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

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

• pyridine as a scavenger for the liberated HCl, gave solutions of crude diacylated product 18 in acceptable purity after simple filtration as work-up. It was reasoned that the activation of the electron-rich pyrrole (with generic electrophile X2 as shown) would hasten cleavage of the ester and that

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

• from Aspergillus niger (AnFaeA, Figure 1C). Coloration is the result of successive reactions: (i) release of the free 5-bromo-4-chloro-indoxyl-3-ol by an enzyme cascade, wherein TxAbf-catalyzed cleavage of the glycosidic bond was made possible by the prior release by AnFaeA of the ferulate moiety [21

• of Faes was investigated (Figure 2), measuring 4NTC release by AnFaeA [42] at 40 °C. The enzyme-catalyzed reaction leads to the cleavage of the ester bond linking the ferulate to the linker–4NTC moiety, and thus to the accumulation of linker–4NTC. Therefore, working in a discontinuous mode, 4NTC is

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

• cell lines [44]. Here, the incorporation of CF3 and CF3O groups as NMR reporters into the tumour-targeting drug conjugates enabled the direct investigation of the mechanism of the pro-drug metabolic cleavage and the pharmacophore release by real-time 19F NMR analysis. 19F NMR was also employed as a

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• hydrogenolysis of benzyl ethers (H2, Pd) [72], DIBAL-H reduction of esters to form alcohols [73], oxidative cleavage of vinyl groups to form carboxylic acids (KMnO4) [74], and the conversion of the acids into amines using the Curtius rearrangement (SOCl2, followed by Me3SiN3, thermolysis, and acid hydrolysis of

• -difluoro-1-alkenylcyclopropanes 90–92 (Scheme 41) [88]. All three compounds underwent a highly regioselective cleavage of the C1–C3 bond. Hence, the major products of all rearrangements were produced via [1,3]-sigmatropic shifts (Scheme 41). The products were the result of the breaking of the C–C bond

• ]. The radical ring-opening polymerization (RROP) provides a synthetic route to fluoropolymers, which are useful materials [91]. The RROP of gem-difluorovinylcyclopropane (90) gave mainly the polymer with an unsymmetrical repeating unit, by the cleavage of the C2–C3 bond in the ring (Scheme 44, path a

Selective synthesis of α-organylthio esters and α-organylthio ketones from β-keto esters and sodium S-organyl sulfurothioates under basic conditions

• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Thiago Barcellos,
• Claudio C. Silveira and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2021, 17, 234–244, doi:10.3762/bjoc.17.24

• tautomers was possible, revealing them as significant intermediates for the mechanism elucidation. Keywords: α-alkylthio esters; α-alkylthio ketones; Bunte salts; C–C bond cleavage; β-keto esters; Introduction During the last ten years, sodium S-organyl sulfurothioates, also known as Bunte salts, were

• , and related compounds. Some of them are catalyzed by expensive transition metals, such as gold, iridium, palladium, and titanium. More recently, the selective formation of C–S bonds using 1,3-dicarbonyl compounds, followed by a C–C bond cleavage has emerged as a versatile and less expensive protocol

• ). However, when compound 5 reacted with sodium S-benzyl sulfurothioate (2a), the enol product 6 was obtained in 86% yield after 2 h at 100 °C. In this case even a longer reaction time and a higher temperature were not effective to achieve the C–C bond cleavage. This interesting result also gave us the

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• EtOH, MeOH, and MeCN in temperature diapasons up to 100 °C, but no conversion of the staring material 2a (R1 = Et) was observed. The change of the solvent to DMF or DMSO resulted in the cleavage of one ethyl ester group [25], but still the SNAr reaction at C2 was not effective. LC–MS analysis of the

• Supporting Information File 1). The cleavage of the ester groups in the presence of NaCl was slower than in the presence of NaN3 (Figure 1 and Table S2 in Supporting Information File 1). Further, the cleavage of the sterically bulky isopropyl ester from phosphonate 2b showed a similar pattern: 5

• ]+ calcd for C20H30N7O5P, 480.2119; found, 480.2121. Screenings of the rate for the ester group cleavage (conversion determined by NMR spectroscopy) in the reactions between dialkyl (2-chloro-9-heptyl-9H-purin-6-yl)phosphonates 2a and 2b, respectively, with NaN3 (a, c) and NaCl (b, d). Reaction conditions

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

• . Exploration of the C-3 amide vector: formation of the pyridine-2(1H)-one motif by ionic hydrogenative cleavage of C-2-OAt ether Encouraged by our results, we started the library production planning to use the 3-step process requiring 2 purification steps by preparative LC–MS. However, as we planned to

