Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• , Baltimore, MD 21250, United States 10.3762/bjoc.14.65 Abstract C-nucleosides have intrigued biologists and medicinal chemists since their discovery in 1950's. In that regard, C-nucleosides and their synthetic analogues have resulted in promising leads in drug design. Concurrently, advances in chemical

• maneuver stereochemistry as well as to incorporate structural modifications. In this review, we describe recent reports on the modular synthesis of C-nucleosides with a focus on D-ribonolactone and sugar modifications that have resulted in potent lead molecules. Keywords: C-nucleosides; convergent

• modified nucleosides arise from changes in hydrogen bonding motifs, electronic effects, hydrophobic interactions, acid-base properties and chemical reactivity [25][26][27][28][29][30][31][32][33][34][35][36][37]. One such modification is the change in the nature of the glycosidic bond [29][37]. Although

AuBr₃-catalyzed azidation of per-O-acetylated and per-O-benzoylated sugars

• Jayashree Rajput,
• Srinivas Hotha and
• Madhuri Vangala

Beilstein J. Org. Chem. 2018, 14, 682–687, doi:10.3762/bjoc.14.56

• purine and pyrimidine nucleoside synthesis using per-O-acyl/per-O-benzoyl furanosyl and pyranosyl o-hexynylbenzoates [23]. Subsequently, Hotha and co-workers utilized propargyl 1,2-orthoesters and alkynyl glycosyl carbonate donors for the synthesis of pyrimidine nucleosides [24][25]. In addition, N

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

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

• the applied conditions, can be efficiently cleaved, at the same time leaving all other protecting groups intact. Thus, a full set of all 20 trimers was synthesized by phosphotriester chemistry starting with the condensation of N-acyl-3'-O-(o-chlorophenylphosphate)nucleosides to 3'-O-(2

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• sodium-salt method [42]. The deoxyribosylation was then achieved using the same Hoffer’s α-chloro sugar, but in presence of a Lewis acid yielding the protected nucleosides 19a–c [48]. The cleavage of the protection groups was achieved with sodium methoxide to furnish compounds 20a–c. The improved

Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids – tutorial

• Tamara Šmidlehner,
• Ivo Piantanida and
• Gennaro Pescitelli

Beilstein J. Org. Chem. 2018, 14, 84–105, doi:10.3762/bjoc.14.5

• derivatives are optically active. The π→π* transitions of the bases (Scheme 1) contribute to the electronic circular dichroism mostly as a result of the chiral perturbation exerted by the sugar moiety. The ECD signals of single nucleosides/nucleotides are, accordingly, quite small. Coupling into

Acid-catalyzed ring-opening reactions of a cyclopropanated 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with alcohols

• Katrina Tait,
• Alysia Horvath,
• Nicolas Blanchard and
• William Tam

Beilstein J. Org. Chem. 2017, 13, 2888–2894, doi:10.3762/bjoc.13.281

• the synthesis of 2’,3’-methano carbocyclic nucleosides via compound 24 (Scheme 5) [17]. Carbocyclic nucleosides are important synthetic targets because of their use as antiviral and antitumor agents [17]. Replacing the oxygen unit in the parent furanose ring with a methylene unit helps to stabilize

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• hydrolytically less stable than other purine nucleosides. Under basic conditions which are commonly used for RNA deprotection and cleavage from the solid support, opening of the imidazole ring of the 7-methylguanine would occur [111]. Thus, for synthesis of the cap structure on the solid support, standard

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• synthesis of modified nucleosides, in particular 8-CF3-2’-deoxyguanosine and 8-CF3-inosine in 39 and 73% yields, respectively [58]. The same copper-free method was applied for the trifluoromethylation of a variety of electron-deficient 4-substituted acetanilides or anilines (Scheme 36). In these reaction

• out under UV irradiation with either a 300 W xenon lamp (emission wavelengths between 200 and 1000 nm) or the photoreactor (λ = 254 nm). This photochemical process allowed the synthesis of trifluoromethylated arenes (Scheme 51), but also heteroarenes and nucleosides in good yields [74]. Further to

