Organic & Biomolecular Chemistry (v.9, #8)

Front cover (2557-2558).

Contents (2559-2578).

Synthetic oligonucleotides (ONs) are valuable tools that interfere with gene expression by specifically binding to target genes in a sequence-specific manner. Reactive ONs containing cross-linking agents are expected to induce efficient inhibition because they bind covalently to target genes. In recent years, researchers have reported several cross-linking reactions that target DNA induced by external stimuli. This short review highlights recently developed novel cross-linking reactions, focusing particularly on nucleoside derivatives developed by our group.

Organic reactions mediated by electrochemically generated ArS+ by Kouichi Matsumoto; Seiji Suga; Jun-ichi Yoshida (2586-2596).
Low-temperature electrochemical oxidation of ArSSAr was carried out to generate a pool of “ArS+”. Spectroscopic studies (1H NMR and CSI-MS) of the resulting solution revealed the accumulation of ArS(ArSSAr)+. The resulting “ArS+” pool reacted with alkenes and alkynes to give diarylthio-substituted products. The “ArS+” pool rapidly reacted with thioacetals to give the corresponding alkoxycarbenium ion pools, which reacted with various carbon nucleophiles (indirect cation pool method). The reaction of the alkoxycarbenium ion pools with stilbene derivatives in the presence of ArSSAr gave thiochroman derivatives. In addition to such stoichiometric reactions, a catalytic amount of “ArS+” serves as an initiator and a chain carrier of some cationic chain reactions involving intramolecular carbon–carbon bond formation. In situ generation of “ArS+” by electrochemical oxidation of ArSSAr with a catalytic amount of electricity in the presence of a substrate is also effective for such cationic chain reactions.

Palladium nanoparticles supported over poly(vinyl)chloride matrix (PVC-Pd0) are prepared through an efficient and inexpensive protocol. The catalyst has been characterized by XRD, SEM and TEM and its utility for the reduction of a range of functional groups as well as for the removal of some common protecting groups employed in peptide chemistry is demonstrated.

Benzaldehyde lyase catalyzed enantioselective self and cross condensation reactions of acetaldehyde derivatives by Peruze Ayhan; İlke Şimşek; Burçe Çifçi; Ayhan S. Demir (2602-2605).
Flexible protected 1,3,4-trihydroxy-2-butanone is synthesized in high enantiomeric excesses by using asymmetric homo- and cross- acyloin coupling of aliphatic aldehydes catalyzed by benzaldehyde lyase.

A novel water soluble Hg2+-selective chemosensor 1 with hemicyanine as fluorescent reporting group and NO2Se2 chelating unit as ion binding site was reported. Chemosensor 1 shows a specific Hg2+ selectivity and discrimination between Hg2+ and chemically similar ions in conjunction with a visible colorimetric change from red to colorless, potentially leading to both “naked-eye” and fluorometric detection of Hg2+ cations.

A novel distyryl boron dipyrromethene substituted with two 4-(dimethylamino)phenylethynyl groups at the 2- and 6-positions has been synthesised and characterised. It exhibits remarkable and reversible pH-responsive changes in the absorption and fluorescence emission spectra, both in organic and in aqueous media.

Dinuclear zinc catalyzed asymmetric Friedel–Crafts amidoalkylation of indoles with aryl aldimines by Bei-Lei Wang; Nai-Kai Li; Jin-Xin Zhang; Guo-Gui Liu; Teng Liu; Qi Shen; Xing-Wang Wang (2614-2617).
The asymmetric Friedel–Crafts amidoalkylation of indoles with aryl aldimines could be efficiently catalyzed by Trost's bis-ProPhenol dinuclear zinc complexes to attain 3-indolyl methanamine derivatives in good to excellent yields (85–98%) with moderate to high enantiomeric ratios (from 70 : 30 up to 95 : 5 er). Remarkably, this approach provides efficient access to enantiomerically enriched 3-indolyl methanamines, which avoids the formation of the undesirable bis- and tris(indolyl)methanes (BIMs and TIMs) byproduct.

We have developed a synthetic strategy to selectively incorporate the imidazole ring into the 1,1′-bi-2-naphthol (BINOL) skeleton at the different position. The resulting conformationally rigid BINOL-based diimidazolyl ligands bearing both hydrogen-bond-acceptors and -donators can self-assemble into homochiral channel-like mono-component organic frameworks via intermolecular O–H⋯N hydrogen bonds between the phenolic hydroxyl group and the N2 or N4 atom of the imidazole ring.

Formation and regulation of fullerene-incorporation in liposomes under the phase transition temperature by Atsushi Ikeda; Yoshihiko Kawai; Jun-ichi Kikuchi; Motofusa Akiyama; Eiji Nakata; Yoshihiro Uto; Hitoshi Hori (2622-2627).
The fullerene-exchange reaction from a cyclodextrin cavity to liposomes represents one of the best methods to prepare lipid membrane-incorporated [70]fullerenes (C70). The C70-exchange reaction occurred completely at temperatures above the phase transition temperature (Tm) of the liposomes; however, lowering the temperature to below the Tm led to C70 aggregation outside the liposomes. This observation has limited the development of more functional LMIC70 using a variety of liposome compositions. In this paper, this reaction was found to occur efficiently by the addition of small amounts of lipids bearing a π-moiety. The π-moieties act as a gate when hydrophobic C70 migrates into the hydrophilic liposome surface. Therefore, the π-moieties should exist in the polar head groups of the lipids and the C70-exchange reaction can be controlled by pH.

Signal control by self-assembly of fluorophores in a molecular beacon—a model study by Sarah M. Biner; Dominic Kummer; Vladimir L. Malinovskii; Robert Häner (2628-2633).
Pyrene excimer fluorescence is efficiently regulated through formation of π-stacked aggregates between dialkynylpyrene (Y) and perylenediimide (E) residues located in the stem region of a molecular beacon (MB). The building blocks form organized, multichromophoric complexes in the native form. Hybridization to the target results in a conformational reorganization of the chromophores. The nature of the aggregates was investigated by changing the number of chromophores and natural base pairs in the beacon stem. The formation of different types of complexes (EYEY→YEY→EY) is revealed by characteristic spectroscopic changes. The data show that signal control is an intrinsic property of the interacting chromophores. The directed assembly of non-nucleosidic chromophores can be used for the generation of an on/off switch of a fluorescence signal. The concept may find applications in various types of light-based input/output systems.

