Organic & Biomolecular Chemistry (v.11, #41)

Front cover (7029-7029).

Inside front cover (7030-7030).

Contents list (7031-7038).

Cope-type hydroaminations are versatile for the direct amination of alkenes, alkynes and allenes using hydroxylamines and hydrazine derivatives. These reactions occur via a concerted, 5-membered cyclic transition state that is the microscopic reverse of the Cope elimination. This article focuses on recent developments, including intermolecular variants, directed reactions, and asymmetric variants using aldehydes as tethering catalysts, and their applications in target-oriented synthesis.

Bifunctional primary amine-thioureas in asymmetric organocatalysis by Olga V. Serdyuk; Christina M. Heckel; Svetlana B. Tsogoeva (7051-7071).
Research disclosed since the demonstration of the first examples of primary amine-thiourea organocatalysis in 2006 has shown that primary amine-based thioureas can successfully catalyze a diverse variety of highly enantioselective transformations providing a wide range of versatile organic compounds. Recent remarkable progress with these chiral catalysts is summarized in this review.

Switching the H-bonding network of a foldamer by modulating the backbone chirality and constitutional ratio of amino acids by Veera V. E. Ramesh; Kuruppanthara N. Vijayadas; Snehal Dhokale; Rajesh G. Gonnade; Pattuparambil R. Rajamohanan; Gangadhar J. Sanjayan (7072-7075).
This communication describes the folding propensity of a heterofoldamer motif featuring proline (Pro) and anthranilic acid (Ant) residues in a 1 : 2 : 1 (α : β : α) constitutional ratio. Structural investigations unequivocally suggest that the hydrogen-bonding network of this foldamer motif can be switched between 9-membered and 6-membered by modulating the backbone chirality and constitutional ratio of the amino acid residues.

A novel methodology for the α-vinylation of amides with arylacetylenes under metal-free conditions has been introduced. This methodology provides a new protocol to synthesize allylamines. In each product, the amount of the cis-isomer was more than that of the trans-isomer.

The first tertiary amine catalyzed asymmetric allylic amination/cycloaddition cascade sequence has been developed, which provided a novel protocol to construct enantioenriched azapolyheterocycles under mild reaction conditions efficiently (up to 95% ee, endo/exo >20 : 1).

A simple, mild and robust method for the stereoselective synthesis of (E)-methyl α-(3-formyl-1H-indol-2-yl)-β-aryl/alkyl-substituted acrylates via a condensation reaction of methyl 2-(3-formyl-1H-indol-2-yl)acetate with several alkyl or aryl aldehydes using l-proline (25 mol%) as a catalyst is presented for the first time. In addition, completely metal free based high yielding methods for the syntheses of highly substituted biologically important carbazoles, γ-carbolines and the marine alkaloid prenostodione have been developed through our methodology.

Visible light photoredox atom transfer Ueno–Stork reaction by Xiangyong Gu; Ping Lu; Weigang Fan; Pixu Li; Yingming Yao (7088-7091).
A visible light-promoted atom transfer Ueno–Stork reaction was developed using Ir(ppy)2(dtb-bpy)PF6 as the sensitizer. 2-Iodoethyl propargyl ethers or 2-iodoethyl allyl ethers were used as the radical precursors to construct tetrahydrofuran-containing fused [6,5] and [5,5] bicyclic frameworks.

The ammonium-promoted formylation of indoles by DMSO and H2O by Haiyang Fei; Jintao Yu; Yan Jiang; Huan Guo; Jiang Cheng (7092-7095).
DMSO and H2O is an efficient combination in the NH4OAc-promoted formylation of indole, where DMSO serves as a C1 carbon source. The mechanism study reveals that the procedure involves a usual and unusual Pummerer reaction.

Template-constrained cyclic sulfopeptide HIV-1 entry inhibitors by Jonathan G. Rudick; Meg M. Laakso; Ashley C. Schloss; William F. DeGrado (7096-7100).
Template-constrained cyclic sulfopeptides that inhibit HIV-1 entry were rationally designed based on a loop from monoclonal antibody (mAb) 412d. A focused set of sulfopeptides was synthesized using Fmoc-Tyr(SO3DCV)-OH (DCV = 2,2-dichlorovinyl). Three cyclic sulfopeptides that inhibit entry of HIV-1 and complement the activity of known CCR5 antagonists were identified.

