Organic & Biomolecular Chemistry (v.9, #10)

Front cover (3573-3574).

Contents (3575-3590).

Unlocked nucleic acid – an RNA modification with broad potential by Anna Pasternak; Jesper Wengel (3591-3597).
The first unlocked nucleic acid (UNA) monomer was described more than a decade ago, but only recent reports have revealed the true potential applications of this acyclic RNA mimic. UNA monomers enable the modulation of the thermodynamic stability of various nucleic acid structures such as RNA and DNA duplexes, quadruplexes or i-motifs. Moreover, UNA monomers were found to be compatible with RNase H activity, a property which is important for single stranded antisense constructs. Notably, UNA monomers can be applied in the design of superior siRNAs, combining potent gene silencing and dramatically reduced off-target effects.

Carbohydrate chemistry in drug discovery by M. Carmen Galan; David Benito-Alifonso; Gregory M. Watt (3598-3610).
The multitude of roles that carbohydrates and their glyco-conjugates play in biological processes has stimulated great interest in determining the nature of their interactions in both normal and diseased states. Manipulating such interactions will provide leads for drug discovery. Of the major classes of biomolecule, carbohydrates are the most structurally diverse. This hetereogeneity makes isolation of pure samples, and in sufficient amounts, from biological sources extremely difficult. Chemical synthesis offers the advantage of producing pure and structurally defined oligosaccharides for biological investigations. Although the complex nature of carbohydrates means that this is challenging, recent advances in the field have facilitated access to these molecules. The synthesis and isolation of oligosaccharides combined with progress in glycoarray technology have aided the identification of new carbohydrate-binding drug targets. This review aims to provide an overview of the latest advancements in carbohydrate chemistry and the role of these complex molecules in drug discovery, focusing particularly on synthetic methodologies, glycosaminoglycans, glycoprotein synthesis and vaccine development over the last few years.

Changing the volume of a giant macrocycle: the swelling of the macrocycle with organic solvents by Aya Harano; Minako Tanaka; Takeshi Nakagaki; Masahiko Annaka; Keiko Ideta; Kenta Goto; Teruo Shinmyozu (3611-3614).
The novel tetrahedral macrocycles 1a–1c have been synthesized. Macrocycles 1a and 1c were revealed to have the property to increase in volume in solution by complexation between the macrocycle and the solvent molecules.

A 2,7-carbazole-based dicationic salt for fluorescence detection of nucleic acids and two-photon fluorescence imaging of RNA in nucleoli and cytoplasm by Xin Liu; Yuming Sun; Yuanhong Zhang; Fang Miao; Guancong Wang; Hongshi Zhao; Xiaoqiang Yu; Hong Liu; Wai-Yeung Wong (3615-3618).
A new carbazole-derived dicationic compound, namely 2,7-bis(1-hydroxyethyl-4-vinylpyridinium iodine)-N-ethylcarbazole (2,7-9E-BHVC), with a large two-photon action absorption cross section in nucleic acids has been obtained. Moreover, it possesses the potential of imaging RNA in nucleoli and cytoplasm in two-photon fluorescence microscopy and exhibits good counterstain compatibility with the commercial fluorescent nucleic dye DAPI.

Chiral Sc-catalyzed asymmetric Michael reactions of thiols with enones in water by Masaharu Ueno; Taku Kitanosono; Masaru Sakai; Shū Kobayashi (3619-3621).
Asymmetric Michael reactions of thiols with enones were catalyzed by a Sc(OTf)3–chiral bipyridine complex at room temperature in water without using any organic solvents, to afford the desired sulfides in high yields with high enantioselectivities.

Catalytic asymmetric 1,3-dipolar cycloaddition of various azomethine ylides with diethyl 2-(3,3-diphenylpropa-1,2-dienylidene)malonate has been developed successfully with good to excellent enantioselectivity for the effcient construction of 3-vinylidene-pyrrolidine derivatives containing a unique allene moiety.

The aza-Henry reaction of chiral fluoroalkyl α,β-unsaturated N-tert-butanesulfinyl ketoimines and nitromethane was achieved in the presence of 0.2 equivalent of anhydrous potassium carbonate to give the corresponding adducts diastereoselectively in high yields. Transformations which highlighted the synthetic potential of these aza-Henry adducts were also performed.

