The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid

• particular heterocyclic compounds. The synthesis of pyrimidines PM, pyrimidine N-oxides PO, oxazoles OX, 1,2-diketones DK and quinoxalines QU starting from β-ketoenamides KE is the topic of the present review. Review Scope of the LANCA three-component synthesis of β-ketoenamides The scope of the LANCA three

• derivatives. Hence, the scope of available β-ketoenamides KE is broader than the eighty examples presented here. This fact should be kept in mind when the reactions of β-ketoenamides to alternative subsequent products are discussed in the following chapters. Synthesis of pyrimidine derivatives The β

Selective benzylic C–H monooxygenation mediated by iodine oxides

• Kelsey B. LaMartina,
• Haley K. Kuck,
• Linda S. Oglesbee,
• Asma Al-Odaini and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2019, 15, 602–609, doi:10.3762/bjoc.15.55

• . Finally, the oxidation of 5-ethyl-2-(4-propylphenyl)pyrimidine to acetate ester 3l in 76% yield indicates that the developed catalytic system is tolerant of nitrogen-containing heterocycles. This reaction shows remarkable selectivity for the alkyl chain appended to the pyrimidine ring as opposed to the

• propyl group attached to the benzene ring. We propose that the methylene group adjacent to the pyrimidine ring possesses lower bond strength C–H bonds than those adjacent to the benzene ring. This difference in bond strength is illustrated when comparing the benzylic C–H bonds of toluene to that of 2

• -methylpyridine (89.7 versus 87.2 kcal/mol, respectively) [56]. Moreover, the electron withdrawing nature of the pyrimidine nitrogen atoms will affect the pKa of the adjacent secondary benzylic C–H bonds. The hydrogen atom abstraction from this position would then be influenced by the pKa of the C–H bond via a

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

• ; Introduction Purine [1][2][3][4][5][6][7] and 7-deazapurine (IUPAC name: pyrrolo[2,3-d]pyrimidine) [8][9][10][11] derivatives have been progressively studied for decades due to their wide range of biological activities and photophysical properties. Currently, the synthesis of push–pull systems is a promising

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

• 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

• pool; glutamate analogues; Introduction L-Glutamic acid (1, Figure 1) plays an important role in the biosynthesis of purine and pyrimidine nucleobases [1]. It also takes part in metabolic transformation to L-glutamine by L-glutamate synthetase (GS) which is crucial for cell maintenance. In neoplastic

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• -hydroxyquinoline N-oxide, HQNO), which is not active in quorum sensing, but interferes with the respiratory electron transport via inhibition of the cytochrome bc1 complex and moreover inhibits pyrimidine biosynthesis [9][12][13][14]. Therefore, HQNO is toxic to many organisms. In dual-species co-cultures of P

Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis

• Ferran Planas,
• Michael J. McLeish and
• Fahmi Himo

Beilstein J. Org. Chem. 2019, 15, 145–159, doi:10.3762/bjoc.15.15

• between the lowest energy conformer and the typical V-conformation of enzyme-bound ThDP [48] is 4.2 kcal/mol. Interestingly, the lowest energy structure also adopts a V-shape, but one in which thiazolium ring is perpendicular to the pyrimidine ring (see Supporting Information File 1 for an optimized

• with ThDP, all of which are expected to affect the cofactor’s geometry and energy. Of particular interest is the conserved Glu47 residue which forms a hydrogen bond to N1' of the pyrimidine ring. It is important to note that, during the geometry optimizations of the three states YIH+, APH+ and TCH

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

• 3’-adjacent nucleotide are thought to favourably contribute in both F-RNA and F-ANA duplexes [13]. Furthermore, in duplexes of the F-ANA with complementary RNA, internucleosidic C–H···F–C pseudohydrogen bonds are proposed at pyrimidine-purine steps to additionally stabilize the structure [14][15

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

• parameters for TthHPRT with natural substrates were determined. Two nucleotides were synthesized: 9-(β-D-ribofuranosyl)-2-chloroadenine 5'-monophosphate (2-Сl-AMP) using TthAPRT and 1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine-4-one 5'-monophosphate (Allop-MP) using TthНPRT. Keywords: adenine

• presented in the Table 3. As expected, TthHPRT is specific to 6-oxopurines, while TthAPRT is specific to 6-aminopurines. Both enzymes do not recognize thymine as a substrate. This is consistent with data that pyrimidine heterocyclic bases are substrates for uracyl phosphoribosyltransferase and orotate

• use of hypoxanthine and adenine transferases in multi-enzyme cascades significantly extends the spectrum of synthetic purine nucleotides. Two nucleotides were synthesized: 9-(β-D-ribofuranosyl)-2-chloroadenine 5'-monophosphate (2-Сl-AMP) using TthAPRT and 1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine

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

• unit and possibly positively impact the duplex stability. Here we report on the synthesis of the two 6’F-bc4,3 pyrimidine analogs with the base T and C, their incorporation into DNA, their biophysical properties, as well as a structural analysis by molecular dynamics simulations of hybrid DNA and RNA

• 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

• successful synthesis of the two 6’F-bc4,3 pyrimidine phosphoramidite building blocks 10 and 16 starting from a bicyclic silyl enol ether. The key step in the synthesis was the transformation of a gem-difluorinated tricyclic nucleoside into a ring-enlarged bicyclic fluoroenone by simultaneous desilylation and

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• pocket, the phenyl, the pyridine and the pyrimidine rings make critical hydrophobic interactions with residues in the shallow groove of the pocket [87]. Nearly simultaneously, the same group reported the SAR studies of a family of biphenylindole derivatives as inhibitors of the same PPI. A structure

