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

• out for the synthesis of stereochemically pure PS-ONs and one of these methods employs the proline-derived bicyclic oxazaphospholidine monomer [122] which was later used in the scalable synthetic process of therapeutic stereopure PS-ASOs [123]. When the modified ONs were hybridized with their

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

• enabled formation of relatively stable triplexes at physiological pH of 7.4. Later, the same research group reported that 1,8-naphthyridin-2,7-(1,8H)-dione (K, Figure 6), a bicyclic mimic of protonated cytosine, afforded stronger binding to G–C base pairs compared to J, most likely due to the increased

• surface area of the bicyclic nucleobases that enabled better π-stacking [97]. Despite the superior binding properties, the original report on K has not been followed up with more detailed studies and J remains the current gold standard for triple-helical recognition of G–C base pairs in PNA. However, more

• , most likely because of enhanced stacking of the bicyclic π-system [104][105]. However, beyond the original studies, 7-Cl-bT has not been further explored for either duplex or triplex stabilization. Similar to L, substitution of thymine with 2-thiouracil (s2U) or 5-halouracils (e.g., BrU, Figure 6

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• diastereoselectivity in the synthesis of bicyclic compounds (dr > 20:1, Scheme 19, 37d, 37e, and 37g). Substrates containing Lewis base moieties (Scheme 19, 36k) were tolerated in the reported reaction conditions, thereby representing a synthetic gain over other olefin isomerization methodologies. An important feature

Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones

• Chandrakanta Parida and
• Subhas Chandra Pan

Beilstein J. Org. Chem. 2021, 17, 1447–1452, doi:10.3762/bjoc.17.100

• contemporarily [19][20][21]. In recent years 4-arylidenepyrrolidine-2,3-diones have been explored mainly for the preparation of bicyclic dihydropyran derivatives through the catalytic inverse-electron-demand hetero-Diels–Alder reaction [22][23][24]. We postulated that 4-arylidenepyrrolidine-2,3-diones could also

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

• methodologies and the biological applications of double-headed nucleosides. Keywords: acyclic double-headed nucleosides; bicyclic double-headed nucleosides; furanosyl double-headed nucleosides; modified nucleosides; pyranosyl double-headed nucleosides; Introduction Nucleosides are the constructional subunits

• ][31][65]. Bicyclic double-headed nucleosides In this section we have included the double-headed nucleoside monomers, which have a locked nucleic acid type conformation and the additional nucleobase is attached at one of the carbon or nitrogen atoms constituting the bridge (Figure 1). All examples

• discussed herewith are constituted by furanosyl carbohydrate moiety. Nielsen and co-workers [67] synthesized the bicyclic double-headed nucleoside (1R,4R/S,5R,6R,8S)-8-hydroxy-1-hydroxymethyl-4,6-di(uracil-1-yl)-3,7-dioxabicyclo[3.2.1]octane (122), where the additional nucleobase is attached at the bridge

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

• Alexei N. Izmest’ev,
• Dmitry B. Vinogradov,
• Natalya G. Kolotyrkina,
• Angelina N. Kravchenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2021, 17, 1141–1148, doi:10.3762/bjoc.17.87

• (Table 1, entries 9–14). The corresponding isomeric imidazo[4,5-e]thiazolo[2,3-c]triazines 5 were formed in trace amounts and were detected only in the 1H NMR spectra of the evaporated reaction mixtures. The reactions of bicyclic structures 3a–g with dimethyl acetylenedicarboxylate proceeded with similar

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• -fused bicyclic transition state model was proposed to rationalize the stereochemical outcome, in which the sodium metal is chelated by the oxygen and the nitrogen atoms of sulfinyl imine (Scheme 17), occurring the nucleophilic attack to the Si face of the imines with RS configuration. Su and Xu reported

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• formation of the expected N-benzylaminodiol either at room temperature or under reflux conditions, probably due to the strong steric hindrance of the bicyclic system and the hydroxymethyl group. The 1H NMR spectroscopic measurements in CDCl3 clearly showed that the crude product was a five-component

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• °C to afford corresponding fluorinated bicyclic compound 284 [108]. A catalytic amount of TMSCl generates TMS-protected alcohol 279 and HCl. The activated aldehyde 280 reacts with 279 to form the intermediate 281. Then, the TMS group in 281 is attacked by F− in the presence of HCl to give the

• . Formation of the oxocarbenium ion 289, followed by an intramolecular nucleophilic attack by the alkynyl bond on the cyclopropane unit gave cyclic oxocarbenium intermediate 290. Further, the attack of a halide anion (from TiX4) leads to the Prins cyclization to give bishalogenated bicyclic THP with all-cis

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

• synthesis of LNA involves the tosylation of a 4'-C-hydroxymethyl derivative, followed by a base-induced ring closure to afford the 2'-O,4'-C-linked bicyclic nucleoside derivative (Scheme 6) [127][128]. Incorporation of LNA into a variety of oligonucleotides with varying lengths and sequences has shown