Facile synthesis of spiroisoquinolines based on photocycloaddition of isoquinoline-1,3,4-trione with oxazoles by Chengmei Huang; Haitao Yu; Zhengrui Miao; Jie Zhou; Shuai Wang; Hoong-Kun Fun; Jianhua Xu; Yan Zhang (3629-3631).
Photocycloaddition of isoquinoline-1,3,4-trione and 5-methoxyoxazoles affords spiroisoquinolineoxetanes with high regio- and diastereoselectivity. The spiroisoquinolineoxetanes can be conveniently converted into novel spiroisoquinolineoxazoline derivatives through acid catalyzed sequential reactions.

The diastereoselective synthesis of cis-2-amino-3-hydroxyindanones was realized by the N-heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and imines, which may involve a tandem aza-benzoin reaction and aldol reaction.

Effect of substituents on the stabilities of multiply-substituted carbon-centered radicals by Ambili S. Menon; David J. Henry; Thomas Bally; Leo Radom (3636-3657).
The bond dissociation energies (BDEs) and radical stabilization energies (RSEs) which result from 166 reactions that lead to carbon-centered radicals of the type ˙CH2X, ˙CHXY and ˙CXYZ, where X, Y and Z are any of the fourteen substituents H, F, Cl, NH2, OH, SH, CHCH2, CCH, BH2, CHO, COOH, CN, CH3, and CF3, were calculated using spin-restricted and -unrestricted variants of the double-hybrid B2-PLYP method with the 6-311+G(3df,2p) basis set. The interactions of substituents X, Y, and Z in both the radicals (˙CXYZ) and in the precursor closed-shell molecules (CHXYZ), as well as the extent of additivity of such interactions, were investigated by calculating radical interaction energies (RIEs), molecule interaction energies (MIEs), and deviations from additivity of RSEs (DARSEs) for a set of 152 reactions that lead to di- (˙CHXY) and tri- (˙CXYZ) substituted carbon-centered radicals. The pairwise quantities describing the effects of pairs of substituents in trisubstituted systems, namely pairwise MIEs (PMIEs), pairwise RIEs (PRIEs) and deviations from pairwise additivity of RSEs (DPARSEs), were also calculated for the set of 61 reactions that lead to trisubstituted radicals (˙CXYZ). Both ROB2-PLYP and UB2-PLYP were found to perform quite well in predicting the quantities related to the stabilities of carbon-centered radicals when compared with available experimental data and with the results obtained from the high-level composite method G3X(MP2)-RAD. Particular selections of substituents or combinations of substituents from the current test set were found to lead to specially stable radicals, increasing the RSEs to a maximum of +68.2 kJ mol−1 for monosubstituted radicals ˙CH2X (X = CHCH2), +131.7 kJ mol−1 for disubstituted radicals ˙CHXY (X = NH2, Y = CHO), and +177.1 kJ mol−1 for trisubstituted radicals ˙CXYZ (X = NH2, Y = Z = CHO).

Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists by Huu-Anh Tran; Pavel I. Kitov; Eugenia Paszkiewicz; Joanna M. Sadowska; David R. Bundle (3658-3671).
Structural pre-organization of the multivalent ligands is important for successful interaction with multimeric proteins. Polymer-based heterobifunctional ligands that contain pendant groups prearranged into heterodimers can be used to probe the active site and surrounding area of the receptor. Here we describe the synthesis and activities of a series of galactose conjugates on polyacrylamide and dextran. Conjugation of a second fragment resulted in nanomolar inhibitors of cholera toxin, while the galactose-only progenitors showed no detectable activity.