Neutral species from “non-protic” N-heterocyclic ionic liquids by Oldamur Hollóczki; László Nyulászi (2634-2640).
Possible isomerisation of 1,2,3-trialkylimidazolium and 1-alkylpyridinium ion pairs by proton transfer and by the nucleophilic addition of the anion to the cation have been investigated at the B3LYP/6-31+G* and B3LYP/6-311+G** levels of density functional theory. The deprotonation energies of 1,2,3-trialkylimidazolium and 1-alkylpyridinium cations to diaza-pentafulvene and pyridinium-ylide, respectively, were only slightly larger than that of 1,3-dialkylimidazolium salts yielding N-heterocyclic carbenes. Accordingly, in the case of 1,2,3-dialkylimidazolium salt ion pairs the stability of the H-bonded complex between the fulvene and the corresponding acid can be comparable to that of the ion pair in the presence of sufficiently basic anions, such as acetate. In the case of the pyridinium salts the nucleophilicity of the cation dominates over the acidity, and the formation of 1,2- or 1,4-dihydropyridine derivatives is preferred over proton transfer.

Dynamic octopus amphiphiles contain one charged “head,” here a guanidinium cation, together several hydrophobic “tails” (or “tentacles”) that can be attached and exchanged in situ by reversible hydrazone formation. Quite surprisingly, their ability to activate DNA as transporters in lipid bilayer membranes was found to increase with the number of tails (up to four) as well as with their length (up to eight carbons). Both encouraged and puzzled by these results, we decided that a comprehensive screening of octopus amphiphiles with regard to number (from one to six) and length (from three to eighteen carbons) of their tails would be appropriate at this point. For this purpose, we here report the synthesis of cationic hexahydrazide peptide dendrons together with that of aldehydes with long, saturated, unsaturated and branched hydrophobic tails. Comprehensive screening of the completed collection of tails and heads reveals that the ability of octopus amphiphiles to activate DNA transporters shifts with increasing number of tails to decreasing length of the tails. Moreover, cis-alkenyl and branched alkyl tails are more active than their linear analogs, branched aromatic tails are best. These overall very meaningful trends for octopus amphiphiles will be of importance for sensing applications and fragrant cellular uptake.

Four new di-substituted phenanthroline-based compounds a–d have been designed and prepared, and they have been shown to induce the formation of anti-parallel structure of human telomeric G-quadruplex DNA by CD spectra. FRET assay indicates that the melting temperature increases (ΔTm values) of G-quadruplex in buffer (pH 7.4) containing 100 mM NaCl are 31.6, 34.6, 17.8 and 32.6 °C for the compounds (1.0 μM) a, b, c and d, respectively. Competitive FRET assay shows that the four compounds exhibit a high G-quadruplex DNA selectivity over duplex DNA. Three of the compounds are the potent telomerase inhibitors and HeLa cell proliferation inhibitors.

Protecting-group-free synthesis of a dual CCK1/CCK2 receptor antagonist by Jing Liu; Xiaohu Deng; Anne E. Fitzgerald; Zachary S. Sales; Hariharan Venkatesan; Neelakandha S. Mani (2654-2660).
In our pursuit of an efficient, protecting-group-free synthesis of the dual CCK1/CCK2 receptor antagonist 1, we have developed chemoselective conditions for sulfonamide formation reaction in pure water and a PhNMe2 mediated carboxamide formation, both in the presence of a carboxylic acid. Practical synthesis of an unnatural, chiral β-aryl-α-amino acid is also described.

Overcoming challenges in the palladium-catalyzed synthesis of electron deficient ortho-substituted aryl acetonitriles by Molly C. Brannock; William J. Behof; Gregory Morrison; Christopher B. Gorman (2661-2666).
Highly electron deficient monoaryl, di-aryl and bis-diaryl acetonitriles were effectively synthesized using either a nucleophilic aromatic substitution (NAS) or a palladium-mediated coupling pathway. Synthesis of di-aryl acetonitriles most conveniently proceeded via NAS – palladium-mediated coupling was not required. This reaction, however, results in a product that is more acidic than the reactants. Facile deprotonation of the product prevents efficient formation of the bis-diaryl acetonitrile through a NAS pathway. Thus, palladium-mediated coupling is required to prepare the bis-diaryl acetonitrile efficiently. In the palladium-catalyzed coupling, choice of base and solvent (and thus the counter cation for the benzylic anion nucleophile) is important. Also, choice of the supporting ligand is important, indicating the sensitivity of the reaction to steric and ligand electronic effects.

Laccase-catalyzed oxidation of substituted catechols followed by reaction with 4-hydroxy-pyrone/-benzopyrone afforded substituted benzofuran regioisomers whose structures with only two aromatic protons in total prevent a rapid structural assignment. Based on the evaluation of 1H–13C long-range coupling constants a rule of thumb could be deduced for an easy and unambiguous differentiation between the possible regioisomers formed. DFT frontier orbital calculations of the reactants offer an interesting tool to explain the regioselectivity of the key reaction.

15N-labeled ionic probe attachment mass spectrometry of carbon clusters by Fumihiro Ito; Kentaro Yamaguchi (2674-2679).
An ionization method that uses metal-complex-based ionization probes, malonic acid 3-[2,6-bis(4,4-dimethyloxazolin-2-yl)pyridin-4-yloxy]propyl ethyl ester (EM-TMpybox) and potassium N-{3-[2,6-bis(4,4-dimethyloxazolin-2-yl)pyridine-4-yloxy]propyl} aminoacetate (Sar-TMpybox), was developed for isotope ratio analysis and the effective ionization of unsubstituted carbon clusters. The preparation of Sar-TMpybox and EM-TMpybox and their applications in cold-spray ionization mass spectrometry are reported. A probe applicable to a substituted fullerene is also demonstrated.

