CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• detail by Tidwell et al. [64][65][66] and Richard et al. [67] in solvolysis studies of di(trifluoromethyl)-substituted tosylates 56 in comparison to the monosubstituted analogue 21f (Figure 8). A linear free-energy relationship was found upon plotting the solvolysis rate against YOTs and ρ+ = −10.7 (TFA

• nontrifluoromethylated analogue (δC1 = 206 ppm and δC2 = 251.8 ppm). The authors suggested that “the positive charge is more unevenly localized in the cation” 100, with the resonance form 100’’ contributing significantly more than 100’ (Scheme 28). This unsymmetrical delocalized structure in carbenium compound 100 was

• analogue (dC–O = 1.438 Å) and strongly inhibits the formation of the α-(trifluoromethyl)bisarylcarbenium ion, as illustrated by the higher activation energy needed for the dehydration (ΔECF3 = 21.0 kcal⋅mol−1 vs ΔECH3 = 14.8 kcal⋅mol−1 at the B3LYP/6-31+G(d,p) level). On the other hand, the first arylation

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• ], 4NTC–linker–Fe (12) is almost certainly a better analogue of ferulate linkages found in plant-based structures. Conclusion The use of immobilized Lipozyme® TL IM provides the means to perform the regioselective transesterification of the vinyl ferulate 2 to the primary hydroxy group of benzylic

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• this technique is that the natural amino acid translation process incorporates the specific fluorinated analogue in all the locations where the original amino acid was present, resulting in a “global” labelling of the protein. This can result in a variety of unwanted side effects, including, in some

• -butyloxyproline, with the 4R analogue exhibiting a higher propensity for the polyproline helix structure than the 4S [17]. This differentiated conformational bias observed highlights the potential application of these amino acids as unique probes for molecular recognition studies. The synthesis of unnatural amino

• the γ-butyrobetaine hydroxylase enzyme (hBBOX) (Figure 5a–c). As the fluorine shift of the metabolised product is distinctively different from the shift of the precursor, by producing a novel fluoromethyl analogue of the γ-butyrobetaine substrate (GBBNF) Rydzik et al. were able to monitor carnitine

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

• -2-thione species 6a in a high yield (Scheme 1, route 2). The red color of the reaction mixture belonging to the parent o-quinone rapidly turns into a brown color of o-quinone 6a. o-Quinone 6a was isolated as red-brown crystals by cooling the acetone/ether mixture. It is a structural analogue of o

• 6a–d and 7 the dioxolene moiety exhibits structure features which are typical of sterically hindered o-quinones. We conducted some reactions in order to characterize these new species. Recently we reported that 3a, which is the carbonyl analogue of 6a, being treated with more than a triple excess

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• obtained for the 3-(2-(dimethylamino)ethyl)aniline analogue 24j was due to the fact the 2-Cl-Py did not transform to the OAt ether in situ and the subsequent hydrolysis step was very sluggish. We postulate that the presence of the more basic N,N,-dimethylaminoethyl side chain (pKa ≈11) must prevent

Supramolecular polymers with reversed viscosity/temperature profile for application in motor oils

• Jan-Erik Ostwaldt,
• Christoph Hirschhäuser,
• Stefan K. Maier,
• Carsten Schmuck and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2021, 17, 105–114, doi:10.3762/bjoc.17.11

• seen as a neutral analogue of the GCP motif. Due to the missing ionic interactions, the self-association is weaker, but still sufficiently strong, in aprotic solvents such as chloroform (Ka > 106 M−1) [27]. As for the LU, we chose the 1,1’-binaphthyl-2,2’-diamine (BINAM) backbone. The attachment of the

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• biosynthesis [1][4], in vitro antimicrobial activity [4][5], and anticancer activity against human prostate cancer cell lines [6][7]. A recent study suggested that the close analogue (+)-11 of inthomycin C was found to exhibit proteasome inhibition activity [8]. The skeletal structures of inthomycins A–C (1–3