Anhydrous TEMPO-H: reactions of a good hydrogen atom donor with low-valent carbon centres by Nick A. Giffin; Miller Makramalla; Arthur D. Hendsbee; Katherine N. Robertson; Cody Sherren; Cory C. Pye; Jason D. Masuda; Jason A. C. Clyburne (3672-3680).
In this paper, we report a novel synthesis of anhydrous 1-hydroxy-2,2,6,6-tetramethyl-piperidine (TEMPO-H). An X-ray crystal structure and full characterization of the compound are included. Compared to hydrated TEMPO-H, its anhydrous form exhibits improved stability and a differing chemical reactivity. The reactions of anhydrous TEMPO-H with a variety of low-valent carbon centres are described. For example, anhydrous TEMPO-H was reacted with 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), an unsaturated NHC. Crystals of [CHNC6H2(CH3)3]2C⋯HO(NC5H6(CH3)4), IMes⋯TEMPO-H, were isolated and a crystal structure determined. The experimental structure is compared to the results of theoretical calculations on the hydrogen-bonded dimer. Anhydrous TEMPO-H was also reacted with the saturated NHC, 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), giving the product [CH2Ni-Pr2C6H3]2CH⋯O(NC5H6(CH3)4). In contrast, the reaction of hydrated TEMPO-H with 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene gave small amounts of the hydrolysis product, N-(2,6-diisopropylphenyl)-N-[2-(2,6-diisopropylphenylamino)ethyl]formamide. Finally, anhydrous TEMPO-H was reacted with (triphenylphosphoranylidene)ketene to generate Ph3PC(H)C(O)O(NC5H6(CH3)4). A full characterization of the product, including an X-ray crystal structure, is described.

Anti-virulence Strategy against Brucella suis: Synthesis, Biological Evaluation and Molecular Modeling of Selective Histidinol Dehydrogenase Inhibitors by Marie-Rose Abdo; Pascale Joseph; Jérémie Mortier; François Turtaut; Jean-Louis Montero; Bernard Masereel; Stephan Köhler; Jean-Yves Winum (3681-3690).
In the facultative intracellular pathogen Brucella suis, histidinol dehydrogenase (HDH) activity, catalyzing the last step in histidine biosynthesis, is essential for intramacrophagic replication. The inhibition of this virulence factor by substituted benzylic ketones was a proof of concept that disarming bacteria leads to inhibition of intracellular bacterial growth in macrophage infection. This work describes the design, synthesis and evaluation of 19 new potential HDH inhibitors, using a combination of classical approaches and docking studies. The IC50-values of these inhibitors on HDH activity were in the nanomolar range, and several of them showed a 70–100% inhibition of Brucella growth in minimal medium. One selected compound yielded a strong inhibitory effect on intracellular replication of B. suis in human macrophages at concentrations as low as 5 μM, with an overall survival of intramacrophagic bacteria reduced by a factor 103. Docking studies with two inhibitors showed a good fitting in the catalytic pocket and also interaction with the second lipophilic pocket binding the cofactor NAD+. Experimental data confirmed competition between inhibitors and NAD+ at this site. Hence, these inhibitors can be considered as promising tools in the development of novel anti-virulence drugs.

An efficient, convenient and enantioselective Michael-hemiketalization reaction has been developed for the synthesis of naphthoquinones. In this work, a novel trans-bifunctional indane thiourea catalyst has been reported to promote this process to afford high yields (up to 99%) and high to excellent enantiomeric excesses (90–98% ee).

Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase by Matilde Aguilar-Moncayo; M. Isabel García-Moreno; Ana Trapero; Meritxell Egido-Gabás; Amadeu Llebaria; José M. García Fernández; Carmen Ortiz Mellet (3698-3713).
A molecular-diversity-oriented approach for the preparation of bicyclic sp2-iminosugar glycomimetics related to nojirimycin and galactonojirimycin is reported. The synthetic strategy takes advantage of the ability of endocyclic pseudoamide-type atoms in five-membered cyclic iso(thio)ureas and guanidines to undergo intramolecular nucleophilic addition to the masked carbonyl group of monosaccharides. The stereochemistry of the resulting hemiaminal stereocenter is governed by the anomeric effect, with a large preference for the axial (pseudo-α) orientation. A library of compounds differing in the stereochemistry at the position equivalent to C-4 in monosaccharides (d-gluco and d-galacto), the heterocyclic core (cyclic isourea, isothiourea or guanidine) and the nature of the exocyclic nitrogen substituent (apolar, polar, linear or branched) has been thus prepared and the glycosidase inhibitory activity evaluated against commercial glycosidases. Compounds bearing lipophilic substituents behaved as potent and very selective inhibitors of β-glucosidases. They further proved to be good competitive inhibitors of the recombinant human β-glucocerebrosidase (imiglucerase) used in enzyme replacement therapy (ERT) for Gaucher disease. The potential of these compounds as pharmacological chaperones was assessed by measuring their ability to inhibit thermal-induced denaturation of the enzyme in comparison with N-nonyl-1-deoxynojirimycin (NNDNJ). The results indicated that amphiphilic sp2-iminosugars within this series are more efficient than NNDNJ at stabilizing β-glucocerebrosidase and have a strong potential in pharmacological chaperone (PC) and ERT-PC combined therapies.