Synthesis of novel functional polycyclic chromones through Michael addition and double cyclizations by Yang Liu; Liping Huang; Fuchun Xie; Xuxing Chen; Youhong Hu (2680-2684).
A base-promoted, microwave-assisted one-pot tandem reaction from simple 3-(1-alkynyl)chromones with 2-halobenzylic nitriles (esters or amides) for the synthesis of novel functional polycyclic chromenones has been developed. This tandem process involves multiple reactions, such as Michael addition and double cyclizations without a transition metal catalyst.

Intramolecular Diels–Alder chemistry of 4-vinylimidazoles by Yong He; Pasupathy Krishnamoorthy; Heather M. Lima; Yingzhong Chen; Haiyan Wu; Rasapalli Sivappa; H. V. Rasika Dias; Carl J. Lovely (2685-2701).
An investigation of 4-vinylimidazoles as diene components in the intramolecular Diels–Alder reaction is described. In the course of these studies several parameters affecting the cycloaddition were evaluated including the nature of the imidazole protecting group, the type of dienophile and the linking group. These investigations established that amino linkers were generally more effective than either ethers or esters. In most cases, the cycloadditions were highly stereoselective, resulting in the formation of products derived from an anti transition state. The polysubstituted tetrahydrobenzimidazole core of the pyrrole-imidazole alkaloid ageliferin can be constructed through the use of pseudo dimeric 4-vinylimidazoles.

The stereoselectivity of the Staudinger reactions involving monosubstituted ketenes with electron acceptor substituents was investigated experimentally by determination of the product stereochemistry and theoretically via DFT calculations. The results indicate that imines preferentially attack the less sterically hindered exo-side of the ketenes to generate zwitterionic intermediates. Subsequently, for cyclic imines, the intermediates undergo a conrotatory ring closure directly to produce β-lactams, while for linear imines, the imine moiety of the intermediates isomerizes to more stable intermediates, which further undergo a conrotatory ring closure to afford trans-β-lactams. The steric hindrance and the isomerization, rather than the torquoelectronic effect, play crucial roles in controlling the stereoselectivity in the practical Staudinger reactions involving monosubstituted ketenes with electron acceptor substituents, although the unaccessible borylketene with a powerful electron acceptor group controls the stereoselectivity torquoelectronically, in theory.

A general approach to the high-yielding asymmetric synthesis of chiral 3-alkyl-4-nitromethylchromans as drug intermediates was achieved through cascade Barbas–Michael and acetalization (BMA) reactions on 2-(2-nitrovinyl)phenols with aldehydes in the presence of a catalytic amount of (R)-DPPOTMS and PhCO2H. Herein, we have also demonstrated the application of chiral BMA products in the synthesis of functionalized chromanes and chromenes in very good yields with high optical purity, which are very useful compounds in medicinal chemistry.

The C-alkylation of cyclic α-nitroketones with α-halobenzyl halides in the presence of DBU followed by a Pd-catalyzed intramolecular C-arylation afforded benzo-and naphtho-fused bicyclo[n.3.1]alkane derivatives (n = 3, 4, 5) in excellent overall yields for the two-step sequence. In some of the reactions starting from α-nitrocyclooctanone, the major products were fused indane derivatives arising from an intramolecular attack of an intermediate Pd species onto the carbonyl group, followed by elimination.

A new series of water compatible primary-tertiary diamine catalysts derived from natural primary amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary diamine-Brønsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91 : 9 (syn/anti) under mild reaction conditions.

Stannylated allylic carbonates are suitable substrates for Pd-catalyzed allylic aminations. In DMF and with [allylPdCl]2 as catalyst the stannylated allyl amines formed can be directly coupled with electrophiles according to the Stille protocol, giving rise to highly functionalized buiding blocks in excellent yields.

Structure and unimolecular chemistry of protonated sulfur betaines, (CH3)2S+(CH2)nCO2H (n = 1 and 2) by Ellie Jung-Hwa Yoo; Linda Feketeová; George N. Khairallah; Jonathan M. White; Richard A. J. O'Hair (2751-2759).
The fixed charge zwitterionic sulfur betaines dimethylsulfonioacetate (DMSA) (CH3)2S+CH2CO2 and dimethylsulfoniopropionate (DMSP) (CH3)2S+(CH2)2CO2 have been synthesized and the structures of their protonated salts (CH3)2S+CH2CO2H⋯Cl [DMSA.HCl] and (CH3)2S+(CH2)2CO2H⋯Pcr [DMSP.HPcr] (where Pcr = picrate) have been characterized using X-ray crystallography. The unimolecular chemistry of the [M+H]+ of these betaines was studied using two techniques; collision-induced dissociation (CID) and electron-induced dissociation (EID) in a hybrid linear ion trap Fourier transform ion cyclotron resonance mass spectrometer. Results from the CID study show a richer series of fragmentation reactions for the shorter chain betaine and contrasting main fragmentation pathways. Thus while (CH3)2S+(CH2)2CO2H fragments via a neighbouring group reaction to generate (CH3)2S+H and the neutral lactone as the most abundant fragmentation channel, (CH3)2S+CH2CO2H fragments via a 1,2 elimination reaction to generate CH3S+CH2 as the most abundant fragment ion. To gain insights into these fragmentation reactions, DFT calculations were carried out at the B3LYP/6-311++G(2d,p) level of theory. For (CH3)2S+CH2CO2H, the lowest energy pathway yields CH3S+CH2via a six-membered transition state. The two fragment ions observed in CID of (CH3)2S+(CH2)2CO2H are shown to share the same transition state and ion-molecule complex forming either (CH3)2S+H or (CH2)2CO2H+. Finally, EID shows a rich and relatively similar fragmentation channels for both protonated betaines, with radical cleavages being observed, including loss of ˙CH3.

