Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue

• Romain Sallio,
• Stéphane Lebrun,
• Frédéric Capet,
• Francine Agbossou-Niedercorn,
• Christophe Michon and
• Eric Deniau

Beilstein J. Org. Chem. 2018, 14, 593–602, doi:10.3762/bjoc.14.46

• bearing an array of acrylamide groups (Scheme 3). Substrate 6a bearing a (R)-α-methylbenzyl chiral auxiliary led to isoindolinone 3a in 80% de and a pure diastereoisomer was recovered after chromatography on silica gel (EtOAc/hexanes 3:7) and crystallization from hexanes/toluene. Reactions of substrates

• crystallization (70% yield, >96% de). Lactam (2R,3S)-25 bearing a α-methyl-para-methoxyphenyl chiral auxiliary was then deprotected with trifluoroacetic acid at room temperature to deliver the NH-free isoindolinone (3S)-26 (76% yield, 98% ee) which is a key building block in the synthesis of benzodiazepine

• isoindolinones (3S)-1 and (3S)-2. Synthesis of parent benzamides 6–8. Synthesis of isoindolinones 3a–d, 4a–e, 5; isolated yield, de by HPLC and 1H NMR. aAfter flash chromatography on silica gel (EtOAc/hexanes 3:7) and crystallization from hexanes/toluene; bafter flash chromatography.on silica gel (EtOAc/hexanes

Addition of dithi(ol)anylium tetrafluoroborates to α,β-unsaturated ketones

• Yu-Chieh Huang,
• An Nguyen,
• Simone Gräßle,
• Sylvia Vanderheiden,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2018, 14, 515–522, doi:10.3762/bjoc.14.37

• reaction. We synthesized eight different dithi(ol)anylium TFBs 1a–d and 2a–d from commercial carbonyl chlorides, isolated them via crystallization or separation and extraction and added them to a set of eight α,β-unsaturated non-cyclic ketones (Scheme 2 and Table 1). It was shown that dithi(ol)anylium TFBs

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• spectroscopic studies. However, X-ray crystallographic studies indicated that the 4,7-dihydropyrazolo[3,4-b]pyridine-5-nitriles 92 underwent aerial oxidation to its aromatic counterpart pyrazolo[3,4-b]pyridine 93 during crystallization and is propeller in shape. Additionally, non-planar rings due to propeller

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• to be prepared in several steps) with MnO2 in poor yield (24% crude product; yield of the final crystallization step for purification not given). In 1965, Bruderer and Brossi [12] reported on an approach whose central step was a Pictet–Gams cyclization of N-acetylated β,3-dimethoxy-4

From dipivaloylketene to tetraoxaadamantanes

• Gert Kollenz and
• Curt Wentrup

Beilstein J. Org. Chem. 2018, 14, 1–10, doi:10.3762/bjoc.14.1

• was achieved by fractional crystallization [24]. Chirality of the bisdioxine dicarbaldehyde, 2,6,9-trioxabicyclo[3.3.l]nona-3,7-diene-4,8-dicarbaldehyde, obtained by extrusion of water from triformylmethane, has also been demonstrated [25], and X-ray crystallography confirmed the structure of this

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

• . Subsequently, the solvent was evaporated to dryness and the residue subjected to column chromatography on SiO2 (2, eluent chloroform/methanol 50:0.5 (v/v), 3, eluent chloroform/methanol 50:1 (v/v)). Crystallization from chloroform/n-hexane afforded pure 2 (54%, 208 mg, yellow solid), or 3 (56%, 220 mg, yellow

• MgSO4, filtered and evaporated to dryness. The residue was subjected to column chromatography on SiO2 (eluent chloroform/methanol 50:2 (v/v)). Crystallization from chloroform/n-hexane gave the pure compound 4 as colourless solid in 91% yield (245 mg). 1H NMR (600 MHz, DMSO-d6) δ 11.14 (s, 1H, NH), 8.38

