Organic & Biomolecular Chemistry (v.13, #9)

Front cover (2485-2486).

Contents list (2487-2498).

Editorial: Supramolecular chemistry in water by Anthony P. Davis; Stefan Kubik; Antonella Dalla Cort (2499-2500).

Halogenated boron-dipyrromethenes: synthesis, properties and applications by Vellanki Lakshmi; Malakalapalli Rajeswara Rao; Mangalampalli Ravikanth (2501-2517).
Boron-dipyrromethene dyes (BODIPYs) containing halogens at pyrrole carbons are very useful synthons for the synthesis of a variety of BOIDPYs for a wide range of applications. Among the functional groups, halogens are the functional groups which can be regiospecifically introduced at any desired pyrrole carbon of the BODIPY framework by adopting appropriate synthetic strategies. The halogenated BODIPYs can undergo facile nucleophilic substitution reactions to prepare several interesting BODIPY based compounds. This review describes the synthesis, properties and potential applications of halogenated BODIPYs containing one to six halogens at the pyrrole carbons of the BODIPY core as well as properties and applications of some of the substituted BODIPYs derived from halogenated BODIPYs.

Antibodies armed with photosensitizers: from chemical synthesis to photobiological applications by Patricia M. R. Pereira; Barbara Korsak; Bruno Sarmento; Rudolf J. Schneider; Rosa Fernandes; João P. C. Tomé (2518-2529).
Targeting photosensitizers to cancer cells by conjugating them with specific antibodies, able to recognize and bind to tumor-associated antigens, is today one of the most attractive strategies in photodynamic therapy (PDT). This comprehensive review updates on chemical routes available for the preparation of photo-immunoconjugates (PICs), which show dual chemical and biological functionalities: photo-properties of the photosensitizer and the immunoreactivity of the antibody. Moreover, photobiological results obtained with such photo-immunoconjugates using in vitro and in vivo cancer models are also discussed.

Ylide formal [4 + 1] annulation by Chunyin Zhu; Ya Ding; Long-Wu Ye (2530-2536).
Over the past few decades, ylide chemistry has been significantly extended to an area beyond olefination and small ring formation, among which ylide [4 + 1] annulation has been extensively explored, and five-membered ring structures, such as dihydrofurans, isoxazolines, pyrrolines, indoles, dihydropyrazoles and cyclopentenones, can be readily constructed through this type of transformation. An overview of the recent advances in this field is presented herein. Ylide [4 + 1] annulations are reviewed by highlighting their product diversity, selectivity and applicability, and the mechanistic rationale is presented when possible.

Synthesis of a β-CCT-lanthanide conjugate for binding the dopamine transporter by Gregory R. Naumiec; Grace Lincourt; Jeremy P. Clever; Michael A. McGregor; Abraham Kovoor; Brenton DeBoef (2537-2540).
The development of a β-CCT-lanthanide conjugate that binds the dopamine transporter (DAT) with high affinity (Kd = 303 nM) is described. Contrast agents such as the one described herein could be used as molecular probes to directly study the binding of small molecules to receptors such as DAT via MRI, PET or SPECT.

“One-pot” synthesis of amidoxime via Pd-catalyzed cyanation and amidoximation by Chu-Ting Yang; Jun Han; Jun Liu; Mei Gu; Yi Li; Jun Wen; Hai-Zhu Yu; Sheng Hu; Xiaolin Wang (2541-2545).
A novel “one-pot” reaction was developed for the synthesis of aryl or heteroaryl-substituted amidoxime compounds containing various functional groups. Fluorescence titration experiments coupled with theoretical analysis revealed that the steric hindrance and electronic effects of substituents influence the binding ability of the amidoxime compounds to uranyl ions.

Oxidative asymmetric umpolung alkylation of Evans’β-ketoimides using dialkylzinc nucleophiles by Tom A. Targel; Jayprakash N. Kumar; O. Svetlana Shneider; Sukanta Bar; Natalia Fridman; Shimon Maximenko; Alex M. Szpilman (2546-2549).
Umpolung alkylation of Evans’ auxiliary substituted β-ketoimides affords the diastereomerically pure products in yields ranging from 40 to 80%. The reaction itself proceeds with diastereoselectivities between 3 : 1 and 18 : 1. Dialkylzinc serves as the nucleophile and umpolung of the β-keto-imide enolate is achieved by the action of Koser's reagent.