• [148], and in the use of antisense oligonucleotides for splice modulation through the induction of Dmd exon-23 skipping in mice in vitro [149]. Recently, a lot of attention has been paid to modifying the LNA scaffold to incorporate various heteroatoms, modify the bicyclic framework, and to change the

• and 2',4'-diF-rC nucleosides (Figure 9C) [206]. Through NMR, these nucleosides were found to be essentially locked in the northern (C3'-endo) sugar pucker, albeit without the need for the bicyclic structures typical for locked nucleic acids [206]. The 2',4'-diF-rU nucleoside was introduced into an RNA

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• the high nucleophilicity of the amino group in the substrate 23 to control the regioselectivity of the reaction (Scheme 9). 3 Indoles Indoles have a bicyclic structure consisting of a six-membered benzene ring fused with a five-membered nitrogen-containing pyrrole ring. Figure 3 depicts some of the

• opening resulting in imine intermediate E. A consecutive intramolecular cyclization and tautomerization yields azepino[5,4,3-cd]indoles 143b. 9 Quinolines Quinolines are bicyclic aromatic heterocycles consisting of a fused pyridine and benzene ring. Quinoline and its derivatives are important both from

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• -lactamase inhibitors. As part of our efforts, we have synthesized a series of DBO derivatives A1–23 containing amidine substituents at the C2 position of the bicyclic ring. These compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• the convex face of the bicyclic system. Amide 9p with an enantiomerically enriched cyclohex-2-enyl substituent cyclized with exclusive diastereoselectivity and only two diastereomers 12pA differing in the orientation of the hydroxy group were obtained in high yield. The radical coupling with TEMPO

• also occurred exclusively at the convex face of the bicyclic system. The configurations of the fused lactams were assigned by chemical derivatization and NOE experiments (vide infra). Functionalization reactions of lactams 12 Base-mediated isomerization reactions Lactams 12 are mixtures of two, four

• bicyclic annulated racemic compound 12o reduced the number of diastereomers as expected to two, 13oA and 13oB, in a 4:1 ratio. The relative configurations of the major and the minor diastereomers were determined by NOE experiments (see Supporting Information File 1). Further functionalization of lactams 12

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• of 1,1-dichloro-1-alkenones. The reaction scope was found to be broad, with various chain lengths and aryl substituents tolerated. For substrates containing an electron-rich aromatic ring, further reactions take place, resulting in bicyclic and/or rearrangement products. Keywords: aluminium

• ) equivalents of AlCl3, a further two products were obtained, whose structures were elucidated as the 8,9-dihydrobenzo[7]annulen-9-ones 9 and 10 (Scheme 4). Presumably, these bicyclic compounds arise via an intramolecular Friedel–Crafts alkylation of 6b, promoted by the ortho/para-directing nature of the

• rise to [6,7]bicyclic ketones 9, and 10 and the linear acid chloride 13, respectively. We have also found that when the ketone is not present, the trifluoroalkyl substrate is converted into bicyclic vinyl chloride 17 when treated with AlCl3. We hope that this short communication will inspire other

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• operations overall from methyl N-Boc-prolinate. The key step proceeds in each case via N,O-diacylation, then selective oxidative hydrolysis of the intermediate bicyclic pyrrole and establishes a precedent for the synthesis of related C(7a)-hydroxylated pyrrolizidines. Keywords: acyloxypyrroles; bacterial

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• fluorinated bicyclic compounds has attracted much attention [40][41][42][43][44][45][46][47]. In this regard, the development of new protocols to relevant monofluorinated bicyclic molecules involving novel versatile fluorine-containing building blocks is of key importance. Fluoroalkenes are recognized to be

• to a new synthetic approach to novel monofluorinated bicyclic compounds, namely norbornenes and bicyclo[2.2.2]oct-2-enes and their subsequent functionalization. The present study is our follow-up work on the Diels–Alder reaction involving β-fluoro-β-nitrostyrenes [57]. A recent review reported that

• straightforward way to numerous fluorine-containing bicyclic compounds not previously available. The syn-dihydroxylation of compound 2f with the N-methylmorpholine-N-oxide (NMO)–OsO4 system resulted in a mixture of the corresponding diols 5 in a 36:64 ratio in 65% yield. Again, exo-dihydroxylation is to be

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• stability of different redox states both in non-coordinated form and as being a ligand. It is important that these bicyclic dioxolene species exhibit the typical properties of sterically hindered o-quinones, such as redox transformations between o-qiunone, semiquinone and catecholate forms as well as

• was discussed previously [29]. The reaction of 4 with malononitrile-derived gem-dithiolate (5b, Scheme 1, route 2) also proceeded under mild conditions in DMF and bicyclic o-quinone 6b was obtained in a good yield. The brown crystals suitable for X-ray analysis were grown from an acetone/diethyl ether