• inthomycins [36]. These triene moieties are a sub-unit of the oxazolomycin class of antibiotics. To prepare the phenyl analogue of racemic inthomycin C (rac-3), at first, the phosphonate 28 was prepared using a Claisen condensation of ethyl propionate (25) followed by methylation of 26a, treatment with

• biological outcomes is of strategic importance and being continued for further discovery. The inthomycins A–C (1–3) and structurally closely related compounds. Syntheses of inthomycins A–C (1–3). The first total synthesis of racemic inthomycin A (rac)-1 by Whiting. Moloney’s synthesis of the phenyl analogue

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

• and the 2-substitued analogue VII and found a significant difference between the two (Figure 4). Indeed, the total allyl charge on the 3-substituted intermediate III results to be almost neutral or even slightly negative (−0.056 e), confirming that the lone pair of the nitrogen atom can stabilize the

• positive charge of the allyl system by conjugation, affecting the following cyclization reaction. Meanwhile, the 2-substitued analogue VII does not present a conjugated system, and the total allyl charge cannot be stabilized, maintaining a positive value (+0.115). As a result, VII seems to be much more

• VIII compared to the analogue IV (−16.7 vs −0.9 kcal⋅mol−1). The π-donating ability of the nitrogen atom might have a clear stabilizing effect in VIII, while the nitrogen and the cationic allyl system are disconnected in IV. This effect is reflected in the corresponding transition states, with TS3

Controlled decomposition of SF₆ by electrochemical reduction

• Sébastien Bouvet,
• Bruce Pégot,
• Stéphane Sengmany,
• Erwan Le Gall,
• Eric Léonel,
• Anne-Marie Goncalves and
• Emmanuel Magnier

Beilstein J. Org. Chem. 2020, 16, 2948–2953, doi:10.3762/bjoc.16.244

• counter electrode. Electrochemical measurements were covered by a wide range of a potentiostat for more effective current detection. A potentiostat–galvanostat such as Princeton Applied Research Model 263 was monitored by its front panel and analogue-to-digital conversion was provided by «Powerlab». A

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

• Danny Lainé,
• Vincent Denavit,
• Olivier Lessard,
• Laurie Carrier,
• Charles-Émile Fecteau,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2020, 16, 2880–2887, doi:10.3762/bjoc.16.237

• at C4 could contribute to a new fluorine effect in nucleophilic substitution. Finally, with the continuous objective of synthesizing novel multi-vicinal fluorosugars, we prepared one difluorinated and one trifluorinated alditol analogue. Keywords: deoxyfluorination; Et3N·3HF; fluorine effect

• (retention of configuration) with a 39% yield along with glucose 11 (inversion of configuration) in 31% yield (Table 1, entry 2) [20][30]. Moreover, the use of the talose analogue 4 generated exclusively the product with retention of configuration 12. This result was surprising since the only difference with

• 3 is the stereochemistry of the fluorine atom at C2. Finally, only decomposition originated from the use of mannose analogue 5 as substrate. The difference in terms of reactivity between 5 and 2 was unexpected since they only differ from the stereochemistry of the fluorine atom at C2 (distal to the

Synthesis of purines and adenines containing the hexafluoroisopropyl group

• Viacheslav Petrov,
• Rebecca J. Dooley,
• Alexander A. Marchione,
• Elizabeth L. Diaz,
• Brittany S. Clem and
• William Marshall

Beilstein J. Org. Chem. 2020, 16, 2739–2748, doi:10.3762/bjoc.16.224

• caffeine analogue, modified by the attachment of two CF3 groups to the methyl group. This is the first example of an introduction of a fluoroalkyl group bigger than CF3 or CF2H into a theophylline (7) molecule, since known examples of fluorinated caffeine derivatives are limited to 7-trifluoromethyl

Selective recognition of ATP by multivalent nano-assemblies of bisimidazolium amphiphiles through “turn-on” fluorescence response