Glyconanoparticles for the plasmonic detection and discrimination between human and avian influenza virus by María J. Marín; Abdul Rashid; Martin Rejzek; Shirley A. Fairhurst; Stephen A. Wharton; Stephen R. Martin; John W. McCauley; Thomas Wileman; Robert A. Field; David A. Russell (7101-7107).
A plasmonic bioassay for the specific detection of human influenza virus has been developed based on gold nanoparticles functionalised with a designed and synthesised thiolated trivalent α2,6-thio-linked sialic acid derivative. The glyconanoparticles consist of the thiolated trivalent α2,6-thio-linked sialic acid derivative and a thiolated polyethylene glycol (PEG) derivative self-assembled onto the gold surface. Varying ratios of the trivalent α2,6-thio-linked sialic acid ligand and the PEG ligand were used; a ratio of 25 : 75 was found to be optimum for the detection of human influenza virus X31 (H3N2). In the presence of the influenza virus a solution of the glyconanoparticles aggregate following the binding of the trivalent α2,6-thio-linked sialic acid ligand to the haemagglutinin on the surface of the virus. The aggregation of the glycoparticles with the influenza virus induces a colour change of the solution within 30 min. Non-purified influenza virus in allantoic fluid was successfully detected using the functionalised glyconanoparticles. A comparison between the trivalent and a monovalent α2,6-thio-linked sialic acid functionalised nanoparticles confirmed that more rapid results, with greater sensitivity, were achieved using the trivalent ligand for the detection of the X31 virus. Importantly, the glyconanoparticles were able to discriminate between human (α2,6 binding) and avian (α2,3 binding) RG14 (H5N1) influenza virus highlighting the binding specificity of the trivalent α2,6-thio-linked sialic acid ligand.

Tuning molecular interactions in lipid-oligonucleotides assemblies via locked nucleic acid (LNA)-based lipids by Amit Patwa; Gilmar Salgado; François Dole; Laurence Navailles; Philippe Barthélémy (7108-7112).
Hybrid nucleotide-lipids containing locked nucleic acid (LNA) show enhanced hybridization properties with complementary single strand RNAs compared to DNA lipid analogues. The LNA adenosine lipid features unique binding properties with a high binding affinity for poly-uridine and the entropically driven formation of a stable complex (Kd≈ 43 nM). Enhanced hybridization properties of LNA-based lipids should be applicable for the development of oligonucleotide (ON) delivery systems or as small molecule binders to RNA for novel therapeutic strategies.

Tetravalent glycocyclopeptide with nanomolar affinity to wheat germ agglutinin by Michele Fiore; Nathalie Berthet; Alberto Marra; Emilie Gillon; Pascal Dumy; Alessandro Dondoni; Anne Imberty; Olivier Renaudet (7113-7122).
A series of tetravalent glycocyclopeptides functionalized with GlcNAc was synthesized using copper(i)-catalysed alkyne–azide cycloaddition, oxime ligation and thiol–ene coupling. The binding ability of these compounds towards wheat germ agglutinin was studied by a competitive ELLA test and ITC experiments. While all compounds were able to inhibit WGA binding to GlcNAc-polymer coated surfaces at low concentrations, derivative 17 having an aliphatic spacer and thioether linkage was 4.9 × 106 times more potent on a per sugar basis than GlcNAc. This remarkably strong effect was confirmed by ITC experiments as these revealed an association constant of 9 nM for this compound, therefore presenting a gain of 200 000 times over GlcNAc. These results for compound 17 represent the highest binding properties reported for WGA.

The reagent system of I2/K2CO3 could efficiently promote the oxazole synthesis from α-bromoketones and benzylamine derivatives in DMF. This method was not only suitable for 2,5-diaryl oxazole synthesis but also for 2,4,5-trisubstituted oxazole and 5-alkyl/alkenyl oxazole synthesis. Furthermore, this method was successfully applied to a one-step synthesis of a natural product halfordinol in 62% yield.

An enzyme-responsive system programmed for the double release of bioactive molecules through an intracellular chemical amplification process by Marion Grinda; Thibaut Legigan; Jonathan Clarhaut; Elodie Peraudeau; Isabelle Tranoy-Opalinski; Brigitte Renoux; Mikaël Thomas; François Guilhot; Sébastien Papot (7129-7133).
The rise of chemical biology has led to the development of sophisticated molecular devices designed to explore and manipulate biological processes. Within this framework, we developed the first chemical system programmed for the selective internalization and subsequent enzyme-catalyzed double release of bioactive compounds inside a targeted population of cells. This system is composed of five distinct units including a targeting ligand, an enzymatic trigger, a self-immolative linker and two active compounds articulated around a chemical amplifier. Designed as such, this molecular assembly is capable in an autonomous manner to recognize a selected population of cells, penetrate into the intracellular medium through endocytosis and transform a single enzymatic activation step into the release of two active units. Demonstrating that an enzyme-catalyzed amplification process can occur spontaneously under the conditions prevailing within the cells could be an important step toward the development of innovative molecular systems for a diverse range of applications spanning drug delivery, biological sensors and diagnostics.