• chloroform/methanol 50:2 (v/v)). Crystallization from chloroform/n-pentane afforded the pure compound 5 as colourless solid in 85% yield (167 mg). 1H NMR (600 MHz, DMSO-d6) δ 8.28–8.26 (m, 4H, Pyr, adenine), 8.18 (s, 1H, H-2 adenine), 8.17 (d, JH,H = 9.6 Hz, 1H, Pyr), 8.15–8.14 (m, 2H, Pyr, adenine), 8.10 (d

Syntheses, structures, and stabilities of aliphatic and aromatic fluorous iodine(I) and iodine(III) compounds: the role of iodine Lewis basicity

• Tathagata Mukherjee,
• Soumik Biswas,
• Andreas Ehnbom,
• Subrata K. Ghosh,
• Ibrahim El-Zoghbi,
• Nattamai Bhuvanesh,
• Hassan S. Bazzi and
• John A. Gladysz

Beilstein J. Org. Chem. 2017, 13, 2486–2501, doi:10.3762/bjoc.13.246

• cases, CF2CF2OCF(CF3)CF2OCF(CF3)- segments have been found to impart higher fluorophilicites than similar perfluoroalkyl groups [42]. However, the multiple CF(CF3) stereocenters are disadvantageous, as they render such compounds mixtures of diastereomers, presenting an impediment to crystallization. In

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• ). Surprisingly, in the solid state (after the crystallization process), compounds 6i (or 7i – azide form) were not observed. In this case, the 7-substituted 5-(trichloromethyl)tetrazolo[1,5-a]pyrimidine was found, in which the CCl3 group is bonded at the 5-position of the heterocyclic ring, while CH3 is bound at

• the 7-position (8i, Figure 6). The observation was supported by DFT data, in which the tetrazole form was found to be 2.84 kcal mol−1 more stable than its azide form. This indicates that an unusual equilibrium is established for 6i (i.e., when R = CH3) in the crystallization process (Figure 7

• of the CX3 group at the 7-position of the ring. In addition, an unusual equilibrium was observed for compound 6i. The result of 8i from 6i crystallization was attributed to the equilibrium 6i7i (in which 7i is the azide form). Lastly, the evaluated series were very important to elucidate the factors

Structure–property relationships and third-order nonlinearities in diketopyrrolopyrrole based D–π–A–π–D molecules

• Jan Podlesný,
• Lenka Dokládalová,
• Oldřich Pytela,
• Adam Urbanec,
• Milan Klikar,
• Numan Almonasy,
• Tomáš Mikysek,
• Jaroslav Jedryka,
• Iwan V. Kityk and
• Filip Bureš

Beilstein J. Org. Chem. 2017, 13, 2374–2384, doi:10.3762/bjoc.13.235

• two large alkyl groups, the solubility of the target chromophores is relatively low, which partially complicated their purification. Hence, column chromatography with very slow elution followed by subsequent crystallization has been necessary. Only derivative 5b was sufficiently pure after column

• chromatography without a need of further crystallization. Hence, this ferrocene derivative was prepared with the highest yield of 73%. In the solid state, all target chromophores resemble dark metallic solids. Differential scanning calorimetry The thermal behaviour of compounds 1–5b was studied by differential

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• product since crystallization, precipitation and dialysis constitute the possible methods of purification. The purification by chromatography requires, due to the high polarity of phosphonic acids, reversed-phase chromatography and is therefore limited to preparative RP-HPLC [218]. Despites these

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• trans-11 (racemic), which could be separated by crystallization or column chromatography [17][32][33]. Trying to avoid as much as possible the use of (toxic) solvents, we considered extending the known nucleophilic substitution in a ball mill [34][35][36][37][38][39][40][41] to this reaction system

Solid-state studies and antioxidant properties of the γ-cyclodextrin·fisetin inclusion compound

• Joana M. Pais,
• Maria João Barroca,
• Maria Paula M. Marques,
• Filipe A. Almeida Paz and
• Susana S. Braga