• degradation with the dominant impurity coming from cleavage of the amide bond (Table 3, entry 2) and dissolving metal reduction conditions using zinc were quickly excluded as just 30% conversion was achieved with the added work-up complications (Table 3, entry 3). Finally and rather fortuitously, we turned

• -azabenzotriazole ring to the 7-azabenzotriazoline ring 18 and cleavage of the N–O bond through delocalization of the lone pair at N-2 to liberate 1 and 1H-[1,2,3]triazolo[4,5-b]pyridine as the byproduct. The second pathway occurs through 4 key steps: a) activation of the pyridine in the acidic media; b) ring

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• with trimesic acid. The coupling steps were performed using HBTU, HOBt, DIPEA in DMF with Fmoc derivatives of ʟ-phenylalanine and ε-aminohexanoic acid while the final capping was achieved using HATU, HOAt, DIPEA in NMP (Scheme 1). After cleavage from the resin the hetero-trifunctional peptide was

• , HOAt, NMM, DMF, 0 °C to rt, 15 h, 93%; iv) SPPS using HBTU, HOBt, DIPEA for coupling (HATU for BTA coupling), 20 vol % piperidine in DMF for Fmoc cleavage, DCM/TFA/TIS 20:20:1 (v/v/v) for final cleavage, 68%; v) azidoacetic acid NHS ester, NMM, DMF, rt, 4 h, 81%; vi) 4, PyBOP, HOAt, NMM, DMF, 0 °C to

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

• (1). Alternatively, the (±)-euphococcinine precursor 6 was prepared from 4, via deprotonation, silylation, and finally, silyl ether cleavage. Swern oxidation of alcohols 5 and 6 gave aldehydes 7 and 8, treated with allylmagnesium bromide, to generate secondary alcohols 9 and 10. These alcohols were

• to intramolecular dipolar cycloaddition to give racemic adducts (±)-13 and (±)-14, with good yields. The synthesis was complete according to the procedure used by Gössinger [25]. Thus, the reductive cleavage of the N–O bond in the presence of Raney-Ni and hydrogen provided the bicyclic alcohols

• azatricyclo[3.3.1.1]decane (+)-23a in 54% yield. Treatment of (+)-23a with Raney nickel resulted in the cleavage of the sulfinyl group and the N–O bond, providing the bicyclic alcohol 24, which was oxidized with PCC to give (+)-euphococcinine (2). The same protocol was applied to (+)-21b, furnishing the

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• ., the protein–protein interface. Limitations of this approach include the possibility of having no protease cleavage regions in the interface region and the size of the probes used [22]. These limitations can be overcome by using HDXMS. Even though HDX dates back to the 1950s [26], advances in data

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

• Vyacheslav I. Supranovich,
• Igor A. Dmitriev and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260

• from nitrones and a fluorinated building block is described. The annelation is based on a sequence of visible-light-promoted redox processes and a substitution reaction, and involves the cleavage of the N–O bond. The construction of tetrafluorinated piperidines from nitrones. The scope of the

Semiautomated glycoproteomics data analysis workflow for maximized glycopeptide identification and reliable quantification

• Steffen Lippold,
• Arnoud H. de Ru,
• Jan Nouta,
• Peter A. van Veelen,
• Magnus Palmblad,
• Manfred Wuhrer and
• Noortje de Haan

Beilstein J. Org. Chem. 2020, 16, 3038–3051, doi:10.3762/bjoc.16.253

• other than IgG and IgA were not considered for further data processing (e.g., fibrinogen, alpha-1-antitrypsin, or clusterin, see Table S1A–E, Supporting Information File 1). Missed-cleavage variants were assigned for IgG1, IgG2/3, and IgA1/2 (Asn263) but not further considered because of their low

• abundance. For the IgA joining chain (JC), the elongated peptide with a missed cleavage was included for further data processing as the cleavage efficiency was previously determined to be glycoform dependent [18][22]. For the assignment of tryptic N-glycopeptides to specific proteins, ambiguities exist for

• database including 71,591 protein sequences (20,205 from Swiss-Prot and 51,386 from TrEMBL). The C-terminal cleavage of lysine and arginine and a maximum of two missed cleavages was allowed. A tolerance of 10 ppm was applied for the precursors and 20 ppm for fragment ions. A carbamidomethylation was set as

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

• produce 135 and 136 in 85% yield in the ratio of 1:1.16. A six-step synthesis from the major product 136 gave lactone 137. This compond was subjected to successive desilylation, OsO4-mediated dihydroxylation and subsequent oxidative cleavage of the C=C double bond with Pb(OAc)4 to give ketoaldehyde 138 in

