Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• bifunctional compounds 74 at the end, allowing the obtention of the 16- to 20-membered tetrazolic macrocycles 75 in only five steps (Scheme 14). A similar approach was used shortly afterwards by the same research group in the synthesis of macrocyclic depsipeptides containing a tetrazole nucleus [31]. The

• intramolecular Passerini reaction was performed using bifunctional isocyanocarboxylate (Scheme 15a). Scheme 15b shows three of the 21 depsipeptides macrocycles synthesized by the authors in this study. Ethyl isocyanoacetate (13b) has also been successfully used as starting material to allow consecutive Ugi

• step was attributed to difficulties during the purification step along with to some oligomerization that might have occurred. Repetitive IMCRs – multicomponent macrocyclizations through bifunctional building blocks A strategy that has been widely used for the synthesis of macroheterocycles is the

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable

• peptidomimetics with potential pharmaceutical applications. Therefore, the development of innovative Ugi reactions is crucial for the synthesis of novel chemical libraries for various purposes [12]. In recent years, one of the modifications for Ugi reactions is the introduction of bifunctional substrates into the

• by acid catalysis from renewable resources, such as sugars, lignocellulosic biomass and waste materials [18]. It can be used as a bifunctional precursor for the synthesis of pharmaceuticals, plasticizers, and different additives [19]. Furthermore, it is recognized as an excellent starting material

Olefin metathesis in multiblock copolymer synthesis

• Maria L. Gringolts,
• Yulia I. Denisova,
• Eugene Sh. Finkelshtein and
• Yaroslav V. Kudryavtsev

Beilstein J. Org. Chem. 2019, 15, 218–235, doi:10.3762/bjoc.15.21

• polymerization of another monomer [53][54][55]. Synthesis from end-functionalized blocks Another strategy to multiblock copolymer preparation is to assemble them by using pre-synthesized telechelic polymers with α,ω-bifunctional end groups, which can be coupled in different ways. The classical technique for

Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

• Falco Fox,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2019, 15, 167–186, doi:10.3762/bjoc.15.17

• used for the C–C coupling in the N-acyl Mannich reaction with activated isochinolin 10, 1-chloroisochroman (18) and chromone 21 with different silyl ketene acetals. Due to more efficient bifunctional Si(OH)2-hydrogen bonding, silandiol 9 tops chlorosilanol 8, also on catalytic application

Copolymerization of epoxides with cyclic anhydrides catalyzed by dinuclear cobalt complexes

• Yo Hiranoi and
• Koji Nakano

Beilstein J. Org. Chem. 2018, 14, 2779–2788, doi:10.3762/bjoc.14.255

• peak molecular weight of the higher molecular weight portion was twice as large as that of the lower molecular weight portion. Accordingly, trace amounts of diacid in PA and/or water contaminants would work as bifunctional chain-transfer agents and gave twice the molecular weight of the copolymer

• initiated by monofunctional pentafluorobenzoate from (R,R,S,S)-1 and [PPN][OCOC6F5] [19]. The formation of the alternating copolymers initiated by monofunctional pentafluorobenzoate and the bifunctional chain-transfer agents was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass

Dispersion-mediated steering of organic adsorbates on a precovered silicon surface

• Lisa Pecher,
• Sebastian Schmidt and
• Ralf Tonner

Beilstein J. Org. Chem. 2018, 14, 2715–2721, doi:10.3762/bjoc.14.249

• theory; dispersion; organic/inorganic interfaces; Introduction The creation of organic/inorganic interfaces is one of the main endeavours in enhancing the application range of modern electronic devices for silicon-based technology [1][2]. One way to achieve this is covalent attachment of bifunctional

• of the parent system 1 thus gives crucial insight that is expected to be transferable to the bifunctional derivatives. The adsorption of a molecule on a surface can proceed either via a direct pathway or via an intermediate species that is crucial for selectivity and the description of adsorption

Transition metal-free oxidative and deoxygenative C–H/C–Li cross-couplings of 2H-imidazole 1-oxides with carboranyl lithium as an efficient synthetic approach to azaheterocyclic carboranes

• Lidia A. Smyshliaeva,
• Mikhail V. Varaksin,
• Pavel A. Slepukhin,
• Oleg N. Chupakhin and
• Valery N. Charushin

Beilstein J. Org. Chem. 2018, 14, 2618–2626, doi:10.3762/bjoc.14.240

• the first examples of the SNH methodology for the synthesis of new heterocyclic carboranes by means of direct C–H/C–Li coupling of non-aromatic 2H-imidazole 1-oxides with carboranyllithium. A growing interest in bifunctional compounds, bearing both the pharmacoactive imidazole motif and a polyhedral

• organoelement bifunctional ensembles, bearing heterocyclic and carborane moieties, which are of particular interest in the design of advanced materials, have been obtained in good yields. The 1H NMR spectra of 1-(5-(4-bromophenyl)-2-ethyl-2-methyl-2H-imidazol-4-yl)-1,2-dicarba-closo-dodecaborane (4d) and 1-(4