Cyclopropanation using flow-generated diazo compounds by Nuria M. Roda; Duc N. Tran; Claudio Battilocchio; Ricardo Labes; Richard J. Ingham; Joel M. Hawkins; Steven V. Ley (2550-2554).
We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.

A combined experimental and computational study suggests that a reduction in the entropy of activation in the solid state can lead to the protodeboronation of boronic acids.

Gas phase chemistry of N-benzylbenzamides with silver(i) cations: characterization of benzylsilver cation by Hezhi Sun; Zhe Jin; Hong Quan; Cuirong Sun; Yuanjiang Pan (2561-2565).
The benzylsilver cation which emerges from the collisional dissociation of silver(i)–N-benzylbenzamide complexes was characterized by deuterium-labeling experiments, theoretical calculations, breakdown curves and substituent effects. The nucleophilic attack of the carbonyl oxygen on an α-hydrogen results in the generation of the benzylsilver cation, which is competitive to the AgH loss with the α-hydrogen.

Synthesis of directly fused porphyrin dimers through Fe(OTf)3-mediated oxidative coupling by Chuan-Mi Feng; Yi-Zhou Zhu; Shao-Chun Zhang; Yun Zang; Jian-Yu Zheng (2566-2569).
An efficient and general Fe(OTf)3-mediated oxidative coupling method was developed for the synthesis of doubly or triply linked porphyrin dimers. Besides the central metal and peripheral substituent, regioselectivity of the oxidative coupling was found to be closely relevant to the onset oxidation potential of the porphyrin substrate, and the reactant with higher Eonset(ox) tends to generate meso-β doubly fused porphyrin dimer.

Computational design of novel peptidomimetic inhibitors of cadherin homophilic interactions by Fabio Doro; Cinzia Colombo; Chiara Alberti; Daniela Arosio; Laura Belvisi; Cesare Casagrande; Roberto Fanelli; Leonardo Manzoni; Emilio Parisini; Umberto Piarulli; Elena Luison; Mariangela Figini; Antonella Tomassetti; Monica Civera (2570-2573).
We report a first set of peptidomimetic ligands mimicking the adhesive interface identified by recent crystallographic structures of E- and N-cadherin. Compounds 2 and 3 inhibit adhesion of epithelial ovarian cancer (EOC) cells with improved efficacy compared to the ADH-1 peptide, a N-cadherin antagonist that is in early clinical trials in EOC patients.

A facile and high-yield formation of dipyrrin-boronic acid dyads and triads: a light-harvesting system in the visible region based on the efficient energy transfer by Masaki Yamamura; Shinya Yazaki; Motofumi Seki; Yasunori Matsui; Hiroshi Ikeda; Tatsuya Nabeshima (2574-2581).
Artificial light-harvesting systems, Ar,O-BODIPY dyads and triads conjugated with a light harvester, were synthesized in high yield by the reaction of an N2O2-type dipyrrin with boronic acids. Dyad 2 having a pyrene unit underwent quantitative Förster resonance energy transfer (FRET) from the antenna unit, pyrene, to the fluorophore unit, Ar,O-BODIPY. Triads 3·5 and 4·5 were quantitatively prepared by mixing pyridine-appended compounds 3 and 4 with saloph·Zn complex 5, respectively. Triad 4·5 underwent efficient FRET from the saloph·Zn complex unit to the fluorophore unit at the rate of 2.0 × 1011 s−1. Interestingly, the fluorescence quenching process in the excited state of the triad 3·5 took place following the energy transfer event. Thus, appropriate positioning of the energy donor and acceptor is necessary to construct a highly efficient FRET system.

Contrasting anion recognition behaviour exhibited by halogen and hydrogen bonding rotaxane hosts by Stuart P. Cornes; Charles H. Davies; David Blyghton; Mark R. Sambrook; Paul D. Beer (2582-2587).
A rotaxane host system containing a novel halogen bonding (XB) 5-iodo-1,2,3-triazole functionalised pyridinium motif, within its axle component, has been prepared via a ring closing metathesis reaction, using chloride as a template. Proton NMR titration experiments, in competitive 1 : 1 CDCl3–CD3OD solvent media, showed the XB rotaxane selectively bound halides over larger, more basic oxoanions. An all hydrogen bonding proto-triazole containing rotaxane analogue was also prepared, which in stark contrast demonstrated a reversal in the anion selectivity trend, with a preference for dihydrogen phosphate over the halides which is unprecedented for an interlocked host system.