The mechanisms of gold(iii)-catalyzed synthesis of highly substituted furans via [3,3]-sigmatropic rearrangements and/or [1,2]-acyloxy migration based on propargyl ketones have been investigated using density functional theory calculations at BHandHLYP/6-31G(d,p) (SDD for Au) level of theory. Solvent effects on these reactions were explored using calculations that included a polarizable continuum model (PCM) for the solvent (toluene). Two plausible pathways that lead to the formation of Au(iii) vinyl carbenoid and an allenyl structure through [3,3]-sigmatropic rearrangements, [1,2]-acyloxy migration via oxirenium and dioxolenylium were performed. Our calculated results suggested: (1) the major pathway of the cycle causes an initial Rautenstrauch-type [1,2]-migration via oxirenium to form an Au(iii) vinyl carbenoid. Subsequent cycloisomerization of this intermediate then provides the corresponding furan whether for the methyl-substituted propargylic acetates or the phenyl-substituted propargylic acetates; (2) for the methyl-substituted propargylic acetates, the formation of Au(iii) vinyl carbenoid structures was the rate-determining step. However, intramolecular nucleophilic attack and subsequent cycloisomerization to give the final product was rate-determining for the phenyl-substituted propargylic acetates. The computational results are consistent with the experimental observations of Gevorgyan, et al. for gold(iii)-catalyzed synthesis of highly substituted furans based on propargyl ketones.

Phenazinolins A–E: novel diphenazines from a tin mine tailings-derived Streptomyces species by Zhang-Gui Ding; Ming-Gang Li; Jie Ren; Jiang-Yuan Zhao; Rong Huang; Qing-Zhong Wang; Xiao-Long Cui; Hua-Jie Zhu; Meng-Liang Wen (2771-2776).
Phenazinolins A–E (1–5), which possess a carbon skeleton unique to diphenazines (the azabicyclo[3.3.1]nonadienol moiety in 1–3 and the oxabicyclo[3.3.1]nonadienol moiety in 4 and 5), were isolated from tin mine tailings-derived Streptomyces diastaticus YIM DT26, with 1–3 exhibited appreciable cytotoxicity and antibiotic effects.

Thiourea catalyzed organocatalytic enantioselective Michael addition of diphenyl phosphite to nitroalkenes by Ana Alcaine; Eugenia Marqués-López; Pedro Merino; Tomás Tejero; Raquel P. Herrera (2777-2783).
Bifunctional thiourea catalyzes the enantioselective Michael addition reaction of diphenyl phosphite to nitroalkenes. This methodology provides a facile access to enantiomerically enriched β-nitrophosphonates, precursors for the preparation of synthetically and biologically useful β-aminophosphonic acids. DFT level of computational calculations invoke the attack of the diphenyl phosphite to the nitroolefin by the Re face, this give light to this scarcely explored process update in the literature. The computational calculations support the absolute configuration obtained in the final adducts.

Sequential two-step multienzyme synthesis of tumor-associated sialyl T-antigens and derivatives by Kam Lau; Hai Yu; Vireak Thon; Zahra Khedri; Meghan E. Leon; Bao K. Tran; Xi Chen (2784-2789).
A series of α2–3-sialylated β1–3-linked galactosides, including sialyl T-antigens, 3′-sialyl galacto-N-biose, 3′-sialyl lacto-N-biose, and their derivatives containing natural and non-natural sialic acid forms have been synthesized from simple monosaccharides using an efficient sequential two-step multienzyme approach.

Pyridinium derivatives of histamine are potent activators of cytosolic carbonic anhydrase isoforms I, II and VII by Khyati Dave; Andrea Scozzafava; Daniela Vullo; Claudiu T. Supuran; Marc A. Ilies (2790-2800).
A series of positively-charged derivatives has been prepared by reaction of histamine with substituted pyrylium salts. These pyridinium histamine derivatives were investigated as activators of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely the human isoforms hCA I, II and VII. Activities from the subnanomolar to the micromolar range were detected for these compounds as activators of the three isoforms, confirming the validity of current and previous designs. The substitution pattern at the pyridinium ring was the main factor influencing activity, the three isoforms showing different structural requirements for good activity, related with the number of pyridinium substituting groups and their nature, among various alkyl, phenyl and para-substituted styryl moieties. We were successful in identifying nanomolar potent and selective activators for each isozyme and also activators with a relatively good activity against all isozymes tested—valuable lead compounds for physiology and pathology studies involving these isozymes.

Stereoselective synthesis of polyhydroxylated aminocyclohexanes by Sajjad Ahmad; Lynne H. Thomas; Andrew Sutherland (2801-2808).
The stereoselective synthesis of a series of di- and tri-hydroxylated aminocyclohexane derivatives has been developed. A one-pot, two step tandem process involving an Overman rearrangement and a ring closing metathesis reaction has been utilised for the asymmetric synthesis of (1S)-1-(2′,2′,2′-trichloromethylcarbonylamino)cyclohexa-2-ene. Oxidation of this cyclohexene derivative was then studied leading to the preparation of two diol analogues in excellent stereoselectivity. (1S)-1-(2′,2′,2′-trichloromethylcarbonylamino)cyclohexa-2-ene was then converted to a novel allylic alcohol via a 4,5-dihydro-1,3-oxazole. Functionalisation of this allylic alcohol by Upjohn dihydroxylation conditions or by a directed epoxidation/hydrolysis sequence of reactions allowed the synthesis of two dihydroconduramines in excellent stereoselectivity. The stereochemical assignment of all compounds prepared was confirmed by NOE experiments or X-ray structure determination.

Total synthesis of the Amaryllidaceae alkaloid clivonine by Helmut Haning; Carles Giró-Mañas; Victoria L. Paddock; Christian G. Bochet; Andrew J. P. White; Gerald Bernardinelli; Inderjit Mann; Wolfang Oppolzer; Alan C. Spivey (2809-2820).
Two syntheses of the Amaryllidaceae alkaloid clivonine (1) are described. Both employ previously reported 7-arylhydrindane 6 as an intermediate but differ in the method employed for subsequent introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a Bischler–Napieralski reaction for this transformation constitutes the first asymmetric synthesis of natural (+)-clivonine. Crystal structures for compounds (±)-13, (±)-16, (−)-20 and (±)-28 are also reported.