Oxidative aromatic C–N bond formation: convenient synthesis of N-amino-3-nitrile-indoles via FeBr3-mediated intramolecular cyclization by Zisheng Zheng; Lina Tang; Yanfeng Fan; Xiuxiang Qi; Yunfei Du; Daisy Zhang-Negrerie (3714-3725).
A variety of functionalized N-amino-3-nitrile-indole derivatives are obtained via an intramolecular hetero-cyclization of 2-aryl-3-substituted hydrazono-alkylnitriles using FeBr3 as a single electron oxidant. This approach allows the N-moiety on the side-chain to be annulated to the benzene ring during the final synthetic step via direct oxidative aromatic C–N bond formation.

Synthesis of the gymnodimine tetrahydrofuran core through a Ueno–Stork radical cyclization by Sylvestre Toumieux; Redouane Beniazza; Valérie Desvergnes; Rómulo Aráoz; Jordi Molgó; Yannick Landais (3726-3732).
A straightforward access to the C10–C20 skeleton of gymnodimine, incorporating a tetrahydrofuran fragment, is described. The elaboration of the THF moiety is based on a stereocontrolled Ueno–Stork cyclization. A Lewis-acid mediated allylation of the resulting acetal at C13 and a Horner–Wadsworth–Emmons olefination on the ketone at C17 complete the synthesis.

Gas-phase ion-molecule reactions using regioselectively generated radical cations to model oxidative damage and probe radical sites in peptides by Christopher K. Barlow; Adam Wright; Christopher J. Easton; Richard A. J. O'Hair (3733-3745).
Collision induced dissociation (CID) of sodiated peptide derivatives containing a nitrate ester functionality was used to regiospecifically generate three isomeric radicals of the model peptide Bz-Ala-Gly-OMe corresponding to radicals formed at: Cα of the alanine residue [4+Na]+; Cα of the glycine residue [5+Na]+; and the side chain of alanine [6+Na]+. The ion-molecule reactions of these peptide radicals were examined to model oxidative damage to peptides and to probe whether the radical sites maintain their integrity or whether they isomerise via intramolecular hydrogen atom transfer (HAT). Only [6+Na]+ is reactive towards O2, forming the peroxyl radical [7+Na]+, which loses O2, HO˙ and HO2˙ under CID. The radical ion [7 + Na]+ abstracts a hydrogen atom from 4-fluorothiophenol to form the hydroperoxide [8+Na]+, which upon CID fragments via the combined loss of HO˙ and CH2O. In contrast, all three of the isomeric sodiated radicals react with NO˙ and NO2˙ to form adducts. CID of the NO adducts only regenerates the radicals via NO˙ loss, thus providing no structural information. In contrast, CID of the NO2 adducts gives rise to a range of product ions and the spectra are different for each of the three adducts, suggesting that the isomeric radicals [4+Na]+, [5+Na]+ and [6+Na]+ are produced as discrete species. Finally, CID of the NO2 adducts was used to probe the rearrangement of the radicals [4+Na]+, [5+Na]+ and [6+Na]+ prior to their reaction with NO2˙: [6 + Na]+ rearranges to a mixture of [4+Na]+ and [5+Na]+ while [5+Na]+ rearranges to [4+Na]+.