One pot syntheses of furan, thiophene, and pyrrole were accomplished by oxidative deacetylation using Mn(iii)/Co(ii) catalysts and the Paal–Knorr reaction from 1,5-dicarbonyl compounds, which are prepared from the conjugate addition of ethyl acetoacetate to α,β-unsaturated carbonyl compounds. The oxidative deacetylation and reductive cyclization of β-ketoesters derived from ethyl acetoacetate and o-nitrobenzyl bromides efficiently produced diversely substituted indoles.

Synthesis of 4-substituted oxazolo[4,5-c]quinolines by direct reaction at the C-4 position of oxazoles by Mahesh Akula; Yadagiri Thigulla; Connor Davis; Mukund Jha; Anupam Bhattacharya (2600-2605).
A facile synthesis of 4-aryl substituted oxazolo[4,5-c]quinolines has been described via a modified Pictet–Spengler method and using Cu(TFA)2 as a catalyst. The developed methodology directly functionalizes the C-4 position of oxazoles without the aid of any prefunctionalization, in the presence of the more reactive C-2 position in good yields. The versatility of the established method has been demonstrated by its application in the synthesis of 4-substituted oxazolo-[1,8]naphthyridine ring systems.

Copper catalyzed straightforward synthesis of 2-alkylbenzoxa(thia)azoles from aryl isocyanates/isothiocyanates and simple alkanes is reported. The protocol utilizes ditertiary butyl peroxide (DTBP) as a radical initiator and involves sequential formation of C–C and C–X (X = O, S) bonds followed by aromatization in a one-pot procedure.

Phototriggerable peptidomimetics for the inhibition of Mycobacterium tuberculosis ribonucleotide reductase by targeting protein–protein binding by Christoffer Karlsson; Magnus Blom; Miranda Johansson (neé Varedian); Anna M. Jansson; Enzo Scifo; Anders Karlén; Thavendran Govender; Adolf Gogoll (2612-2621).
Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.

Chemiluminescent acridinium dimethylphenyl esters are highly sensitive labels that are used in automated assays for clinical diagnosis. Light emission from these labels and their conjugates is triggered by treatment with alkaline peroxide. Conjugation of acridinium ester labels is normally done at the phenol. During the chemiluminescent reaction of these acridinium esters, the phenolic ester is cleaved and the light emitting acridone moiety is liberated from its conjugate partner. In the current study, we report the synthesis of three new acridinium esters with conjugation sites at the acridinium nitrogen and compare their properties with that of a conventional acridinium ester with a conjugation site at the phenol. Our study is the first that provides a direct comparison of the emissive properties of acridinium dimethylphenyl esters (free labels and protein conjugates) with different conjugation sites, one where the light emitting acridone remains attached to its conjugate partner versus conventional labeling which results in cleavage of the acridone from the conjugate. Our results indicate that the conjugation at the acridinium nitrogen, which also alters how the acridinium ring and phenol are oriented with respect to the protein surface, has a minimal impact on emission kinetics and emission spectra. However, this mode of conjugation to three different proteins led to a significant increase in light yield which should be useful for improving the assay sensitivity.

Synthesis and biological studies of the thiols-triggered anticancer prodrug for a more effective cancer therapy by Yuanzhen Xu; Jianjun Chen; Ya Li; Shoujiao Peng; Xueyan Gu; Meng Sun; Kun Gao; Jianguo Fang (2634-2639).
A novel anticancer prodrug compound 1, which was designed to be triggered by thiols and release the chemotherapeutic agent mechlorethamine, was successfully prepared and evaluated for the first time. The activation of compound 1 was determined by NMR analysis and denaturing alkaline agarose gel electrophoresis. A fluorescence image and comet assay indicated that the inducible reactivity of 1 could be accomplished in cell media. The anticancer activities are also discussed.

Domino [4 + 1]-annulation of α,β-unsaturated δ-amino esters with Rh(ii)–carbenoids – a new approach towards multi-functionalized N-aryl pyrrolidines by J. J. Medvedev; O. S. Galkina; A. A. Klinkova; D. S. Giera; L. Hennig; C. Schneider; V. A. Nikolaev (2640-2651).
Catalytic decomposition of diazomalonates and other diazoesters using Rh(ii)- and Cu(ii)-complexes in the presence of α,β-unsaturated δ-(N-aryl)amino esters gives rise to the formation of multi-functionalized pyrrolidines with yields of up to 82%. The reaction apparently occurs as a domino process involving the initial N-ylide formation followed by intramolecular Michael addition to the conjugated system of amino esters to afford the pyrrolidine heterocycle. The whole process can also be classified as a [4 + 1]-annulation of the δ-amino α,β-unsaturated ester with the carbenoid intermediate.