A one pot three-step process for the synthesis of an array of arylated benzimidazoribosyl nucleosides by Jolanta Hałuszczak; Simon J. F. Macdonald; Marie E. Migaud (2821-2831).
A three-step one pot reaction/purification protocol was developed to facilitate rapid access to benzimidazole-based nucleosides, for which benzoylated benzimidazoribosyl nucleosides incorporating boronic esters were key reaction intermediates.

An anomalous hydration/dehydration sequence for the mild generation of a nitrile oxide by Nagatoshi Nishiwaki; Kazuya Kobiro; Hideyuki Kiyoto; Shotaro Hirao; Jun Sawayama; Kazuhiko Saigo; Yoshikazu Okajima; Toshiharu Uehara; Asaka Maki; Masahiro Ariga (2832-2839).
A nitrile oxide containing a carbamoyl group is readily generated upon the treatment of 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with water under mild reaction conditions, even in the absence of special reagents. The obtained nitrile oxide undergoes cycloaddition with dipolarophiles, alkynes and alkenes, to afford the corresponding isoxazol(in)es, which are useful intermediates in the synthesis of polyfunctionalized compounds. A plausible mechanism underlying the formation of the nitrile oxide is proposed, which involves an anomalous hydration/dehydration sequence. DFT calculations were also performed to support this mechanism.

Incorporation of porphyrin acetylides into duplexes of the simplified nucleic acid GNA by Hui Zhou; Andrew T. Johnson; Olaf Wiest; Lilu Zhang (2840-2849).
A porphyrin-acetylide-modified GNA (glycol nucleic acid) phosphoramidite building block was synthesized in an economical fashion starting from (S)-glycidyl-4,4′- dimethoxytrityl ether in just 4 steps with an overall yield of 48%. The porphyrin acetylide nucleotide was incorporated into GNA duplexes opposite ethylene glycol abasic sites and the duplexes were analyzed by UV-melting, UV-vis, fluorescence spectroscopy, and circular dichroism. The modified GNA duplexes display lower thermal stabilities, however, the stabilities of the duplexes can be modulated by the incorporation of Zn2+ (further destabilization) or Ni2+ (stabilization relative to the uncomplexed porphyrin). Uncomplexed as well as Ni2+-coordinated porphyrins intercalate into the GNA duplex whereas Zn2+-coordinated porphyrins are most likely located outside the base stack. Adjacent porphyrins in opposite strands of GNA duplexes show an electronic interaction with each other which might be exploited in the future for the design of photoelectrical devices.

Rhodamine-based highly sensitive colorimetric off-on fluorescent chemosensor for Hg2+ in aqueous solution and for live cell imaging by Hengguo Wang; Yapeng Li; Shufei Xu; Yanchun Li; Chen Zhou; Xiaoliang Fei; Lei Sun; Chaoqun Zhang; Yaoxian Li; Qingbiao Yang; Xiaoyi Xu (2850-2855).
A novel rhodamine-based highly sensitive and selective colorimetric off-on fluorescent chemosensor for Hg2+ ions is designed and prepared by using the well-known thiospirolactam rhodamine chromophore and furfural hydrazone as signal-reporting groups. The photophysical characterization and Hg2+-binding properties of sensor RS1 in neutral N, N-dimethylformamide (DMF) aqueous solution are also investigated. The signal change of the chemosensor is based on a specific metal ion induced reversible ring-opening mechanism of the rhodamine spirolactam. The response of the chemosensor for Hg2+ ions is instantaneous and reversible. And it successfully exhibits a remarkably “turn on” response toward Hg2+ over other metal ions (even those that exist in high concentration). Moreover, this sensor is applied for in vivo imaging in Rat Schwann cells to confirm that RS1 can be used as a fluorescent probe for monitoring Hg2+ in living cells with satisfying results, which further demonstrates its value of practical applications in environmental and biological systems.

The synthesis of the novel nucleotide analogues 5′-deoxynucleoside-5′-S-methylphosphonates, starting from 5′-deoxy-5′-haloribonucleosides, 5′-O-tosylribonucleosides, and 2′-O-triflylnucleosides, is described. The phosphonothiolation of these compounds was achieved using S-(diisopropylphosphonomethyl)isothiouronium tosylate, a new, odourless, and efficient equivalent of mercaptomethylphosphonate. The thiolate anion of mercaptomethylphosphonate was generated in situ from the isothiouronium salt in both protic and aprotic solvents using two equivalents of sodium iso-propoxide. The prepared nucleoside 5′-S-methylphosphonates were deprotected, and the free phosphonic acids were transformed into diphosphoryl derivatives (the NTP analogues). Both mononucleotides and NTP analogues were studied as substrates/inhibitors of several enzymes that are involved in the nucleoside/nucleotide metabolism.

Incubation of (3S)-3-fluoro-3-deoxy-d-arabino-heptulosonate 7-phosphate with dehydroquinate (DHQ) synthase from three phylogenetically distinct sources resulted in the production of (6S)-6-fluoroDHQ and its epimer 1-epi-(6S)-6-fluoroDHQ. The differences in the product ratios of the reactions catalysed by each enzyme imply that 1-epi-(6S)-6-fluoroDHQ formation occurs by an unusual partial leakage of a reaction intermediate from the enzyme.

The treatment of β,γ-unsaturated α-ketoesters with phenols in the presence of trityl chloride and 4 Å molecular sieves in refluxing trifluoroacetic acid afforded 4-aryl-2H-chromenes in high yields, in which a reverse of the regiochemistry of Jørgensen–Rutjes chromane synthesis was observed. The isolation of 4H-chromene intermediates, confirmed by single-crystal X-ray analysis, indicates that the early stage of the reaction involves a Friedel–Crafts alkylation/cyclodehydration processes. Stirring of the 4H-chromene intermediate with trityl chloride in deuterotrifluoroacetic acid under reflux afforded the 2H-chromene and triphenylmethane in high yields, which implies the late stage of the reaction involves a hydrogen transfer process. Highly selective derivation of the hydroxyl esters to the corresponding hydroxyl amides, amino acids, amino esters and Friedel–Crafts adducts was further accomplished. Our endeavors will lead to a better understanding of the controlling elements behind their structural motifs. The products were confirmed unambiguously from their spectra and by single-crystal X-ray analysis.