Spiro-bicyclo[2.2.2]octane derivatives as paclitaxel mimetics. Synthesis and toxicity evaluation in breast cancer cell lines by Sophie Manner; Viveca T. Oltner; Stina Oredsson; Ulf Ellervik; Torbjörn Frejd (7134-7144).
Paclitaxel is one of the most important anti-cancer agents introduced during the last 20 years. However, the use of paclitaxel is limited by undesirable side effects as well as the development of drug resistance. Here, we report a synthetic strategy towards spiro-bicyclo[2.2.2]octane derivatives, which includes double Michael addition and ring-closing metathesis as key synthetic steps. This strategy was used to synthesize a series of spiro-bicyclic compounds designed to be paclitaxel mimetics, which were evaluated in human breast-derived cell lines. One of these paclitaxel mimetics showed toxicity, although at higher concentrations than paclitaxel itself. In addition, two other spiro-bicyclic compounds, lacking the paclitaxel side chain, showed toxicity.

Synthesis of charged bis-heteroaryl donor–acceptor (D–A+) NLO-phores coupling (π-deficient–π-excessive) heteroaromatic rings by Marco Antonio Ramirez; Raul Custodio; Ana M. Cuadro; Julio Alvarez-Builla; Koen Clays; Inge Asselberghs; Francisco Mendicuti; Obis Castaño; José L. Andrés; Juan J. Vaquero (7145-7154).
Charged chromophores based on heteroaromatic cations were prepared by reaction of alkylazinium salts with N-heteroarylstannanes under Stille conditions. This approach provides easy access to potential single donor D–A+ chromophores in which the acceptor moiety A+ is the pyridinium cation and the donors are different π-excessive N-heterocycles. The β hyperpolarizabilities were measured in hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including density functional theory and correlated Hartree–Fock-based methods. In some chromophores, the absence of a bridge between donor and acceptor fragments increases the NLO properties.

Tailor-made LasR agonists modulate quorum sensing in Pseudomonas aeruginosa by Nira Rabin; Antonia Delago; Boaz Inbal; Pnina Krief; Michael M. Meijler (7155-7163).
The primary quorum sensing system in the opportunistic pathogen Pseudomonas aeruginosa is regulated through the synthesis and secretion of N-3-oxo-dodecanoyl-l-homoserine lactone (C12) which binds the transcriptional activator LasR. In this study we report the design, synthesis and biological evaluation of new analogs of C12. Analysis of the autoinducer binding site cavity of LasR revealed a positively charged cavity near the center of bound C12. Accordingly, we synthesized two piperidine-C12 diastereoisomers and tested their biological activity. Both analogs proved to be strong LasR agonists that showed a synergistic effect when presented together with the natural ligand. Moreover, binding of the analogs resulted in phenotypic changes characteristic of QS controlled receptor activation.

Structure–transfection activity relationships in a series of novel cationic lipids with heterocyclic head-groups by Ekaterina A. Ivanova; Mikhail A. Maslov; Tatyana O. Kabilova; Pavel A. Puchkov; Anna S. Alekseeva; Ivan A. Boldyrev; Valentin V. Vlassov; Galina A. Serebrennikova; Nina G. Morozova; Marina A. Zenkova (7164-7178).
Cationic liposomes are promising candidates for the delivery of various therapeutic nucleic acids. Here, we report a convenient synthesis of carbamate-type cationic lipids with various hydrophobic domains (tetradecanol, dialkylglycerol, cholesterol) and positively charged head-groups (pyridinium, N-methylimidazolium, N-methylmorpholinium) and data on the structure–transfection activity relationships. It was found that single-chain lipids possess high surface activity, which correlates with high cytotoxicity due to their ability to disrupt the cellular membrane by combined hydrophobic and electrostatic interactions. Liposomes containing these lipids also display high cytotoxicity with respect to all cell lines. Irrespective of chemical structures, all cationic lipids form liposomes with similar sizes and surface potentials. The characteristics of complexes composed of cationic liposomes and nucleic acids depend mostly on the type of nucleic acid and P/N ratios. In the case of oligodeoxyribonucleotide delivery, the transfection activity depends on the type of cationic head-group regardless of the type of hydrophobic domain: all types of cationic liposomes mediate efficient oligonucleotide transfer into 80–90% of the eukaryotic cells, and liposomes based on lipids with N-methylmorpholinium cationic head-group display the highest transfection activity. In the case of plasmid DNA and siRNA, the type of hydrophobic domain determines the transfection activity: liposomes composed of cholesterol-based lipids were the most efficient in DNA transfer, while liposomes containing glycerol-based lipids exhibited reasonable activity in siRNA delivery under serum-free conditions.