• Rakesh Biswas,
• Surya Ghosh,
• Shubhra Kanti Bhaumik and
• Supratim Banerjee

Beilstein J. Org. Chem. 2020, 16, 2728–2738, doi:10.3762/bjoc.16.223

• , Figure S10b and 10c). The absorption maxima red shifted slightly and increased scattering was observed at higher amounts of ATP. The A0–0/A0–1 values were also found to decrease upon formation of the co-aggregates with ATP (Supporting Information File 1, Table S5). The small-chain analogue, PBIm4 (100 µM

Synthesis and characterization of S,N-heterotetracenes

• Astrid Vogt,
• Florian Henne,
• Christoph Wetzel,
• Elena Mena-Osteritz and
• Peter Bäuerle

Beilstein J. Org. Chem. 2020, 16, 2636–2644, doi:10.3762/bjoc.16.214

• systems. The various obtained heteroatom sequences ‘SSNS’ (SN4), ‘SNNS’ (SN4’’), and ‘NSSN’ (SN4’) allowed for evaluation of structure–property relationships relative to the sulfur analogue tetrathienoacene (‘SSSS’). In line with the results for the whole series of S,N-heteroacenes, we find that

• azide precursors, and a Cadogan cyclization of nitro-substituted precursors were successfully applied. The various heteroatom sequences ‘SSNS’, ‘SNNS’, and benzannulated ‘NSSN’ allowed for evaluation of structure–property relationships relative to sulfur analogue tetrathienoacene (‘SSSS’). In line with

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

• was similar to the N-benzyl analogue 19. The treatment of 24 with Deoxo-Fluor®/NBS yielded two bromofluorinated products and the dibrominated compound 26. Unfortunately, from the two bromofluorinated products, only (rac)-25a could be isolated in a pure form (Scheme 14). The reaction of 24 with NIS

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• [CpRu(η6-sumanene)]PF6 126 along with its bowl-to-bowl inversion and anticipated it to be more flexible in comparison to the iron analogue 123a, may be due to the longer C–Ru bond (Scheme 32) [64]. The complex 126 was prepared in a similar manner as its iron analogue was prepared. Quite recently

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• naphthalene diimde analogue (NDI) equipped at the imide positions with two guanidinio-carbonyl-pyrrole (GCP) pendant arms interacted significantly stronger with ds-DNA at pH 5 than at pH 7, due to reversible protonation of the GCP arms. This was consequence of a pH-switchable threading intercalation into ds

• most likely bind within one of the DNA/RNA grooves, as in previously described aryl-GCP conjugates [16][17][18][19][20][21][22]. Further, the designed novel naphthalene diimide (NDI) analogue 4 (Scheme 1) is characterized by four pH-dependent positive charges, two of them present at neutral conditions

• analogue poly(dAdT)2 (Table S2, Supporting Information File 1). For comparison between double-stranded (ds) DNA and ds-RNA, poly(rA)–poly(rU) was chosen as an A-helical structure having a major groove convenient for binding of bulky small molecules. Results and Discussion Synthesis The synthesis of

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• give analogue 7b reduced the lipophilicity. Interestingly, while the nonfluorinated 7a and 7c diastereomers have different logD7.4 values, this is not the case for their fluorinated analogues 7b and 7d. Oxazine derivative 8 featured in the development of centrally active β-secretase (BACE1) inhibitors

• [24]. Although the logD7.4 of the unsubstituted cyclopropyl containing analogue was not provided, it can be seen that two-carbon extension of 8a, and one-carbon extension of 8b,c to give the cyclopropyl derivative 8e, cause a lipophilicity increase. Conversely, changing a CF2Me for a cPrF group (8d to

• (compare E1 with F1). A much lower lipophilicity decrease is seen when converting the acyclic β-fluorinated compounds D2 and G2 to the cyclopropyl analogue E2, but an appreciable logP decrease is still seen going from E2 to the oxetanyl derivative F2. With γ-fluorination, the logP decreases are similarly