• , respectively). A subsequent antibacterial screening showed that the lead pyrimidine 40 was also a moderate inhibitor of the growth of the Gram-positive pathogen B. subtilis and the Gram-negative microorganism E. coli. The same research group developed further SAR studies using compound 41 (Figure 9) as lead of

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• sulfonyl-pyrimidine class, compound 56 was generated and its ability to reduce pyocyanin evaluated (Figure 23) [84]. While exhibiting IC50 values of 15 µM on PqsR and 21 µM on PqsD, the compound was able to inhibit the pyocyanin production with an IC50 of 86 µM. Moreover 56 also proved to be efficient in

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

• . 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

• )° and 168.6 (2)° (Figure 2). The triple bond shows a coplanar orientation to the pyrimidine ring with an inclination angle of 1.0 (4)°. The torsion angle χ [46] (−103.6° (2)) is high-anti [47]. This conformation results from restriction caused by the cyclic structure. Most nucleosides including dT (χ

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• in the presence of CoCp*(CO)I2 and AgNTf2 (Scheme 38) [98]. The reaction tolerated various pyrimidine containing arenes, such as indole, phenyl, and pyrrole with different ketenimines to form enaminylation products 61. Subsequently, the hydroarylation products 61 were further converted into bioactive

• hydroarylation of glyoxylate with pyrimidine containing indoles and pyrroles 7 to provide products 63 with high productivity (Scheme 40) [79]. Similar to the imine, isocyanate is also an efficient electrophile for hydroarylation of C=N bond. It provides a high atom- and step-economical method for the preparation

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

• 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

• , Minakawa decided to use hypervalent iodine for the glycosylation reaction [59] as in Nishizono’s synthesis of 4’-thionucleosides [45]. First, they optimized the reaction conditions by examining the reaction of 73 with uracil in the presence of hypervalent iodine reagents. None of the desired pyrimidine

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• the cleavage conditions used in the solid phase-supported synthesis of native DNA and also allowed the introduction not only of pyrimidine, but also of purine bases into the oligonucleotide analogue [53]. The method was based on the activation of the 5′-monomethoxytrityl (MMTr)-protected 3'-thiourea

Rhodium-catalyzed C–H functionalization of heteroarenes using indoleBX hypervalent iodine reagents

• Erwann Grenet,
• Ashis Das,
• Paola Caramenti and
• Jérôme Waser

Beilstein J. Org. Chem. 2018, 14, 1208–1214, doi:10.3762/bjoc.14.102

• -methoxypyridine and the electron-poor 5-trifluoromethylpyridine directing groups gave products 7b and 7c in 82% and 72% yield, respectively. When a nitro group was present on the pyridine (5d), the product was not observed, probably due to a weaker coordination of the nitrogen on the pyridine. Pyrimidine could

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

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

• latter reaction rapidly decomposed during work-up in solution. Regioselective and stereoselective glycosidation of adenine, N6-benzoyladenine, N4-benzoylcytosine, thymine and uracil to the corresponding β-N9-purine or β-N1-pyrimidine ribosides was achieved on gram scales under Vorbrüggen-type conditions

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

• give the desired cyclopentane ring (23) [73]. The biological data of these compounds has yet to be reported. Wang et al. synthesized a series of pyridine and pyrimidine C-nucleosides (24–26) that mimic the riboside of favipiravir in their effort to develop novel anti-influenza compounds (Figure 10A

• exhibited potent activity against the H1N1 influenza strain (A/WSN/33) in cell based assays [74]. The pyrimidine compound 26 was synthesized using an identical approach and is not shown here. The activity of 24 and 25 as nucleosides was comparable to favipiravir and its riboside. Furthermore, they found

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

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• the methyl group at the 5-position of the pyrimidine ring, shielded the leaving group-bearing phosphate from incoming water from some angles of attack. For OAt esters of ribonucleotides, we also measured the rates of hydrolysis at 0 °C and −20 °C, and the detailed data can be found in Supplementary

Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs)

• Thanh-Tuân Bui,
• Fabrice Goubard,
• Malika Ibrahim-Ouali,
• Didier Gigmes and
• Frédéric Dumur

Beilstein J. Org. Chem. 2018, 14, 282–308, doi:10.3762/bjoc.14.18

• -TADF white OLEDs with 16% EQE could be fabricated [30]. 4. Triazine–pyrimidine based emitters Among possible electron acceptors, another structure has been extensively regarded as an adequate electron acceptor for the design of blue TADF emitters and this structure is the triazine unit. When combined

• -based devices is among the best so far reported for blue OLEDs. Attesting the interest of the community for this new acceptor, other authors developed quasi-simultaneously a structure–performance relationship with T24, T25 and T27–T28 (see Figure 8) [58]. The choice of pyrimidine as the electron

• acceptor was notably justified by authors due to the easier synthesis of the central core and a versatile peripheral substitution. Additionally, compared to triazine, the LUMO level of pyrimidine is slightly destabilized, facilitating the access to wide bandgap materials. In this work, a more intriguing

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• pyrimidine rich sequences. Therefore, the performance of light-up probes is rather sequence-dependent, although it could be marginally improved by increasing the temperature. Rapid and specific detection of PCR products by light-up PNA probes in a simple mix-and-read fluorescence assay [160] or by real-time

• PCR [161][162] have been demonstrated in the context of pyrimidine rich sequences. A pair of pseudo-complementary PNA probes terminally labeled with TO allowed the detection of specific DNA sequences in long dsDNA and plasmids without requiring prior denaturation [163]. Although non-selective binding