Beilstein J. Org. Chem. 2017, 13, 2138–2145, doi:10.3762/bjoc.13.212

• evaluation of the antioxidant activity of the inclusion compound by the DPPH assay, and its comparison with that of pure fisetin. Preparation and characterization of γ-CD·fisetin The preparation of the γ-CD·fisetin inclusion complex was carried out by co-dissolution, followed by either co-crystallization or

• compound herein produced is adequate for human consumption. The co-crystallization experiments allowed the isolation of small crystals but these were not suitable for a structural determination by single crystal X-ray diffraction. Therefore the detailed characterization of the inclusion compound was thus

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• the fast screening of their activities, as well as powerful molecular modelling and crystallization of proteins. No doubt then that such biocatalysts will represent a competitive tool for glycosylation so to obtain complex O-, S- or C-glycoconjugates of biological interests. Mechanisms of O-GTs

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• polymeric macromolecular catalysts, e.g., PEG 200 and PEG 10000 as solid auxiliaries to enhance crystallization under LAG mechanochemical conditions in "polymer and liquid-assisted grinding" or POLAG [22][23]. While the focus in these investigations has been on the improvement of the macroscopic parameters

Molecular recognition of N-acetyltryptophan enantiomers by β-cyclodextrin

• Spyros D. Chatziefthimiou,
• Mario Inclán,
• Petros Giastas,
• Athanasios Papakyriakou,
• Konstantina Yannakopoulou and
• Irene M. Mavridis

Beilstein J. Org. Chem. 2017, 13, 1572–1582, doi:10.3762/bjoc.13.157

• crystallization, as a consequence of accumulation of many soft host–guest interactions and of the imposed crystallographic order, thus resulting in very dissimilar propensity of each enantiomer to produce crystals with β-CD. Keywords: β-cyclodextrin; enantiomeric discrimination; N-acetyltryptophan; NMR; X-ray

• lead to the grown crystals and differentiates them slight from hydrated β-CD. It is worth noting that hydrothermal treatment in crystallization trials has yielded uncommon structures such as, novel packing of β-CD–ethanol crystals [31] during trials to crystallize the β-CD–N-(1-adamantyl

• of the NAcPhe enantiomers. Numerous crystallization trials failed to produce crystals of the β-CD–D-NAcTrp complex yielding only hydrated β-CD crystals. The fact that β-CD–D-NAcTrp could not be crystallized in dimers as the β-CD–L-NAcTrp might be due to destabilization of the interface between dimers

Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions

• Manuel Anselmo,
• Lisa Moni,
• Hossny Ismail,
• Davide Comoretto,
• Renata Riva and
• Andrea Basso

Beilstein J. Org. Chem. 2017, 13, 1456–1462, doi:10.3762/bjoc.13.143

• -diphenylethanol was isolated, although the origin of water was not clear (possibly trapped by the diazonium salts during crystallization since, due to their potential explosivity in the dry state, they were not dried under vacuum). At this stage we postulated that A could be more favourably attacked in an

1-Imidoalkylphosphonium salts with modulated C_α–P⁺ bond strength: synthesis and application as new active α-imidoalkylating agents

• Jakub Adamek,
• Roman Mazurkiewicz,
• Anna Węgrzyk and
• Karol Erfurt

Beilstein J. Org. Chem. 2017, 13, 1446–1455, doi:10.3762/bjoc.13.142

• –N bond instead of the Cα–OMe bond more favorable in this case. The phosphonium salts 5 were purified by crystallization, usually from a mixture of CH2Cl2/Et2O. However, in a few cases preliminary purification by column chromatography proved to be necessary. Their structures were confirmed by 1H, 13C

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

• Olga Bakulina,
• Alexander Ivanov,
• Vitalii Suslonov,
• Dmitry Dar’in and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2017, 13, 1413–1424, doi:10.3762/bjoc.13.138