Metal-mediated base pairs in parallel-stranded DNA

• Jens Müller

Beilstein J. Org. Chem. 2017, 13, 2671–2681, doi:10.3762/bjoc.13.265

• ligand-based nucleosides has also been applied to triplexes and quadruplexes [27][28][29][30]. More recently, metal-mediated base pairs have also been investigated in the context of parallel-stranded duplexes. This review presents an overview of metal-mediated base pairs introduced into parallel-stranded

• < 2FurIC (pKa = 8.8, 7.9, and 7.3 for the respective nucleosides), which is identical to the trend in stabilization [72]. For all XIC-derived base pairs, parallel-stranded duplexes were obtained by enforcing reversed Watson–Crick base pairing. 1,N6-Ethenoadenine (εA) is an exocyclic etheno adduct of

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

• chromophores [19][20][21]. This helical twist was evidenced by circular dichroism, in particular a strong bisignate Cotton effect for the DNA-templated pyrene assemblies [19][20]. Figure 1 shows selected examples of pyrene-modified nucleic acids and nucleosides. On the other hand, pyrene–nucleobase conjugates

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• , heterocyclic natural products and nucleosides [29][30][31][32][33][34][35][36]. Therefore, the fluorinated β-amino acid derivative (±)-5, obtained through transformation of (±)-4 with chemodiscrimination of the alcoholic groups, might represent a promising bioactive framework. As the fluorination of the five

Enzymatic separation of epimeric 4-C-hydroxymethylated furanosugars: Synthesis of bicyclic nucleosides

• Neha Rana,
• Manish Kumar,
• Vinod Khatri,
• Jyotirmoy Maity and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2017, 13, 2078–2086, doi:10.3762/bjoc.13.205

• , which is a key precursor for the synthesis of different types of bicyclic/spiro nucleosides, led to the formation of an inseparable 1:1 mixture of the desired product and 4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-xylofuranose. A convenient environment friendly Novozyme®-435 catalyzed selective

• acetylation, has been confirmed by an X-ray study on their corresponding 4-C-p-toluenesulfonyloxymethyl derivatives. Furthermore, the two separated epimers were used for the convergent synthesis of two different types of bicyclic nucleosides, which confirms their synthetic utility. Keywords

• : bicyclonucleosides; biocatalysis; lipase; Novozyme®-435; separation of epimers; Introduction Sugar-modified bicyclic nucleosides have drawn the attention of synthetic chemists because of their effect on the conformational restriction of the furanose moiety of the nucleoside [1][2][3][4][5][6][7][8][9]. The

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

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

• , none of them has really tested at such a scale that the feasibility of their industrial use could be critically judged. Keywords: DNA; oligonucleotides; RNA; soluble support; synthesis; Introduction The synthesis of oligonucleotides (ONs) consists of linking nucleosides to each other in a specified

• the early 1980s, according to which appropriately protected nucleosides could rapidly be coupled as 3´-(O-alkyl-N,N-dialkylphosphoramidite)s to 5´-OH of a support bound nucleoside by using tetrazole as an activator [7]. Since then, this solid-supported phosphoramidite chemistry has almost exclusively

• was removed with 3% TCA in DCM and the derivatized support was isolated by precipitation with Et2O and recrystallization from a 1:9 (v/v) mixture of DCM and Et2O. 5´-O-DMTr-nucleosides (3.0 equiv of dT, dCBz, dGibu, dGDpa, dABz) were then coupled as 3´-(2-chlorophenylphosphate)s in a mixture of

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

• acceptor, with the product of the reaction termed glycoside. Examples of acceptor molecules in nature are other saccharides to form oligosaccharides, nucleobases to form nucleosides, and amino acid side chains to form glycoproteins. The donor is the electrophile in the reaction and, therefore, when

• nucleosides have been developed. We highlight some classical enzymatic and synthetic strategies below before discussing chemical strategies that have been developed or rediscovered chiefly since the beginning of this century. Special emphasis is drawn to the mechanisms by which the glycosylations take place

• the synthesis of oligosaccharides, glycoproteins, and nucleosides, both, natural and synthetic. The advantages of utilizing this approach are obvious as the reactions take place using unprotected saccharide donors and acceptor molecules. However, these methods are not without substantial challenges. A