• and AIBN to a refluxing solution of cyclopropane 155 afforded 156 in 38% yield. It was subjected to cleavage of the Boc group followed by N-allylation to give 157 in 73% yield over two steps. A ring-closing metathesis of freshly prepared 157 was effected by the second generation Hoveyda–Grubbs (HG II

• on 160 to the enone and produces 161. The newly formed 161 was subjected to 5-exo radical addition to the allyl sulfane and subsequent loss of a thiyl radical produces 162. A successive hydrolysis/decarboxylation upon heating and cleavage of acetal on 162 afforded aldehyde 163 in 90% yield. Coupling

On the mass spectrometric fragmentations of the bacterial sesterterpenes sestermobaraenes A–C

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2020, 16, 2807–2819, doi:10.3762/bjoc.16.231

• radical cation 1•+ is obtained from which the methyl group C23 can directly be lost by an α-cleavage leading to fragment a1+ (Scheme 1A). However, the radical centred at the bridgehead carbon C11 is orthogonal to, or in other words, not in conjugation with the radical cation at C12–13. Therefore, an

• energetically more feasible process may be represented by an inductive cleavage leading to b1•+, a hydrogen rearrangement to c1•+, and an α-cleavage to d1+ (Scheme 1B). The formation of the fragment ion at m/z = 312 proceeds through a highly specific loss of the C8–9 portion of 1. This is explainable from b1

• •+ by a sequence of two α-cleavages first to e1•+ and then to f1•+ with a neutral loss of ethylene (Scheme 1C). The fragment ion at m/z = 297 requires the loss of C3H7 which can be achieved by various reactions, as indicated by the PMA297. This may be realised by the cleavage of an intact C3H7 unit

Enzyme-instructed morphological transition of the supramolecular assemblies of branched peptides

• Dongsik Yang,
• Hongjian He and
• Bing Xu

Beilstein J. Org. Chem. 2020, 16, 2709–2718, doi:10.3762/bjoc.16.221

• assemblies of the peptides. The attachment of DEDDDLLI sequences to the ε-amine of the lysine residue of a tetrapeptide produces branched peptides that form micelles. Upon the proteolytic cleavage of the branch, catalyzed by proteinase K, the micelles turn into nanofibers. We also found that the acetylation

• proteolysis to cleave the branch off 1, the micelles turn into nanofibers. Acetylation of the N-terminal of the branch forms 2, which exhibits an enhanced stability towards the proteolysis. In addition, the cleavage also occurs at other sites in the branch of 2, albeit less frequently, due to the acetylation

• role in endocytic pathways. Figure 1A shows the molecular design of the branched peptides, which also act as hydrogelator precursors [44][45]. The branch consists of (i) a hydrophilic ʟ-peptide segment for enzymatic recognition and cleavage, (ii) a self-assembling ᴅ-peptide sequence composed of a 2

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

• on the catalytic cleavage of the C–N bond in the diaziridine ring under the influence of Lewis acids [23][24]. However, the selectivity of the cycloaddition for thermal or catalytic conditions can be different [25]. It was possible to obtain the cycloaddition products of unstable azomethine imines

Activation of pentafluoropropane isomers at a nanoscopic aluminum chlorofluoride: hydrodefluorination versus dehydrofluorination

• Maëva-Charlotte Kervarec,
• Thomas Braun,
• Mike Ahrens and
• Erhard Kemnitz

Beilstein J. Org. Chem. 2020, 16, 2623–2635, doi:10.3762/bjoc.16.213

• acidic centers can induce dehydrofluorination reactions, involving the abstraction of a fluoride ion by heterolytic bond cleavage [28][29][30][31]. AlF3-based catalysts are among the strongest Lewis acidic materials. They exhibit an effective activity in C–F bond conversion reactions and are widely

• presence of silane. Additionally, 1 can further react with any silylium ion species at the surface of ACF, resulting in a C–F bond cleavage at the CF3 group, yielding once again a surface hydride and the corresponding carbenium ion. Subsequently, the allylic hydrodefluorination product 2 is formed. Allylic

• remarkable since other catalytic conversions at chromia-based catalysts require elevated temperatures [11][19][59][60][61][62]. The mechanisms for the C−F bond cleavage starting from 10c to yield the isomers 4 are similar to the ones proposed in the activation of 10a in the presence of silane (see above

Synthesis of 4-substituted azopyridine-functionalized Ni(II)-porphyrins as molecular spin switches

