the vinyl ether analog as a side product, the reaction time should not exceed 5 minutes. The isolated yields of the protected nucleosides are typically between 70–90%. However, reagent 1e forms an

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• reported that 2,6-diazidopurine nucleosides exhibit opposite regioselectivity with aliphatic thiols, which do SNAr reactions at C(2) position of purines [50][51]. Taking this information into account, we performed an SNAr reaction between 2,6-diazidopurine 2a and piperidine and obtained the C(2

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• efficient synthesis of NAD+ in humans. Unlike other nucleosides, ribosylated nicotinamide displays a relatively labile glycosidic bond, which renders its synthesis and its manipulation challenging. Yet, modifications of NR+ through the introduction of appendages and synthesis of structural analogues open

• + chemistry. Finally, Lee et al. [27] studied in detail the regiochemical outcomes of the synthesis of the bromosugars 7a and 7b of the glycosylation of Nam (1a) with these bromosugars as well as the deprotection of the acylated nucleosides 8a,b. It was observed that the bromination of 2a with HBr gas in

• appropriate work-up procedures for NR+/NRH derivatives, as this class of nucleoside greatly differs from the canonical purine and pyrimidine nucleosides. For instance, the glycosyl bond of NR+ was shown to be very susceptible to cleavage in methanolic solutions of ammonia [39]. As such, to get the

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• into 2'-deoxy-L-thymidine and other nucleosides [119]. Syntheses of all four enantiomers of tricholomic acid of interest as a flycidal compound as well as in receptor studies [120] were accomplished starting from enantiomeric 3-hydroxyglutamic acid, e.g., (2S,3R)-3-hydroxyglutamic acid was converted in

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

• conducted. This experiment revealed that the oligonucleotide containing five modified units was able to elicit the RNase H-mediated cleavage of the complementary RNA strand. Keywords: DNA/RNA affinity; fluorinated cyclopropanes; fluorinated nucleic acids; RNase H activity; sugar modified nucleosides

• the presence of persilylated thymine to produce the iodine intermediates 2α/β (Scheme 1, Table 1, entry 1). These instable intermediates were then directly reduced with tributyltin hydride (Bu3SnH) to yield the tricyclic nucleosides 5α/β as main compounds. However, we observed the occurrence of the

• formation of the nucleoside 6 took place, they had to be analyzed separately. Therefore, a sample of the iodinated nucleosides 2α/β was purified and subjected to the reduction reaction, where nucleosides 5α/β were formed as single products (Table 1, entry 2). Also, the conversion of the nucleosides 5α/β

Thermophilic phosphoribosyltransferases Thermus thermophilus HB27 in nucleotide synthesis

• Ilja V. Fateev,
• Ekaterina V. Sinitsina,
• Aiguzel U. Bikanasova,
• Maria A. Kostromina,
• Elena S. Tuzova,
• Larisa V. Esipova,
• Tatiana I. Muravyova,
• Alexei L. Kayushin,
• Irina D. Konstantinova and
• Roman S. Esipov

Beilstein J. Org. Chem. 2018, 14, 3098–3105, doi:10.3762/bjoc.14.289

• the preparation of nucleosides and nucleotides due to the regio- and stereospecificity of enzymes [4][10][11], performing metabolic transformations of substrates. Phosphoribosyltransferases are increasingly being widely used as key enzymes in multi-enzymatic systems [2]. The substrate specificity of

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

• either by a NIS-mediated or Vorbrüggen nucleosidation yielded in both cases the β-tricyclic nucleoside as major anomer. Subsequent desilylation and cyclopropane ring opening of these tricyclic intermediates afforded the unsaturated 6’F-bc4,3 nucleosides. The successful incorporation of the corresponding

• modification might be a substrate for RNase H. Keywords: DNA/RNA affinity; fluorinated cyclopropanes; fluorinated nucleic acids; molecular dynamics simulations; sugar modified nucleosides; Introduction A powerful strategy for the treatment of various disorders like cancer, viral and inherited diseases is the