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• a suitable target to prevent toxin secretion. The anti-PcrV antibody KB001 [68] and the bifunctional antibody MEDI3902 [69], which targets PcrV and the biofilm-associated exopolysaccharide psl, are both currently in phase II clinical trials. 6. Bacterial communication Quorum sensing (QS) is employed

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• -activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating

• magnesium enolate of malonic acid half ester, prepared in situ from potassium methyl malonate, MgCl2 and triethylamine in acetonitrile, was added [24][25]. The acylation of magnesium methyl malonate by the preformed imidazole 3 led to the desired bifunctional starting material 4 in good yield (79

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

• . Conclusion The synthesis of a macrocycle is often described as an intramolecular cyclization of a bifunctional precursor molecule. However, in many cases competition exists with dimerization and polymerization. Therefore, we were delighted to see that the intramolecular cyclization, utilizing dU and dC

Asymmetric Michael addition reactions catalyzed by calix[4]thiourea cyclohexanediamine derivatives

• Zheng-Yi Li,
• Hong-Xiao Tong,
• Yuan Chen,
• Hong-Kui Su,
• Tangxin Xiao,
• Xiao-Qiang Sun and
• Leyong Wang

Beilstein J. Org. Chem. 2018, 14, 1901–1907, doi:10.3762/bjoc.14.164

• ]. In 2016, Hernández-Rodríguez and co-workers reported the preparation of bifunctional thioureas that contained either a methyl or trifluoromethyl group [14]. They discovered that the employment of chiral moieties with an α-trifluoromethyl group in thioureas show a positive effect on the selectivity

• of ortho- or para-halogenated substrates. Mechanism study There are two possibilities for the bifunctional thiourea-catalyzed asymmetric Michael addition reaction mechanism as has been summarized by Wang and co-worker [41]. In case of 1,3-dicarbonyl compounds or nitroolefins as substrates in the

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• Supporting Information File 1. Chemical structures of the GnRH-drug conjugates synthesized and investigated in the present work. Abbreviations: Aoa: aminooxyacetyl; Dox: doxorubicin; Dau: daunorubicin; Mtx: methotrexate; Glp: pyroglutamic acid; gult: glutaric acid. Chemical structures of the bifunctional

• bifunctional daunorubicin-GnRH-III conjugates without spacer and modified in position 4 with Lys; (e) {GnRH-III(Dau=Aoa-C)}2 dimer and conjugates modified in position 4 with N-MeSer; (f) GFLG or YRRL spacer containing monomer and dimer conjugates (g) GnRH-III conjugates containing methotrexate and daunorubicin

• conjugates containing doxorubicin without spacer sequence; (c) with spacer sequence GFLG; (d) oxime bond-linked, mono- and bifunctional daunorubicin-GnRH-III conjugates without spacer and modified in position 4 with Lys; (e) {GnRH-III(Dau=Aoa-C)}2 dimer and conjugates modified in position 4 with N-MeSer; (f

Cobalt–metalloid alloys for electrochemical oxidation of 5-hydroxymethylfurfural as an alternative anode reaction in lieu of oxygen evolution during water splitting

• Jonas Weidner,
• Stefan Barwe,
• Kirill Sliozberg,
• Stefan Piontek,
• Justus Masa,
• Ulf-Peter Apfel and
• Wolfgang Schuhmann

Beilstein J. Org. Chem. 2018, 14, 1436–1445, doi:10.3762/bjoc.14.121

• [4]. The elaborate separation of TEMPO from FDCA appeared to be an additional disadvantage [24]. Recently, Sun and co-workers reported the electrochemical oxidation of HMF using various non-precious cobalt and nickel based bifunctional HER/OER water splitting electrocatalysts, namely CoP on copper

• foam, Ni2P and Ni3S2 on nickel foam, in a one compartment batch type electrochemical reactor [5][28][29]. We recently reported on the synthesis and application of alloys of cobalt with boron and phosphorus as exceptionally active bifunctional HER/OER catalysts for water splitting. Inspired by these

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• asymmetric synthesis. In 2013, we described a novel class of calix[4]arene-based chiral primary amine–thiourea catalysts 47a and 47b derived from p-tert-butylcalix[4]arene (Figure 7) [49]. To evaluate the catalytic efficiency, bifunctional catalysts were applied to promote the Michael addition of aldehydes

• -diaminocyclohexane moiety from (1R,2R) to (1S,2S) without loss of activity or selectivity. Bifunctional organic molecules combining the thiourea moiety with a tertiary amine functionality are remarkably useful catalysts capable of simultaneous activation of both electrophiles and nucleophiles [51]. Therefore, a

• series of calixarene-based chiral bifunctional tertiary amine–thiourea organocatalysts 54–56 have been synthesized by us and Genc et al. (Scheme 15) [52][53]. Among them, 54a,b were applied to the asymmetric Michael addition of 1,3-dicarbonyl compounds 34 and 57 to a variety of nitroolefins. Although