Photocontrol of ion permeation in lipid vesicles with amphiphilic dithienylethenes by Yamuna S. Kandasamy; Jianxin Cai; Alisha Beler; M.-S. Jemeli Sang; Patrick D. Andrews; R. Scott Murphy (2652-2663).
The integration of photochromic dithienylethenes (DTEs) with lipid vesicles as photoresponsive membrane disruptors for ion transport applications has been examined. We have synthesized three amphiphilic DTEs 1–3 that incorporate a terminally charged alkyl chain, and contain methyl or phenylethynyl substituents at the reactive carbons. Our photochromic reactivity studies suggest that the inclusion of a single alkyl chain favors the photoactive antiparallel conformation of DTEs, given the significant improvement in the cyclization quantum yield over previous phenylethynyl derivatives. Our ion permeation studies show that the open-ring isomers of these DTEs are more disruptive than the closed-ring isomers in the four lipid vesicle systems studied, regardless of their lamellar phase at room temperature. In addition, a steric effect was clearly observed as DTEs incorporating the comparatively smaller methyl group exhibited lower rates of ion permeation than the bulkier phenylethynyl group. In all cases, UV irradiation led to a reduction in ion permeability. In fact, the methyl analog exhibited a significant reduction in ion permeability in gel-phase lipid vesicles upon UV exposure. Also, the hexyl chain derivatives had a greater effect on membrane permeability than the dodecyl derivative owing to their relative position in the bilayer membrane of lipid vesicles.

Ligand orientation in a membrane-embedded receptor site revealed by solid-state NMR with paramagnetic relaxation enhancement by Christopher A. P. Whittaker; Simon G. Patching; Mikael Esmann; David A. Middleton (2664-2668).
NMR relaxation enhancement by paramagnetic metals provides powerful restraints on the three-dimensional structures of proteins in solution, and this approach has recently been utilized in several NMR structural investigations of proteins in the solid-state. Here we utilize paramagnetic relaxation enhancement (PRE) by Mn2+ with cross-polarization magic-angle spinning (CP-MAS) solid-state NMR to investigate the interaction of a membrane-embedded protein the Na,K-ATPase (NKA) with a cardiotonic steroid inhibitor. The inhibitor, a diacetonide derivate of the cardiac glycoside ouabain, with 13C labelled acetonide groups in the rhamnose sugar and steroid moieties ([13C2]ODA), is 1000-fold less potent than the parent compound. It is shown that the 13C CP-MAS solid-state NMR spectra of the NKA-[13C2]ODA complex exhibit distinct signals for the two 13C labels of the inhibitor when bound to the ouabain site of membrane-embedded NKA. Recent crystal structures of NKA indicate that the catalytic α-subunit binds a single Mn2+ in a transmembrane site close to the high-affinity ouabain site. Here, complexation of NKA with Mn2+ broadens the resonance line from the rhamnose group substantially more than the steroid peak, indicating that the rhamnose group is closer to the Mn2+ site than is the steroid group. These observations agree with computational molecular docking simulations and are consistent with ODA adopting an inverted orientation compared to ouabain in the cardiac glycoside site, with the modified rhamnose group drawn toward the transmembrane centre of the protein. This work demonstrates that PRE can provide unique information on the positions and orientations of ligands within their binding pockets of transmembrane proteins.

A novel Prins cascade process for the stereoselective synthesis of oxa-bicycles by B. V. Subba Reddy; A. Venkateswarlu; B. Sridevi; Kanakaraju Marumudi; A. C. Kunwar; G. Gayatri (2669-2672).
E- and Z-9-Methyldeca-3,8-dien-1-ols undergo smooth cyclization with aldehydes in the presence of 20 mol% AgSbF6 under extremely mild conditions to generate the corresponding oxa-bicycles in good yields with excellent selectivity. In fact, E-olefin affords the trans-product exclusively, whereas the Z-olefin gives the cis-product predominantly. In the case of E- or Z-8-methylnona-3,8-dien-1-ol, the product is formed via the termination of Prins cyclization with an allylic C–H bond through olefin migration. The termination of Prins cyclization with tethered olefin is an unprecedented reaction, which provides a useful motif of various natural products.