First total synthesis of kipukasin A

• Chuang Li,
• Haixin Ding,
• Zhizhong Ruan,
• Yirong Zhou and
• Qiang Xiao

Beilstein J. Org. Chem. 2017, 13, 855–862, doi:10.3762/bjoc.13.86

• ; Introduction Endogenous nucleosides are involved in DNA and RNA synthesis, cell signalling, enzyme regulation and metabolism etc. [1][2]. Therefore, the synthesis of novel nucleosides to mimic their physiological counterparts has potential therapeutic significance, which has led to the development of a large

• number of antiviral and antitumor drugs [3][4]. On the other hand, naturally occurring nucleosides, especially marine nucleosides, have also played an indispensable role in drug discovery, which make great contribution in the commercialization of cytosine arabinoside (Ara-C), adenine arabinoside (Ara-A

• ) and AZT, etc. [5][6]. Nucleosides and their analogues will continue to play an important role in future drug discovery [7]. In the past decades, exploration of novel naturally occurring marine nucleosides has made expeditious achievements [8][9][10]. Some of them showed promising antibiotic, antiviral

Synthesis of ribavirin 2’-Me-C-nucleoside analogues

• Fanny Cosson,
• Aline Faroux,
• Jean-Pierre Baltaze,
• Jonathan Farjon,
• Régis Guillot,
• Jacques Uziel and
• Nadège Lubin-Germain

Beilstein J. Org. Chem. 2017, 13, 755–761, doi:10.3762/bjoc.13.74

• carbon atom in the 2’-position are an indium-mediated alkynylation and a 1,3-dipolar cyclization. Keywords: alkynylation; antiviral; cancer; C-nucleosides; ribavirin; Introduction The triazole nucleoside ribavirin (RBV, Figure 1) is used for the treatment of a number of viral infections and may be

• the combination, due to its particular role. Recently, we developed an alkynyl glycosylation protocol allowing us to obtain C-nucleoside derivatives and we turned our attention to ribavirin C-nucleoside analogues. Moreover, recently De Clerq [13] outlined the potential of C-nucleosides in the arsenal

• the Huisgen cycloaddition reaction onto the C-alkynyl riboside intermediately obtained [14]. Herein we describe the synthesis of two new carbonated analogues 2 and 3 of RBV modified at the 2’-position (Figure 1). In fact, a quaternization in 2’-position of various nucleosides led to a higher efficacy

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

• 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

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

• Bemba Sidi Mohamed,
• Christian Périgaud and
• Christophe Mathé

Beilstein J. Org. Chem. 2017, 13, 251–256, doi:10.3762/bjoc.13.28

• -Boc-adenine or 2-amino-6-chloropurine in the presence of diisopropyl azodicarboxylate (DIAD) and PPh3, provided the N9 carbocyclic nucleosides (+/−)-8 and (+/−)-9 as racemic mixtures. No concomitant formation of the N7 regioisomer was observed. The removal of Boc and acetyl groups from (+/−)-8

A postsynthetically 2’-“clickable” uridine with arabino configuration and its application for fluorescent labeling and imaging of DNA

• Heidi-Kristin Walter,
• Bettina Olshausen,
• Ute Schepers and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2017, 13, 127–137, doi:10.3762/bjoc.13.16

• the energy transfer between them [31]. Among the tested combinations, there are some remarkable examples in this array in which mixed energy transfer duplexes, meaning the combination of donor dyes linked to arabino-configured nucleosides (DNA2a) with acceptor dyes attached to ribo-configured

• nucleosides (DNA3r) and vice versa (DNA2r with DNA3a) yield significantly enhanced emission color contrasts. As a representative example, the fluorescence color readout for the combinations of D1 with D5 (Figure 1) ranges from green (DNA2aD1–DNA3rD5) to orange/red (DNA2rD1–DNA3aD5). Especially, the

• λexc = 488 nm (argon ion laser), λem = 490–550 nm (green) and 675–800 nm (red), scale bar = 20 µm. 2’-Propargylated nucleosides as “clickable” DNA/RNA building blocks with ribo (1) and arabino (2) configuration. Synthesis of phosphoramidite 7 and modified DNA. a) TIPDSiCl2, pyridine, 2 h at 0 °C, 16 h

Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

• Olga Eguaogie,
• Patrick F. Conlon,
• Francesco Ravalico,
• Jamie S. T. Sweet,
• Thomas B. Elder,
• Louis P. Conway,
• Marc E. Lennon,
• David R. W. Hodgson and
• Joseph S. Vyle

Beilstein J. Org. Chem. 2017, 13, 87–92, doi:10.3762/bjoc.13.11

• ′-tosylates in five to 60 minutes. Under these conditions, commonly-encountered nucleoside cyclisation byproducts (especially of purine nucleosides) were not observed. Liquid-assisted grinding of the same 5'-iodide and 5′-tosylate substrates with potassium selenocyanate in the presence of DMF produced the

• from nucleosides by 4-methoxybenzylthiolate using vibration ball milling (VBM) where competing intramolecular cyclisation reactions are completely avoided. We further demonstrate the application of liquid-assisted grinding to related displacements using potassium selenocyanate. Results and Discussion

• were avoided by pre-milling the substrate with MobSH prior to addition of the base (during the initial milling, no chemical reaction was observed). In addition, the work-up developed for MobSdA (2a) had to be modified in response to the aqueous solubility of nucleosides containing lactam groups which

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

• Vladimir A. Stepchenko,
• Anatoly I. Miroshnikov,
• Frank Seela and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2016, 12, 2588–2601, doi:10.3762/bjoc.12.254

• ; recombinant E. coli uridine, thymidine and purine nucleoside phosphorylases; substrate properties; 4(2)-thioxo- and 6(5)-aza-uacil and -thymine; Introduction Nucleosides of 4- and 2-thioxopyrimidines and 6-azapyrimidines attract much attention from the time of pioneering works in the early 1950s on the

• chemical synthesis and investigation of their physicochemical and biological properties (early works are reviewed in [1][2]). Studies on thioxo- and azapyrimidine nucleosides are an inspiring subject of investigation due to their very special biochemical [3][4][5][6][7] and biophysical properties in

• comparison with the natural pyrimidine nucleosides in order to understand the impact of such modifications as monomers or constituents of oligonucleotides [8][9][10][11][12][13][14]. Thioxopyrimidine nucleosides as such, as well as building blocks of artificial oligonucleotides demonstrate promising

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

• ; carbohydrate; peptidyl nucleosides; Introduction Peptidyl nucleoside antibiotics are a class of complex molecules that encompass an extensive array of natural products [1]. The notable structural features of peptidyl nucleosides are responsible for their miscellaneous biological activities such as antitumor

• , antiviral, antibacterial and antifungal [2]. Peptidyl nucleosides in which the sugar part is in the furanose form are common, however, the sugar framework in the pyranose form, with a nucleobase and a peptide linker at either ends, are rare in nature. A few examples of this category are amipurimycin and

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• (Table 6). These γ-lactone acids are valuable substrates for the synthesis of compounds with potentially useful pharmacological properties, such as homocitrates, alkyl- and aryl-substituted nucleosides [270][271][272]. The reaction starts with an asymmetric epoxidation of the substituted cyclopentane-1,2

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• their corresponding nucleosides [2][3]. Recent studies on patients affected by haematological malignancies, such as acute myeloid leukaemia (AML) and myelodysplasic syndrome (MS), have demonstrated the involvement of cN-II in the resistance to cytotoxic drugs such as mercaptopurines and suggested the

• of a research program on phosphonate derivatives of nucleosides as mimics of 5’-monophosphate nucleosides, we explored the SAR of various beta-hydroxyphosphonate analogues. Such derivatives have been extensively studied and exhibited Ki values in the same range as the known natural substrates (IMP

• compound high flexibility. Initially reported by K. Seley-Radtke’s group, the replacement of the nucleobase by a “flexi-moiety” where the imidazole ring and a six-membered heterocycle is linked through a C–C bond lead to new derivatives behaving as nucleosides and even as enzyme inhibitors [11][12][13