A novel fluorescent system has been assembled by using ATP, surfactant, and a squaraine dye in an aqueous buffer solution. In the system, a cationic surfactant such as cetyl trimethyl ammonium bromide (CTAB) forms a sphere-like micelle, whose positive charge at the surface of the micelle attracts the negatively charged ATP to form a unique organized nanostructure. Such an organized system is shown to interact with the squaraine dye (SQ) to perturb its aggregate structure, thereby generating the optical response. The nanostructure of the assembly has been characterized by dynamic light-scattering (DLS) and atomic force microscopy (AFM). The unique feature of the developed sensing system is that the analytes ATP form part of the assembly structure. The system utilizes forces such as electrostatic interaction and π–π stacking of the aromatic segment of ATP and SQ to achieve the selective detection of ATP.

The SAMP alkylation: A computational study by Rainer Koch (2885-2891).
In a computational study of a stereoselective C–C bond formation, the SAMP alkylation, a previously proposed SE2′-front mechanism is evaluated taking into account all current experimental evidence. Using semiempirical, density functional and perturbation theoretical methods, the structure of the key intermediate is revealed and the metalloretentive nature of the mechanism is explained. The experimental ee values of a range of reactions with different electrophiles and carbonyl sources can be correlated with calculated differences in activation energies. Furthermore, it can be concluded that the selectivity derives from the internal stabilization of the transition state 3_syn (corresponding to an electrophilic attack from above the lithiohydrazone plane) by electrophile–lithium interactions. The fast computational approach can be used best as a screening method which excludes less promising candidates to guide this synthetic method.

Structural effects on the photodissociation of alkoxyamines by Davy-Louis Versace; Yohann Guillaneuf; Denis Bertin; Jean Pierre Fouassier; Jacques Lalevée; Didier Gigmes (2892-2898).
The search for photosensitive alkoxyamines represents a huge challenge. The key parameters governing the cleavage process remain unknown. The dissociation process of light sensitive alkoxyamines is studied as a function of their chemical structures. The photochemical properties of 6 selected compounds are investigated by ESR and laser flash photolysis. It is found that (i) the selectivity of the cleavable N–O vs. C–O bond and (ii) the efficiency of the nitroxide formation are strongly related to the alkoxyamine structure. The distance between the chromophore and the aminoxy group is a key parameter for an efficient pathway of the radical generation as displayed by the photopolymerization ability of these alkoxyamines.

Novel biotinylated bile acid amphiphiles: Micellar aggregates formation and interaction with hepatocytes by Luca Rizzi; Marta Braschi; Miriam Colombo; Nadia Vaiana; Gianpaolo Tibolla; Giuseppe Danilo Norata; Alberico Luigi Catapano; Sergio Romeo; Davide Prosperi (2899-2905).
Amphiphilic bile acids linked through an oligoethylene glycol to a biotin moiety were synthesized and shown to create micellar structures in aqueous environment, interact with avidin and be efficiently incorporated into hepatocyte cells, suggesting their potential as a drug delivery system against liver diseases.

Release of bioactive volatiles from supramolecular hydrogels: influence of reversible acylhydrazone formation on gel stability and volatile compound evaporation by Barbara Buchs (née Levrand); Wolfgang Fieber; Florence Vigouroux-Elie; Nampally Sreenivasachary; Jean-Marie Lehn; Andreas Herrmann (2906-2919).
In the presence of alkali metal cations, guanosine-5′-hydrazide (1) forms stable supramolecular hydrogels by selective self-assembly into a G-quartet structure. Besides being physically trapped inside the gel structure, biologically active aldehydes or ketones can also reversibly react with the free hydrazide functions at the periphery of the G-quartet to form acylhydrazones. This particularity makes the hydrogels interesting as delivery systems for the slow release of bioactive carbonyl derivatives. Hydrogels formed from 1 were found to be significantly more stable than those obtained from guanosine. Both physical inclusion of bioactive volatiles and reversible hydrazone formation could be demonstrated by indirect methods. Gel stabilities were measured by oscillating disk rheology measurements, which showed that thermodynamic equilibration of the gel is slow and requires several cooling and heating cycles. Furthermore, combining the rheology data with dynamic headspace analysis of fragrance evaporation suggested that reversible hydrazone formation of some carbonyl compounds influences the release of volatiles, whereas the absolute stability of the gel seemed to have no influence on the evaporation rates.

Nitroxide biradicals as thread units in paramagnetic cucurbituril-based rotaxanes by Elisabetta Mileo; Costanza Casati; Paola Franchi; Elisabetta Mezzina; Marco Lucarini (2920-2924).
The first example of paramagnetic rotaxane containing cucurbit[6]urils has been reported and characterized both by ESR and NMR spectroscopy.

The synthesis of indoline substituted nitrobenzene on a PEG support and its further elaboration to structurally diverse benzene-fused pyrazino/diazepino indoles is disclosed. A reagent based diversification approach coupled with Pictet–Spengler type condensation reactions furnished these fused polycyclic scaffolds. Microwave irradiation was used as a means of rate acceleration for soluble polymer-supported reactions. The efficiency of these fused heterocyclic molecules to inhibit the vascular endothelial growth factor receptor 3 (VEGFR-3) was examined in vitro using kinase receptor activation enzyme-linked immunosorbant assay (KIRA-ELISA). Based on the preliminary results obtained, a small set of potential drug candidates were identified as novel leads in this therapeutic area to be further explored as anti-metastatic agents.