• Jannis Ludwig,
• Tobias Moje,
• Fynn Röhricht and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2589–2597, doi:10.3762/bjoc.16.210

• cleavage of the methyl 3-mercaptopropionate under the Suzuki conditions. Nevertheless, azopyridines 14, 18 and 20 were converted almost quantitatively to the corresponding cross-coupling products, while the yield with 21 to 1j is only 52%. The tert-butyl protection group on 1f was cleaved according to a

• procedure of Nishimura et al. using mercury acetate in trifluoroacetic acid and anisole as radical scavenger (Scheme 5) [34]. Cleavage of the tert-butyl protection group yielded the disulfide 1g, which was reduced with catecholborane in tetrahydrofuran to give the free thiol 1h, which readily reoxidizes

• /def2SVP level of theory (for details see Supporting Information File 1) revealed that the thermodynamically most stable structure is a trans configuration, where each of the pyridine units coordinate the nickel of the opposite porphyrin. Reductive cleavage of 1g by catecholeborane yields the

Catalytic trifluoromethylation of iodoarenes by use of 2-trifluoromethylated benzimidazoline as trifluoromethylating reagent

• Tatsuhiro Uchikura,
• Nanami Kamiyama,
• Taisuke Ishikawa and
• Takahiko Akiyama

Beilstein J. Org. Chem. 2020, 16, 2442–2447, doi:10.3762/bjoc.16.198

• benzimidazoline 2 was completely consumed after 24 h, the yield of the trifluoromethylation product continued to increase up to 48 h. This suggests that product generation proceeded slower than the cleavage of the C–CF3 bond of benzimidazoline. We propose a mechanism for the reaction, as shown in Figure 5. The Cu

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

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• cleavage reactions [80] and 1,5-HAT [81] and iii) the excited state of the simple organic molecule target can possess an ultrashort lifetime [82] that precludes photochemistry in favor of photophysical or nonradiative deactivation, e.g., fluorescence or internal conversion (IC). Instead of direct UV

• on polar aprotic solvents, which are typically required for SET processes. Photosensitization also permits the facile and complementary access to radical intermediates via homolytic cleavage, without the need for SET [101][102]. 1.1.5 Justification and scope of the review: Considering these

• the excitation of the complex RC1 directly allowed N–F cleavage to form the Selectfluor® radical cation. The reaction of the C3 2° pentane radical with Selectfluor® in an FAT was exergonic, with an energy barrier of 7.6 kcal⋅mol−1 relative to Int7, affording Int8 (Scheme 19). Since the Selectfluor

GlypNirO: An automated workflow for quantitative N- and O-linked glycoproteomic data analysis

• Toan K. Phung,
• Cassandra L. Pegg and
• Benjamin L. Schulz

Beilstein J. Org. Chem. 2020, 16, 2127–2135, doi:10.3762/bjoc.16.180

• , downloaded April 20, 2018 with 20,303 reviewed proteins) [26]. Cleavage specificity was set as C-terminal to Arg/Lys with a maximum of one missed cleavage. The precursor mass tolerance was 10 ppm and fragment ion mass tolerances for CID and HCD were 0.5 Da and 20 ppm, respectively. Carbamidomethylation of

Access to highly substituted oxazoles by the reaction of α-azidochalcone with potassium thiocyanate

• Mysore Bhyrappa Harisha,
• Pandi Dhanalakshmi,
• Rajendran Suresh,
• Raju Ranjith Kumar and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2020, 16, 2108–2118, doi:10.3762/bjoc.16.178

• give the intermediate A which undergoes homolytic cleavage yielding B. Subsequent cyclisation results in the oxazole ring. During these optimization trials, it was interesting to note the formation of 2-aminothiazole, when ferric chloride was employed along with thiocyanate (Table 1, entry 3). There is

pH- and concentration-dependent supramolecular self-assembly of a naturally occurring octapeptide

• Goutam Ghosh and
• Gustavo Fernández

Beilstein J. Org. Chem. 2020, 16, 2017–2025, doi:10.3762/bjoc.16.168

• nanostructures as well as the secondary structures. Results and Discussion Solid-phase peptide synthesis and purification The target octapeptide was synthesized in the solid phase following four steps, including: i) deprotection of the Fmoc protecting group, ii) coupling of an amino acid, iii) cleavage of the

• temperature, and this was stirred for 2 hours following the same procedure as before. At the final stage, we cleaved the peptide from the resin by using a proper cleavage cocktail: TFA/phenol/water/TIPS 88:5:5:2. DTT was included, as this peptide contains cysteine. After adding the cleavage cocktail to the