• were then used to calculate the atomic charges of the corresponding nucleosides using the R.E.D. III.5 tools package [66]. The obtained parameters were added to the Amber94 force field [67] which besides the GROMACS 5.0.6 simulation package [68] was utilized for the molecular dynamics simulations. 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

• and 1H,1H-NMR coupling constants. The sugar conformation (N vs S) was different in solution as compared to the solid state. Keywords: click cyclization; conformation; macrocycles; nucleosides; X-ray; Introduction The field of macrocycles was initiated by the work of Ruzicka and his structure

• . 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

• macrocyclic systems [18][19][20][21][22][23][24][25]. DNA mimics with triazole linkages were constructed [26][27]. The click reaction was used to generate a cyclic ADP-ribose second messenger mimic [28]. Modelling studies using MM+ energy minimization showed that pyrimidine nucleosides are useful synthons for

Practical tetrafluoroethylene fragment installation through a coupling reaction of (1,1,2,2-tetrafluorobut-3-en-1-yl)zinc bromide with various electrophiles

• Ken Tamamoto,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 2375–2383, doi:10.3762/bjoc.14.213

• intriguing biological activities of CF2CF2-containing pyranose and furanose derivatives (Figure 1a) [7][8][9]. Subsequently, Gouverneur et al. also developed novel CF2CF2-containing C-nucleosides (Figure 1b) [10]. Meanwhile, in the field of materials sciences, Kirsch et al. revealed that the incorporation of

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

• , chemical syntheses can technically be divided into two parts; deprotection and coupling reactions, enabling simple repeated procedures for their production, and bioactivities can potentially be tuned by alteration of their sequences. Nowadays, not only canonical amino acids and/or nucleosides but also

• solvents, and washing the precipitates with polar solvents simultaneously rinses away excess amino acids or nucleosides and coupling reagents. We have demonstrated multistep syntheses of up to 28-mers for peptides and 21-mers for oligonucleotides without column purification. In all cases, the C-terminal

• -activated amino acids or 3’-terminal-activated nucleosides are coupled to the N- or 5’-terminus of the supported reactants via amide or phosphodiester linkages (Figure 1). Such couplings could also be possible in the opposite activating manner. Namely, the activation of the N- or 5’-terminus of the

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

• 6-chloropurine with various reducing sugars using methyldiphenylphosphine as activator. Extension to the D-ribo series with 6-chloro- and 2,6-dichloropurines was later reported by Hertel and co-workers [103]. In the course of an exploration of modified L-nucleosides, 6-chloropurin-9-yl derivatives

• 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

• published a direct one-pot synthesis of exclusively β-configured nucleosides from unprotected or 5-O-monoprotected D-ribose using optimized Mitsunobu conditions with various purine- and pyrimidine-based heterocycles. Here, DBU was applied first, followed by DIAD and P(n-Bu)3 [106]. Two years later Seio and

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

• 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

• used for the glycosylation of glycals and thioglycosides to produce disaccharides. In this paper, we review the use of hypervalent iodine-mediated glycosylation reactions for the synthesis of nucleosides and oligosaccharide derivatives. Keywords: glycosylation; hypervalent iodine; Lewis acid

• reaction coupled with oxidation. The concept of the oxidative glycosylation reaction was successfully applied to the synthesis of other nucleoside derivatives, including 4’-selenonucleosides and carbocyclic nucleosides. The hypervalent iodine-mediated glycosylation has also been used for oligosaccharide

Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA

• Timo Weinrich,
• Eva A. Jaumann,
• Ute M. Scheffer,
• Thomas F. Prisner and
• Michael W. Göbel

Beilstein J. Org. Chem. 2018, 14, 1563–1569, doi:10.3762/bjoc.14.133

• , Max-von-Laue-Str. 7, D-60438 Frankfurt am Main, Germany 10.3762/bjoc.14.133 Abstract TEMPO spin labels protected with 2-nitrobenzyloxymethyl groups were attached to the amino residues of three different nucleosides: deoxycytidine, deoxyadenosine, and adenosine. The corresponding phosphoramidites