A highly sensitive water-soluble system to sense glucose in aqueous solution by Liheng Feng; Fei Liang; Yue Wang; Ming Xu; Xiaoju Wang (2938-2942).
A glucose sensing switch is formed by water soluble conjugated polymer (PP–S-BINOL) and boronic acid-functionalized benzyl viologen (o-BBV). The two-component system shows a high sensitivity for glucose sensing with a 17-fold increase in the fluorescence intensity in the presence of 100 mM glucose.

MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure–activity relationship in specific β-N-acetylglucosaminidase inhibition by Hirokazu Usuki; Yukihiro Yamamoto; Yuya Kumagai; Teruhiko Nitoda; Hiroshi Kanzaki; Tadashi Hatanaka (2943-2951).
The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatus NBRC13369. The inhibitor shows a unique inhibitory spectrum, that is, selectivity toward enzymes from chitin-containing organisms such as insects and fungi. Nevertheless, its structure-selectivity relationship remains to be clarified. In this study, we conducted a structure-guided search of analogues of 1 in order to obtain diverse N,N,N-trimethylglucosaminium (TMG)-containing chitooligosaccharides. In this approach, the specific fragmentation profile of 1 on ESI-MS/MS analysis was used for the selective detection of desired compounds. As a result, two new analogues, named TMG-chitomonomycin (3) and TMG-chitobiomycin (2), were obtained from a culture filtrate of 1-producing Streptomyces. Their enzyme-inhibiting activity revealed that the potency and selectivity depended on the degree of polymerization of the reducing end GlcNAc units. Furthermore, a computational modeling study inspired the inhibitory mechanism of TMG-related compounds as a mimic of the substrate in the Michaelis complex of the GH20 enzyme. This study is an example of the successful application of a MS/MS experiment for structure-guided isolation of natural products.

Assessing the whole range of CuAAC mechanisms by DFT calculations—on the intermediacy of copper acetylides by David Cantillo; Martín Ávalos; Reyes Babiano; Pedro Cintas; José L. Jiménez; Juan C. Palacios (2952-2958).
The archetypal Cu(i)-catalyzed alkyne-azide click cycloaddition (CuAAC) has been explored thoroughly via density functional calculations, modeling copper nuclei with the LANL2DZ basis set and aqueous environments with CPCM solvation. All the mechanistic proposals, ranging from the intermediacy of copper acetylides to π-complexes and multinuclear clusters have been compared. The known features of the CuAAC reaction such as the observed second order kinetics for the Cu(i) species and the marked regioselectivity have been taken into account. The calculated energy barriers point to the intermediacy of copper(i) acetylides with two metal centers, in agreement with the observed kinetics, which exhibit barriers of 10.1 kcal mol−1 and 13.7 kcal mol−1 for the 1,4- and 1,5-regiochemistries, respectively, thus accounting for the marked regioselectivity of the copper catalyzed azide-alkyne cycloaddition. The copper acetylide versusπ-complexes dilemma has also been experimentally addressed through the click reaction of benzyl azide and isotopically labeled phenylacetylene. The total proton/deuterium exchange in the afforded triazole demonstrates the formation of a copper acetylide intermediate during the transformation.

Photochemical [2 + 2] cycloaddition reactions of 6-alkenyl-3-phenylcyclohex-2-en-1-ones: using biradical conformation control to account for exceptions to the “rule of five” by Stephen A. Bradley; Brian J. Bresnan; Sylvia M. Draper; Niall W. A. Geraghty; Mark Jeffares; Thomas McCabe; T. Brian H. McMurry; John E. O'Brien (2959-2968).
A series of 6-alkenyl-3-phenylcyclohex-2-enones has been synthesised and the structures of the products obtained from them on irradiation have been determined. The 6-propenyl compounds afforded a tricyclic ‘parallel’ [2 + 2] cycloaddition product and a bicyclic enone resulting from hydrogen abstraction in the biradical intermediate. The 6-butenyl and 6-pentenyl analogues gave ‘crossed’ cycloaddition products only. Although the regiochemistry of these cycloaddition reactions cannot be explained in terms of the ‘rule of five’, it is compatible with the concept of ‘biradical conformation control’ which is based on a consideration of the energy and structure of the possible 1,4-biradical intermediates.

The photostimulated reaction of arylthiolate ions with endo-3-bromocamphor produced both reduction and substitution products. The pKa and proton affinities of the conjugated acids were found to be good indicators of the reactivity.

Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA by Wei-Bin Wu; Shu-Han Chen; Jin-Qiang Hou; Jia-Heng Tan; Tian-Miao Ou; Shi-Liang Huang; Ding Li; Lian-Quan Gu; Zhi-Shu Huang (2975-2986).
A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.

Iodination of anilines and phenols with 18-crown-6 supported ICl2 by Hannah W. Mbatia; Olbelina A. Ulloa; Daniel P. Kennedy; Christopher D. Incarvito; Shawn C. Burdette (2987-2991).
A highly crystalline iodinating reagent, {[K·18-C-6]ICl2}n, was synthesized in high yield (93%). The trihalide is supported by an 18-crown-6 macrocycle and forms a coordination polymer in the solid state. This reagent iodinates anilines and phenols efficiently under mild conditions. Controlled mono-iodination with anilines was easily achieved while poly-iodination was observed with phenols.

A series of 2-(3,5-dimethylpyrazol-1-yl)ethylseleno derivatives has been synthesized. The glutathione peroxidase like catalytic activity of these compounds has been studied in a model system, in which reduction of hydrogen peroxide with dithiothreitol (DTTred), in the presence of an organoselenium compound was investigated by 1H NMR spectroscopy. All these compounds exhibit GPx like catalytic activities and the catalytic reaction proceeds through a selenoxide intermediate, identified by 77Se{1H} NMR spectroscopy.

Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels–Alder cycloadducts by Joshua K. Bolger; Wen Tian; William R. Wolter; Wonhwa Cho; Mark A. Suckow; Marvin J. Miller (2999-3010).
Acylnitroso cycloadducts have proven to be valuable intermediates in the syntheses of a plethora of biologically active molecules. Recently, organometallic reagents were shown to open bicyclic acylnitroso cycloadducts and, more interestingly, the prospect of highly regioselective openings was raised. This transformation was employed in the synthesis of a compound with excellent inhibitory activity against 5-lipoxygenase ((±)-4a, IC50 51 nM), an important mediator of inflammation intimately involved in a number of disease states including asthma and cancer. Optimization of the copper-mediated organometallic ring opening reaction was accomplished allowing the further exploration of the biological activity. Synthesis of a number of derivatives with varying affinity for metal binding as well as pendant groups in a range of sizes was accomplished. Analogues were tested in a whole cell assay which revealed a subset of the compounds to be inhibitors of enzyme translocation, a mode of action not previously known and, potentially, extremely important for better understanding of the enzyme and inhibitor development. Additionally, the lead compound was tested in vivo in an established colon cancer model and showed very encouraging anti-tumorogenic properties.

Probing the enantioselectivity of a diverse group of purified cobalt-centred nitrile hydratases by S. van Pelt; M. Zhang; L. G. Otten; J. Holt; D. Y. Sorokin; F. van Rantwijk; G. W. Black; J. J. Perry; R. A. Sheldon (3011-3019).
In this study a diverse range of purified cobalt containing nitrile hydratases (NHases, EC 4.2.1.84) from Rhodopseudomonas palustris HaA2 (HaA2), Rhodopseudomonas palustris CGA009 (009), Sinorhizobium meliloti 1021 (1021), and Nitriliruptor alkaliphilus (iso2), were screened for the first time for their enantioselectivity towards a broad range of chiral nitriles. Enantiomeric ratios of >100 were found for the NHases from HaA2 and CGA009 on 2-phenylpropionitrile. In contrast, the Fe-containing NHase from the well-characterized Rhodococcus erythropolis AJ270 (AJ270) was practically aselective with a range of different α-phenylacetonitriles. In general, at least one bulky group in close proximity to the α-position of the chiral nitriles seemed to be necessary for enantioselectivity with all NHases tested. Nitrile groups attached to a quaternary carbon atom were only reluctantly accepted and showed no selectivity. Enantiomeric ratios of 80 and >100 for AJ270 and iso2, respectively, were found for the pharmaceutical intermediate naproxennitrile, and 3-(1-cyanoethyl)benzoic acid was hydrated to the corresponding amide by iso2 with an enantiomeric ratio of >100.

Both anomers of the methyl glycoside of 6-O-benzyl-N-dimethylmaleoyl-d-allosamine (6 and 7) are glycosylated exclusively on O3 when reacting with the trichloroacetimidate of peracetylated α-d-galactopyranose (5). This regioselectivity is expected for 6, the α-anomer, as a strong hydrogen bond of its H(O)3 with the carbonyl group of the dimethylmaleoyl group occurs, as shown by NMR temperature dependence. However, this hydrogen bond was not encountered experimentally for 7, the β-anomer. A DFT study of the energies implied in an analog of the glycosylation reaction charged intermediate has explained neatly this behavior, in terms of strong hydrogen bonds occurring at these charged intermediates. This approach explains both the experimental regioselectivities found for 6 and 7, but furthermore the calculations have shown a marked agreement with the regioselectivities found for other related compounds in the literature.

Optimized strategies to synthesize β-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers by Romain Le Provost; Timo Wille; Ludivine Louise; Nicolas Masurier; Susanne Müller; Georg Reiter; Pierre-Yves Renard; Olivier Lafont; Franz Worek; François Estour (3026-3032).
A new generation of organophosphate (OP) scavengers was obtained by synthesis of β-cyclodextrin-oxime derivatives 8–12. Selective monosubstitution of β-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the oligosaccharide was closely related to the nature of the incoming group. For this purpose, non-conventional activation conditions were also evaluated. Intermediates 5 and 7 were then obtained with the better yields under ultrasounds irradiation. Finally, the desired compounds 8–10 were obtained from 5–7 in high purity by desilylation using potassium fluoride. Quaternarisation of compounds 8 and 9 was carried out. OP hydrolytic activity of compounds 8–12 was evaluated against cyclosarin (GF) and VX. None of the tested compounds was active against VX, but these five cyclodextrin derivatives detoxified GF, and the most active scavengers 10 and 11 allowed an almost complete hydrolysis of GF within 10 min. Even more fascinating is the fact that compounds 9 and 10 were able to hydrolyze enantioselectively GF.

A novel hydrazide type organocatalyst for enantioselective Diels–Alder reactions by Ichiro Suzuki; Masafumi Ando; Rumiko Shimabara; Ai Hirata; Kei Takeda (3033-3040).
The development of a new class of hydrazide type organocatalyst, (4R,5R)-1,3-bis(isopropylamino)-4,5-dihenylimidazolidin-2-one 2a, for enantioselective Diels–Alder reactions between cyclopentadiene and α,β-unsaturated aldehydes are presented. The new organocatalyst 2a promoted the reaction, affording Diels–Alder adducts in good yields with good levels of enantioselectivity.

Synthesis and biological activity of 2-aminoimidazole triazoles accessed by Suzuki–Miyaura cross-coupling by Samuel Reyes; Robert W. Huigens III; Zhaoming Su; Michel L. Simon; Christian Melander (3041-3049).
A pilot library of 2-aminoimidazole triazoles (2-AITs) was synthesized and assayed against Acinetobacter baumannii and methicillin-resistant Staphylococus aureus (MRSA). Results from these studies show that these new derivatives have improved biofilm dispersal activities as well as antibacterial properties against A. baumannii. With MRSA biofilms they are found to possess biofilm inhibition capabilities at low micromolar concentrations.

An enantioselective Biginelli reaction has been developed by using a bifunctional primary amine-thiourea–TfOH (BPAT·TfOH) as a chiral phase-transfer catalyst and t-BuNH2·TFA as an additive in saturated brine at room temperature. The corresponding dihydropyrimidines were obtained in moderate-to-good yields with up to 99% ee under mild conditions. A plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.

Back cover (3055-3056).