Radical arylation of tyrosine and its application in the synthesis of a highly selective neurotensin receptor 2 ligand by Gerald Pratsch; Johannes F. Unfried; Jürgen Einsiedel; Manuel Plomer; Harald Hübner; Peter Gmeiner; Markus R. Heinrich (3746-3752).
A small library of Fmoc-protected 3-arylated tyrosines was created by radical arylation. The new building blocks were successfully applied in the synthesis of two novel neurotensin receptor ligands. Both isomers showed high affinity for the human NTS2 receptor with Ki values in the nanomolar range. Interestingly, subtype selectivity strongly depends on the configuration of the peptide in position 11. Isomer (11R)-3 displayed an excellent preference for NTS2 compared to NTS1.

The free-radical copolymerization of alkyl-substituted 1,3-butadienes with sulfur dioxide using a redox initiating system in toluene at −78 °C produced poly(diene sulfone)s consisting of a highly alternating and 1,4-regiospecific repeating structure, irrespective of the position and number of alkyl substituents, and the highly regioselective propagation via a free radical reaction mechanism is well accounted for by DFT calculations using model reactions.

We report a new and fast domino synthesis of aminoalcohols under mild conditions. The free-radical reaction of aliphatic and aromatic amines with alcohol cosolvents is promoted by means of the TiCl4–Zn/t-BuOOH system. According to the proposed mechanism, the amine reacts with two molecules of alcohol in an electrophilic–nucleophilic cascade process. This procedure, if compared with the TiCl3/t-BuOOH-mediated protocol previously reported, appears to be more selective, of more general applicability and affords the desired products in higher yields. Besides, with the same catalytic system it was possible to promote the reaction of primary arylamines with two molecules of cyclic ether, leading to the formation of a wider range of functionalized aminoalcohols.

When a mixture of o-alkynylaryl isocyanides and organic dichalcogenides such as diselenides or ditellurides was irradiated with light of wavelength over 300 or 400 nm, the intramolecular cyclization of the isocyanides took place to afford the corresponding 2,4-bischalcogenated quinolines selectively. The photochemical cyclization of 2-(phenylethynyl)phenyl isocyanide could also proceed in the presence of hydrogen transfer reagents such as tris(trimethylsilyl)silane, tributylgermyl hydride, alkanethiols, and benzeneselenol, providing the corresponding 3-phenylquinoline as the result of 2,4-dihydrogenation.

The thermal C2–C6/[2 + 2] cyclisation of enyne-allenes: Reversible diradical formation by Mehmet Emin Cinar; Chandrasekhar Vavilala; Jian Fan; Michael Schmittel (3776-3779).
New enyne-allenes, structurally designed toward the thermal C2–C6/[2 + 2] cyclisation mode, were prepared and characterised, one of them even by X-ray crystallography. The mechanism of their transformation to formal [2 + 2] cycloadducts was interrogated by trapping experiments and DFT computations. The results support a stepwise mechanism that involves the reversible formation of the C2–C6 diradical intermediate.

Radical carbonylation of ω-alkynylamines leading to α-methylene lactams. Synthetic scope and the mechanistic insights by Ilhyong Ryu; Takahide Fukuyama; Mami Tojino; Yoshitaka Uenoyama; Yuka Yonamine; Nozomi Terasoma; Hiroshi Matsubara (3780-3786).
Tin hydride mediated radical carbonylation and cyclization reaction was investigated using a variety of ω-alkynyl amines as substrates. In this reaction α-methylene and α-stannylmethylene lactams having five to eight membered rings were obtained as principal products. In cases where the nitrogen has a substituent capable of giving stable radicals, such as an α-phenethyl group, the lactam ring formation again took place with extrusion of an α-phenethyl radical. Coupled with the subsequent protodestannylation procedure (TMSCl plus MeOH), these reactions provide a useful entry to α-methylene lactams with incorporation of CO as a lactam carbonyl group. In cases where the amines do not have a substituent acting as a radical leaving group, a reaction course involving a 1,4-H shift is chosen so as to liberate tin radicals ultimately. Thus the proposed mechanism involves (i) nucleophilic attack of amine nitrogen onto a carbonyl group of α,β-unsaturated acyl radicals/α-ketenyl radicals via lone pair–π* interaction, which leads to zwitterionic radical species, (ii) the subsequent proton shift from N to O to give hydroxyallyl radicals, (iii) 1,4-hydrogen shift from O to C, and (iv) β-scission to give lactams with liberation of tin radicals. DFT calculations reveal that the 1,4-hydrogen shifts, the key step of the reaction mechanism, can proceed under usual reaction conditions. On the other hand, an SHi type reaction to give lactams may be the result of the β-scission of the similar zwitterionic radical intermediates. DFT calculations also predict that an SHi type reaction would result when the intermediate has a good (radical) leaving group such as a phenethyl group.