• syn-configured CCR product (Table 1, entries 3, 8, 11 and 13, anti/syn ratio ranging from 3.3:1 to 6.5:1), the latter was removed by crystallization and the respective pure anti-diastereomers (anti-10c, 10h, 10k and 10m) were obtained and characterized. In certain instances (Table 1, entries 5–7, and

An improved preparation of phorbol from croton oil

• Alberto Pagani,
• Simone Gaeta,
• Andrei I. Savchenko,
• Craig M. Williams and
• Giovanni Appendino

Beilstein J. Org. Chem. 2017, 13, 1361–1367, doi:10.3762/bjoc.13.133

• -irritant phorboid mixture from croton oil was telescoped to only five operational steps, and phorbol could then be purified by gravity column chromatography and crystallization. Evidence is provided that two distinct phorboid chemotypes of croton oil exist, differing in the relative proportion of type-A

• crystallization step. A solution for these issues is provided, suggesting that the poor-reproducibility of croton oil-based anti-inflammatory assays are the result of poor quality and/or inconsistent composition of croton oil. Keywords: croton oil; diterpenoids; natural products; phorbol; transesterification

• issues with this protocol. The first one is the repeated handling of croton oil, a very toxic and obnoxious material, during the methanol extraction step, that requires several hours of stirring and then of resting to achieve a good phase separation, and the second one is the capricious crystallization

Switchable highly regioselective synthesis of 3,4-dihydroquinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

• Juraj Dobiaš,
• Marek Ondruš,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2017, 13, 1350–1360, doi:10.3762/bjoc.13.132

• regioisomers was purified by crystallization from DMSO to yield 64.6 mg (0.19 mmol, 48%) of 16d (SYN). Mp: 363.0–365.0 °C (DMSO), yellow solid compound. 1H NMR (600 MHz, DMSO-d6) δ 13.48 (s, 1H, H-NA(4)), 12.92 (br s, 1H, -COOH), 12.26 (s, 1H, H-NA(1)), 8.04 (d, J(A5,A7) = 1.5 Hz, 1H, H-CA(5)), 7.99 (d, J(B2

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

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

• dimensions of 0.5 × 0.01 × 0.01 mm, could be grown using protein crystallization methods. Data were collected using synchrotron radiation, and the structure was solved using direct methods. Four independent molecules were found in each asymmetric unit (which contains 284 non-hydrogen atoms) in a highly

• dramatic impact on the throughput and on the complexity of the structures determined. However, despite the development in nano-volume liquid handling for high-throughput screens, the crystallization of biological macromolecules still represents an important bottleneck in structure determination. Nanoliter

• handling devices allow the screening of hundreds of crystallization conditions even with a limited amount of sample of a few tens of microliters [19]. Furthermore, a successful example of automation in crystal harvesting were recently reported [20], while robots are now used to handle cryo-cooled samples

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• -polar regions of the GPCR, especially intracellular loop 3 (IL3), that do not form the rigid, specific interactions needed for crystallization. Such problems are sometimes overcome by truncating the flexible termini, complexing the GPCR with antibody fragments [9], or by replacing IL3 with a stable

• stable enough for crystallization. The solution to this problem has been to use the variable domains of camelid antibodies, which are generally designated protein nanobodies, as a surrogate for the G-protein [18]. This technique will be discussed in the context of the simulations below. Note, however

Regioselective (thio)carbamoylation of 2,7-di-tert-butylpyrene at the 1-position with iso(thio)cyanates

• Anna Wrona-Piotrowicz,
• Marzena Witalewska,
• Janusz Zakrzewski and
• Anna Makal

Beilstein J. Org. Chem. 2017, 13, 1032–1038, doi:10.3762/bjoc.13.102

• , for the reaction with p-methoxyphenyl isothiocyanate we were able to obtain, by crystallization, the major product, C(1)-substituted thioamide 3n, contaminated with only ≈5% of its C4-substituted counterpart. We tentatively explain this poorer regioselectivity by possible π–π interaction of pyrene

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97