The asymmetric synthesis of vicinal diols is a very important process in organic chemistry, as it allows the preparation of a large variety of useful derivatives. One of the most interesting methods to accomplish this synthesis is the asymmetric epoxidation of activated olefins, catalysed by chiral organic or organometallic catalysts. In this paper we study, with computational tools, two possible mechanisms for the asymmetric epoxidation of conjugated aldehydes with hydrogen peroxide, catalysed by chiral pyrrolidine derivatives lacking proton donor groups. Our results indicate that the mechanism that proceeds by the initial formation of an iminium intermediate is more probable than the mechanism proceeding by general base catalysis. We also conclude that besides the oxidant role of hydrogen peroxide, it also has a very important role as a co-catalyst in the initial formation of the iminium intermediates. Moreover, epoxide formation is suggested to be a two-step process that needs the explicit participation of a hydroxyl ion. In the absence of this ion, epoxidation was calculated to be a single step process that does not explain the experimental selectivity. In contrast with the currently accepted idea, the overall calculated selectivity results mainly from the iminium formation steps and from the second step of the epoxidation reaction.

Various imidazolium-functional ionic liquids (ILs) composed of different cations and anions were grafted onto Candida antarctica lipase B (CALB) through lysine coupling, and 4–6 of the 9 primary amino groups of the lysine residues were modified. The catalytic activity and stability were investigated in a p-nitrophenyl palmitate hydrolysis reaction. After modification, CALB was activated and achieved a high catalytic efficiency in the aqueous phase (e.g., [HOOCMMIm][Cl] modification showed a 1.5-fold increase in the catalytic efficiency). The thermostability and organic solvent tolerance were significantly increased with the ILs modification (e.g., [HOOCBMIm][Cl] owned kosmotropic cation and chaotropic anion modification showed a 7-fold thermostability increase at 70 °C, 1-fold increase in 50% aqueous dimethylformamide and 5-fold increase in 50% aqueous methanol). Conformation changes were confirmed by fluorescence spectroscopy, circular dichroism spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy.

Fast preparation of an N-acetylglucosaminylated peptide segment for the chemoenzymatic synthesis of a glycoprotein by Yuya Asahina; Mika Kanda; Akemi Suzuki; Hidekazu Katayama; Yoshiaki Nakahara; Hironobu Hojo (7199-7207).
A novel GlcNAc-Asn unit carrying trifluoroacetic acid (TFA)-sensitive O-protecting groups was prepared. The unit was used for the solid-phase peptide synthesis (SPPS) of the N-acetylglucosaminylated emmprin (35–69) thioester via one-step deprotection by TFA combined with the N-alkylcysteine thioesterification method. This segment was used for the synthesis of the first Ig domain (22–104) of emmprin carrying GlcNAc by one-pot ligation with other segments using the thioester method. Finally, the sugar chain was elongated by transglycosylation using glycosynthase to give the Ig domain carrying the disialo- and asialo-complex-type sugar chain.

The reaction of several primary amines with acrolein smoothly provided the corresponding 2,6,9-triazabicyclo[3.3.1]nonanes through a formal [4 + 4] reaction of the intermediary unsaturated imines. The reactivity profiles in aqueous media and the results from cytotoxic activity assays suggested that the caged products may be relevant in biological systems and may contribute to the mechanisms underlying the oxidative stress response to acrolein.

Halonium-initiated double oxa-cyclization cascade as a synthetic strategy for halogenated furo[3,2-c]pyran-4-ones by Enxiang Wei; Bing Liu; Shaoxia Lin; Baozhong Zhao; Fushun Liang (7212-7217).
The reaction of 1-alkenoylcyclopropane carboxylic acids with NBS or NIS was investigated, which provides an efficient route to biologically important 7-halogenated furo[3,2-c]pyran-4-ones in a one-pot transformation. The major pathway for the formation of the O–O heterocycles was proposed as a halo-oxa-cyclization, HBr elimination, cyclopropane ring-opening and recyclization (intramolecular oxa-cyclization), and bromination cascade. The double-oxa-cyclization represents a novel synthetic strategy towards functionalized furo[3,2-c]pyranones.

Synthesis of the C1–C25 southern domain of spirastrellolides B and F by Gowravaram Sabitha; Allu Senkara Rao; J. S. Yadav (7218-7231).
Synthesis of the C1–C25 ABC spiroketal ring system of spirastrellolides B and F has been executed. The synthetic strategy relied on radical cyclization, HWE olefination, (BDP)CuH conjugate reduction and spiro acetalization reactions.

An efficient chemoselective process for the synthesis of 14- and 15-membered triazole-containing macrocycle compounds has been developed through the combination of two multicomponent reactions and an intramolecular Sonogashira cross-coupling reaction.

Back cover (7239-7240).