Volatiles from nineteen recently genome sequenced actinomycetes by Christian A. Citron; Lena Barra; Joachim Wink; Jeroen S. Dickschat (2673-2683).
The volatiles released by agar plate cultures of nineteen actinomycetes whose genomes were recently sequenced were collected by use of a closed-loop stripping apparatus (CLSA) and analysed by GC/MS. In total, 178 compounds from various classes were identified. The most interesting findings were the detection of the insect pheromone frontalin in Streptomyces varsoviensis, and the emission of the unusual plant metabolite 1-nitro-2-phenylethane. Its biosynthesis from phenylalanine was investigated in isotopic labelling experiments. Furthermore, the identified terpenes were correlated to the information about terpene cyclase homologs encoded in the investigated strains. The analytical data were in line with functionally characterised bacterial terpene cyclases and particularly corroborated the recently suggested function of a terpene cyclase from Streptomyces violaceusniger by the identification of a functional homolog in Streptomyces rapamycinicus.

In tandem or alone: a remarkably selective transfer hydrogenation of alkenes catalyzed by ruthenium olefin metathesis catalysts by Grzegorz Krzysztof Zieliński; Cezary Samojłowicz; Tomasz Wdowik; Karol Grela (2684-2688).
A system for transfer hydrogenation of alkenes, composed of a ruthenium metathesis catalyst and HCOOH, is presented. This operationally simple system can be formed directly after a metathesis reaction to effect hydrogenation of the metathesis product in a single-pot. These hydrogenation conditions are applicable to a wide range of alkenes and offer remarkable selectivity.

A benzyl alcohol derivative of the BDPA radical for fast dissolution dynamic nuclear polarization NMR spectroscopy by J. L. Muñoz-Gómez; E. Monteagudo; V. Lloveras; T. Parella; J. Veciana; J. Vidal-Gancedo (2689-2693).
The synthesis, structural characterization and the successful application of a carbon centered radical derived from 1,3-bisdiphenylene-2-phenylallyl (BDPA), its benzyl alcohol derivative (BA-BDPA), as a polarizing agent for Dynamic Nuclear Polarization (DNP) are described. The reported BA-BDPA radical meets all the requirements to become a promising candidate for its use in in vivo DNP-NMR experiments: it is soluble in neat [1-13C]pyruvic acid, insoluble in the dissolution transfer solvent and is effective as a polarizing agent in fast dissolution DNP-NMR applications, without the need for using glassing agents. Moreover, it enables a simple but effective in-line radical filtration to obtain hyperpolarized solutions of [1-13C]pyruvic acid free of radicals that offers a better polarization performance.

P-stereogenic PNP pincer-Pd catalyzed intramolecular hydroamination of amino-1,3-dienes by Zehua Yang; Chao Xia; Delong Liu; Yangang Liu; Masashi Sugiya; Tsuneo Imamoto; Wanbin Zhang (2694-2702).
A new P-stereogenic PNP pincer-Pd complex was readily prepared from optically pure 2,6-bis[(boranato(tert-butyl)methylphosphino)methyl]pyridine. It was used in the asymmetric intramolecular hydroamination of amino-1,3-dienes, with the desired products being obtained in good yields and with excellent regioselectivities and up to moderate enantioselectivities. The absolute configuration of one of the hydroamination products was determined by X-ray crystallography studies. This simple and efficient procedure can be used for the synthesis of allyl-type chiral pyrrolidine derivatives.

Synthesis of locked cyclohexene and cyclohexane nucleic acids (LCeNA and LCNA) with modified adenosine units by Michal Šála; Milan Dejmek; Eliška Procházková; Hubert Hřebabecký; Jiří Rybáček; Martin Dračínský; Pavel Novák; Šárka Rosenbergová; Jiří Fukal; Vladimír Sychrovský; Ivan Rosenberg; Radim Nencka (2703-2715).
We describe here the preparation of conformationally locked cyclohexane nucleic acids designed as hybrids between locked nucleic acids (LNAs) and cyclohexene nucleic acids (CeNAs), both of which excel in hybridization with complementary RNAs. We have accomplished the synthesis of these adenine derivatives starting from a simple ketoester and installed all four chiral centres by means of total synthesis. The acquired monomers were incorporated into nonamer oligonucleotides.