• of this species is the subject of further investigations. The bicyclic fragment in 7 is essentially flat (Figure S5 in Supporting Information File 1). The steric interactions between the tert-butyl groups and atoms of the fused heterocycle are weaker for the four-membered thiete ring than in the case

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• ), isolated from the Colorado blue spruce Picea pungens, are members of this alkaloid family. Their unique bicyclic system with a quaternary stereocenter, and the potent biological activity exerted by these homotropane alkaloids, make them attractive synthetic targets. This work aims briefly to review the

• as an early warning signal to the attacker. The fluid toxicity and bitterness, added to the characteristic odor of these insects, have been regarded as a protection against insect or vertebrate predators [3]. Bicyclic ring systems bearing a nitrogen bridge are often found in nature [4][5][6]. Typical

• have provided new opportunities to develop synthetic strategies [21][22][23]. Structurally, it has an unsymmetrical bicyclic arrangement, incorporating a secondary amine and bearing a quaternary center. Since the pioneering Tursch’s work [24], a variety of approaches to obtain these alkaloids have been

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• being higher in energy than TS6. As mentioned before, after the slow cyclization step in TS3, we focused our analysis on the transformation of the bicyclic intermediate IV to the final diene product. Basically, the final steps have to include a deprotonation, protodeauration, and in some cases acetate

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• ] and [3.4.0] bicyclic systems bearing two quaternary atoms at the bridgehead position [49]. For instance, enynol 110 was treated with 5 mol % of [RhCl(CO)2]2 and carbon monoxide to afford a [3.3.0] bicycle 111 in 87% yield (Scheme 8A). The proposed catalytic cycle of this elegant rhodium-catalyzed

• [52][53] with the allenyl rhodium to the enal and gives the allenyl rhodium species C. A Conia-ene-type reaction [54] between the Rhoda-enolate species and the allene of complex C produces the desired [3.3.0] bicycle D. Protonolysis [55][56][57] of complex D with the alcohol 110 gives bicyclic product

• to give the desired bicyclic [3.3.0] aldehyde 124 in 88% yield. A seven-step synthesis from aldehyde 124 gave azide 125. It was converted to alcohol 126 in seven steps. Alcohol 126 was treated with LDA and vinylMgBr to facilitate a γ-OH directed 1,4-addition [63] to give C-7-vinylated tricycle 127 in

Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: application of ¹J_C,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites

• Md. Rokon Ul Karim,
• Enjuro Harunari,
• Amit Raj Sharma,
• Naoya Oku,
• Kazuaki Akasaka,
• Daisuke Urabe,
• Mada Triandala Sibero and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 2719–2727, doi:10.3762/bjoc.16.222

• actinomycete origin. For example, salinosporamide A, an antitumor drug candidate in clinical trials, is a proteasome inhibitor with an unusual γ-lactam-β-lactone bicyclic core produced by marine Salinospora tropica [10]. Abyssomicin, another example of uncommon polycyclic frameworks, is an antibacterial

Selective and reversible 1,3-dipolar cycloaddition of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones under microwave irradiation

• Alexander P. Molchanov,
• Mariia M. Efremova,
• Mariya A. Kryukova and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2020, 16, 2679–2686, doi:10.3762/bjoc.16.218

• ]. A wide range of pharmaceuticals, agrochemicals, and other biologically active compounds are prepared using different types of (3 + n) cycloadditions, mainly with alkenes and alkynes [3][4][5][6][7]. For example, N,N'-cyclic azomethine imines are precursors of biologically active bicyclic

• the hexahydropyrazolo[1,2-a]pyrazole ring, respectively, apparently through zwitterionic intermediates [28][29]. At the same time, the cycloaddition of azomethine imine to 1,3-diphenylprop-2-en-1-ones (chalcones) in IL proceeds stereo- and regioselectively giving two diastereomeric bicyclic anti

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• (rac)-11b was unequivocally established by single-crystal X-ray diffraction (Figure 1). Then, the preparation of another model compound, the trans-annelated bicyclic carbamide derivative (rac)-13, was attempted. This compound was also unknown in the literature. In the reaction of commercially available

• mind, further plans concerning compound (rac)-13 were abandoned. We continued our studies with strained, rigid bicyclic systems. First, the N-Boc-protected Vince lactam (rac)-14 was subjected to halofluorination reactions. Despite the asymmetric nature of the olefin, the compounds (rac)-15a and (rac

• both NOESY measurements and single-crystal X-ray diffraction (Figure 2 and Figure 3). The next rigid bicyclic system studied was the methyl diendo norbornene dicarboxylate 16. The treatment of 16 with NBS/Deoxo-Fluor® yielded the bromolactone (rac)-17a [37]. The reaction, when repeated only with NBS

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• to allenes 80 to give complex bicyclic products 81 in moderate yields and good enantioselectivities (20 examples, up to 92:8 er) (Scheme 9b) [47]. The Bach group recently developed an enantioselective synthesis of cyclobutane 82 from enal 83 and diene 84 (Scheme 11a) [48]. Most of the examples