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

• Annike Weißenstein,
• Myroslav O. Vysotsky,
• Ivo Piantanida and
• Frank Würthner

Beilstein J. Org. Chem. 2020, 16, 2032–2045, doi:10.3762/bjoc.16.170

• ). Schematic representation of the alignment of the intercalating 3a (left) and 3b (right) between the base pairs of the oligonucleotide. The complex with 3b was prepared analogously to the NDI analogue [53] by replacing the threading intercalator in PDB258D [54] with 3b, and performing MM2 minimisation in

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• )pyrrole (GCP) cation 1 as a synthetic analogue of the guanidinium cations, somehow a “super-guanidinium” conceived to drive “arginine magic” [20][21] to the extreme (Figure 1) [23]. The power of the Schmuck cation to bind carboxylate and phosphate anions in competitive water has several origins [22

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• -selectivity (as determined by 1H NMR of the crude). As in case of the fluorinated analogue, a substantial part of the newly formed alcohol 5d reacted with acetic acid forming the corresponding acetate 5d’. Interestingly, it appeared that only the E-isomer of 5d reacted with AcOH giving pure E-5d’ in 44

• ) and CSA (2 equiv) an 84% conversion into mainly brominated lactone 15 (79%) with traces of hydroxylated lactone 14, and of bromoalkene Z-13 was determined by crude 19F NMR. The remaining 8% appeared to be the β-chloromethyllactone 19 (see Scheme 7 below), an analogue of 15 as determined by NMR

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• fluorinated exo-glycal analogue of UDP-Galf in a radiometric assay with a glycolipid acceptor substrate and crude mycobacterial enzymes [31]. Therefore, we decided to examine compounds 1bα and 3a, representing the best and the worst inhibitors, respectively, according to the docking study, in the range of 1

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• chemically inert under most biologically relevant conditions. The presence of these groups adjacent to the proline structure helps to modulate the conformational landscape of the parent amino acid, and this effectively alters the folding of the peptide chain when an analogue is included in it as a residue

• complex structures: peptides and proteins. Results and Discussion Model compounds The study was originally set up following an assumption that a peptide containing a proline analogue would form a system of three dipoles. The peptide bond itself creates a strong dipole, with a direction that roughly aligns

• fluorine-containing substituent adds a new dipole to the system. A C–F dipole is estimated as 1.9 D, whereas a CF3-group dipole is about 2.4 D [60]. Thus, a proline analogue that contains these substituents would form a system of three mutually interacting dipoles (Figure 3). To mimic this situation, a

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• steric or electronic nature of the other substituent. These results contrast with those obtained for non-fluorinated analogue (ethyl 2-butynoate) for which the expected regioisomer 60 was formed, bearing the methyl group at the α-position and the electron-withdrawing ester group in the β-position. These

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

Recent synthesis of thietanes

• Jiaxi Xu

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

• as inhibitor of kinases, insecticides, and acaricides, its sulfur analogue, 6-amino-2-thiaspiro[3,3]heptane (28) was prepared from the cheap starting material 2,2-bis(bromomethyl)propane-1,3-diol (11). Compound 11 was converted into 3-(tert-butoxycarbonyl)-1,1-bis(hydroxymethyl)aminocyclobutane (25

• ). Following similar protocols, (S,S)-2,3-bis(benzoyloxymethyl)thietane (34) was synthesized from diethyl L-tartrate (32), which was further converted into thietanocin A (35), a sulfur analogue of oxetanocin A [39] (Scheme 7). The double displacement cyclic thioetherification strategy was also utilized for the

• succeeded in the synthesis of a 4’,4’-spirothietane-2’,N3-cycloadenosine 46 as a highly constrained analogue of 5’-deoxy-5’-methylthioadenosine. They first prepared tritosylate derivative 44 from D-glucose which was treated with KSAc to give the spirothietane derivative 45. The latter compound was further