Synthesis of 2-aryl-3-(2-cyanoethyl)aziridines and their chemical and enzymatic hydrolysis towards γ-lactams and γ-lactones by Karen Mollet; Lena Decuyper; Saskia Vander Meeren; Nicola Piens; Karel De Winter; Tom Desmet; Matthias D'hooghe (2716-2725).
Trans- and cis-2-aryl-3-(2-cyanoethyl)aziridines, prepared via alkylation of the corresponding 2-aryl-3-(tosyloxymethyl)aziridines with the sodium salt of trimethylsilylacetonitrile, were transformed into variable mixtures of 4-[aryl(alkylamino)methyl]butyrolactones and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones via KOH-mediated hydrolysis of the cyano group, followed by ring expansion. In addition, next to this chemical approach, enzymatic hydrolysis of the former aziridinyl nitriles by means of a nitrilase was performed as well, interestingly providing a selective route towards the above-mentioned functionalized γ-lactams.

Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch–Cope sequence with intramolecular Friedel–Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product.

Highly enantioselective 1,3-dipolar cycloaddition reactions of α-substituted diazoacetates are accomplished by catalysis of the chiral oxazaborolidinium ion. Functionalized 2-pyrazolines are synthesized in high to excellent enantiomeric ratios (up to >99 : 1). The synthetic utility of 2-pyrazoline was expanded via preparation of 2,4-diamino ester compounds bearing a chiral quaternary carbon center.

Silver catalysed decarboxylative alkylation and acylation of pyrimidines in aqueous media by Wen-Peng Mai; Bin Sun; Li-Qin You; Liang-Ru Yang; Pu Mao; Jin-Wei Yuan; Yong-Mei Xiao; Ling-Bo Qu (2750-2755).
Decarboxylative alkylation or acylation reactions of simple pyrimidines have been developed in aqueous media. Using aliphatic carboxylic acids or 2-oxocarboxylic acids and pyrimidines as substrates and silver as the catalyst, the 4-substituted alkyl or acyl pyrimidines were isolated in moderate to good yields.

Templating carbohydrate-functionalised polymer-scaffolded dynamic combinatorial libraries with lectins by Clare S. Mahon; Martin A. Fascione; Chadamas Sakonsinsiri; Tom E. McAllister; W. Bruce Turnbull; David A. Fulton (2756-2761).
A conceptually new approach to the design of macromolecular receptors for lectins is outlined. Carbohydrate-functionalised Polymer-Scaffolded Dynamic Combinatorial Libraries (PS-DCLs) have been prepared in aqueous solution by the reversible conjugation of carbohydrates possessing acylhydrazide functionalities in their aglycone on to an aldehyde-functionalised polymer scaffold. PS-DCLs have been shown to undergo compositional change in response to the addition of lectin templates, with polymer scaffolds preferentially incorporating carbohydrate units which recognise the lectin added. This compositional change has been shown to generate polymers of significantly enhanced affinity for the lectin added, with enhancements in free energy of binding in the range of 5.2–8.8 kJ mol−1 observed. Experiments indicate that these enhancements are not only as a consequence of increased display of the preferred carbohydrate upon the polymer scaffold, but that templation also reorganises key residues into strategic positions in order to interact more strongly with the target.

TEMPO-mediated homocoupling of aryl Grignard reagents: mechanistic studies by Sandip Murarka; Juri Möbus; Gerhard Erker; Christian Mück-Lichtenfeld; Armido Studer (2762-2767).
The mechanism of the TEMPO mediated oxidative homo-coupling of aryl Grignard reagents is investigated in detail by experimental and computational studies. Experimental data reveal that the nitroxide-mediated homocoupling reaction of aryl Grignard reagents does not occur via free aryl radicals. Evidence for the presence of biaryl radical anions as intermediates in the coupling reaction is provided. It is also shown that PhMgPh under bromide free conditions in the presence of TEMPO does not undergo homocoupling. However, upon addition of MgBr2, C–C bond formation smoothly proceeds documenting the important role of the bromide anions in the oxidative homocoupling. DFT calculations show that an intramolecular electron transfer to a Mg-complexed TEMPO ligand with subsequent biaryl formation in a dimeric complex is viable and in agreement with experimental reaction conditions.