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• -isatin imines 3 with naphthols performed in the presence of cinchona alkaloid-derived thiourea 40 [66]. As shown in Scheme 15, the reaction of 1-naphthols 42 promoted by 2 mol % of this bifunctional catalyst in toluene at room temperature led to the corresponding chiral 3-substituted 3-amino-2-oxindoles

• either chiral organocatalysts or chiral metal complexes. Among the organocatalysts, chiral bifunctional guanidine 50 was applied by Feng et al. in 2015 to promote the reaction of nitromethane 51 with N-Boc-isatin imines 3 (Scheme 18) [71]. The reaction performed at −30 °C using 10 mol % of this catalyst

• reactions performed with bifunctional guanidines. In addition, excellent results (97% ee) were reported in unprecedented domino reactions promoted by squaramides recently. Miscellaneous transformations, including additions of methanol, hydroperoxides and arylboronic acids, were also developed with high

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• ). A phylogenetic analysis of 878 fungal terpene synthase homologs (Figure S1 in Supporting Information File 1) demonstrates that this enzyme is closely related to the bifunctional ent-copalyl diphosphate synthase/ent-kaurene synthase from Fusarium fujikuroi [33]. The N-terminal domain shows the DXDD

• TS homologs (accession numbers GAA83682, GAA88217 and GAA91251, locus tags AKAW_01797, AKAW_06331 and AKAW_09365). The first enzyme GAA83682 shows close homology to the bifunctional ent-kaurene synthases from Fusarium and is likely involved in diterpene biosynthesis. The fact that no corresponding

• enzyme XP_001276070 (ACLA_076850), likely a bifunctional diterpene synthase (DTS), seems to be not expressed in laboratory culture, but another function cannot be excluded for this enzyme. Esters were the predominant class of compounds emitted by A. clavatus. The observed pattern of volatiles was very

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• -2-naphthols [81]. These bifunctional compounds were reacted with various cyclic imines such as 4,5-dihydrobenzo[c]azepine or 6,7-dihydrothieno[3,2-c]pyridine to have new naphthoxazinobenzazepine 44 and -thienopyridine 45 derivatives [82]. Transformations at 80 °C in 1,4-dioxane as solvent were

• indication that the application of this highly-reactive intermediate has made the modified Mannich reaction to be a hot topic again in organic chemistry. This review presents a wide range of applications including cycloadditions and the synthesis of bifunctional amino- or amidonaphthols that can later be

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• and pregabalin [9][10]. Later, hydrogen-bonding activation proved to be more general for obtaining Michael adducts via the addition of 1,3-dicarbonyl compounds to nitroalkenes. Chiral thioureas and squaramides, particularly those with the bifunctional mode of action, served as excellent catalysts in

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• [70][71]. For example, using a fragment-based approach, Tran et al. synthesised and evaluated a library of polymer-based hetero-bifunctional ligands and found that some compounds showed low nanomolar multivalent inhibition [68]. Alpha-galactoside 38 (Figure 17) showed the highest activity when

• -bifunctional inhibitor designed by Bundle and co-workers. Glycopolymers with exchangeable sugar ligands and variable length linkers. Acknowledgements This review is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• synthetic peptides or peptidomimetics containing these sequences have been prepared and show low nanomolar IC50 values for integrin αVβ3 binding [21][22][23][24][25][26][27]. A number of cyclic RGD and isoDGR ligands containing a bifunctional diketopiperazine (DKP) scaffold have been developed by the

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

• Lingjun Xu,
• Shuwen Han,
• Linjie Yan,
• Haifeng Wang,
• Haihui Peng and
• Fener Chen

Beilstein J. Org. Chem. 2018, 14, 309–317, doi:10.3762/bjoc.14.19

• )-GABOB. Keywords: alcoholysis desymmetrization; bifunctional organocatalysis; chloramphenicol base; Introduction Over the past decade, remarkable advances in the utilization of natural products as chiral structural motifs for the design of bifunctional organocatalysts have been achieved. A high

• development of chiral bifunctional urea 1 [35], thiourea 2 and 3 [36][37], sulfonamide 4 [38][39][40] and squaramide 5 [38][39][40] catalysts derived from chloramphenicol base (Figure 1), which showed excellent reactivity and enantioselectivity for this asymmetric transformation. A typical example of the

• -derived bifunctional derivatives catalyzed asymmetric alcoholysis of anhydride, the exploration of new effective and easily accessible fully synthetic organocatalysts through further modification of this privilege motif are always needed. Our present design is inspired by cinchona-derived sulfonamides

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• vinylphosphonium salts are important reagents and building blocks in organic synthesis mainly due to the convenience of their transformation into reactive ylides by addition of a variety of nucleophiles, including carbon, nitrogen, sulfur, and oxygen nucleophiles. The addition of a bifunctional nucleophile with a

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

• synthesis, DFT calculations, photophysical characterization, oligonucleotide binding studies, and confocal microscopy studies of the novel pyrene–nucleobase conjugates 2–5 (nucleobase = thymine (2 and 4), and adenine (3 and 5)). Our compounds represent a simple bifunctional design combining the fluorescent