BF3-Et2O mediated skeletal rearrangements of norbornyl appended cyclopentanediols by Chintada Nageswara Rao; Faiz Ahmed Khan (2768-2775).
An unusual cascade rearrangement has been noticed as a competitive reaction during the treatment of norbornyl appended cyclopentanediols with a Lewis acid (LA): a BF3-Et2O mediated pinacol–pinacolone rearrangement. Deketalization and pinacolone rearrangement occur at two different sites in the molecule and are responsible for the observed cascade rearrangement product. However, deketalization appears to be triggering the cascade steps. The kinetically more stable pinacolone product with an exo-Me group was observed in the case of the bromo analogue, whereas, the thermodynamically more stable pinacolone product with an endo-Me group was observed in the case of the chloro analogue. Epimerization via tautomerization of one diastereomer to the other diastereomer under Lewis acid reflux conditions is possible. On the contrary, the diol equivalent epoxides provide only the diastereomeric mixture of pinacolone products under similar LA reaction conditions. The lower yields observed in the case of the epoxides are due to unwanted side reactions taking place between the two competitive reactive centers, namely, ketal and epoxide. Further, a sequence of elimination, nucleophilic substitution and Ritter type hydrolysis reactions of the epoxides resulted in unexpected elimination products. This transformation not only facilitates a regioselective epoxide opening, but also provides a new route for the preparation of allylic amides of the norbornyl appended cyclopentane ring system.

Peptidic foldamers have recently emerged as a novel class of artificial oligomers with properties and structural diversity similar to that of natural peptides, but possessing additional interesting features granting them great potential for applications in fields from nanotechnology to pharmaceuticals. Among these, foldamers containing 1,4- and 1,5-substitued triazole amino acids are easily prepared via the Cu- and Ru-catalyzed click reactions and may offer increased side chain variation, but their structural capabilities have not yet been widely explored. We here describe a systematic analysis of the conformational space of the two most important basic units, the 1,4-substitued (4Tzl) and the 1,5-substitued (5Tzl) 1,2,3-triazole amino acids, using quantum chemical calculations and NMR spectroscopy. Possible conformations of the two triazoles were scanned and their potential minima were located using several theoretical approaches (B3LYP/6-311++G(2d,2p), ωB97X-D/6-311++G(2d,2p), M06-2X/6-311++G(2d,2p) and MP2/6-311++G(2d,2p)) in different solvents. BOC-protected versions of 4Tzl and 5Tzl were also prepared via one step transformations and analyzed by 2D NOESY NMR. Theoretical results show 9 conformers for 5Tzl derivatives with relative energies lying close to each other, which may lead to a great structural diversity. NMR analysis also indicates that conformers preferring turn, helix and zig-zag secondary structures may coexist in solution. In contrast, 4Tzl has a much lower number of conformers, only 4, and these lack strong intraresidual interactions. This is again supported by NMR suggesting the presence of both extended and bent conformers. The structural information provided on these building units could be employed in future design of triazole foldamers.

Various tetrasubstituted pyrroles/pyrazoles have been prepared from nitro-substituted 1,3-enynes with aromatic amines/hydrazines via a copper-catalyzed cascade aza-Michael addition, cyclization and aromatization at room temperature. This protocol is also effective for the synthesis of tetrasubstituted pyrazoles in high yields.

Alkylidene malonates and α,β-unsaturated α′-hydroxyketones are demonstrated to be efficient classes of electrophiles for the scandium(iii) triflate/sodium dodecyl sulphate (SDS) catalysed vinylogous Friedel–Crafts alkylation of indoles and pyrroles in water. These substrates contain an easily removable auxiliary group that increases affinity for the catalytic metal ion in such a way that they can compete with water for binding to the catalytic metal ion. Thus, alkylidene malonates and α,β-unsaturated α′-hydroxyketones are attractive substitutes for, e.g., α,β-unsaturated carboxylic acids and -esters, which in aqueous media are not reactive enough in these reactions. The combination of Lewis acid and SDS in catalysis results in considerable acceleration of the reaction in water compared to organic solvents. The method presented is attractive because the reactions are fast, experimentally straightforward and give rise to high yields of products.

An extension of our reported protocol to benzofused heterocyclic derivatives (benzofurans, indoles, isochromeneimines), involving a palladium-induced cascade of N-cyclization and oxidative Heck reactions of o-alkynylanilines, has allowed the preparation of indolobenzazepinones (paullones) with an alkylidene group at C7 in just 3–4 steps from ortho-iodoanilines. Some of these compounds behave as Sirt1 activators in biochemical assays.

Back cover (2811-2812).