The peptide Boc-Val-Phe-OMe 1 bearing sequence similarity with the central hydrophobic cluster (CHC) of Alzheimer's Aβ18-19 peptide self-assembles to produce amyloid-like straight unbranched fibrils as examined by atomic force microscopy and Congo red assay. Single crystal X-ray diffraction offers the atomic level structure of the supramolecular parallel β-sheet aggregation and antiparallel separation between layers (cross-β-structure).

Ascorbic acid (vit. C) is a cofactor whose reactivity toward peroxyl and other radical species has a key-role in its biological function. At physiological pH it is dissociated to the corresponding anion. Derivatives of ascorbic acid, like ascorbyl palmitate, are widely employed in food or in cosmetics and pharmaceuticals. While the aqueous chemistry of ascorbate has long been investigated, in non-aqueous media it is largely unexplored. In this work oxygen-uptake kinetics, EPR and computational methods were combined to study the reaction of peroxyl radicals with two lipid-soluble derivatives: ascorbyl palmitate and 5,6-isopropylidene-l-ascorbic acid in non-aqueous solvents. In acetonitrile at 303 K the undissociated AscH2 form of the two derivatives trapped peroxyl radicals with kinh of (8.4 ± 1.0) × 104 M−1 s−1, with stoichiometric factor of ca. 1 and isotope effect kH/kD = 3.0 ± 0.6, while in the presence of bases the anionic AscH form had kinh of (5.0 ± 3.3) × 107 M−1 s−1. Reactivity was also enhanced in the presence of acetic acid and the mechanism is discussed. The difference in reactivity between the AscH2/AscH forms was paralleled by a difference in O–H bond dissociation enthalpy, which was determined by EPR equilibrations as 81.0 ± 0.4 and 72.2 ± 0.4 kcal mol−1 respectively for AscH2 and AscH in tert-butanol at 298 K. Gas-phase calculations for the neutral/anionic forms were in good agreement yielding 80.1/69.0 kcal mol−1 using B3LYP/6-31+g(d,p) and 79.0/67.8 kcal mol−1 at CBS-QB3 level. EPR spectra of ascorbyl palmitate in tBuOH consisted of a doublet with HSC = 0.45 G centred at g = 2.0050 for the neutral radical AscH˙ and a doublet of triplets with HSCs of 1.85 G, 0.18 G and 0.16 G centred at g = 2.0054 for Asc˙ radical anion.

Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and one-pot sequential ring-closing/cross metathesis by Kalyan Dhara; Sushovan Paladhi; Ganesh Chandra Midya; Jyotirmayee Dash (3801-3807).
A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis (RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been demonstrated to prepare substituted azaspiro-[4.4]nonenediones. The X-ray crystal structure of a spirocyclic thiazolidinedione dimer is described, which has been prepared in two steps from thiazolidinedione using a one-pot sequential ring-closing and self metathesis. Cross metathesis proceeds smoothly with both electron rich and poor olefins. The symmetrical bis-thiazolidinedione spirocyclic system can be used as CM coupling partner with olefins. One-pot sequential RCM-CM has been developed for the synthesis of substituted spirocyclic compounds. The methodology allows a quick access to thia-azaspiro-[4.4]nonene and -[4.5]decene-dione ring systems from readily available starting materials which are not otherwise accessible.

Sequential coupling/desilylation–coupling/cyclization in a single pot under Pd/C–Cu catalysis: Synthesis of 2-(hetero)aryl indoles by R. Mohan Rao; Upendar Reddy CH; Alinakhi; Naveen Mulakayala; Mallika Alvala; M. K. Arunasree; Rajamohan R. Poondra; Javed Iqbal; Manojit Pal (3808-3816).
A new one-pot synthesis of 2-(hetero)aryl indoles via sequential C–C coupling followed by C–Si bond cleavage and a subsequent tandem C–C/C–N bond forming reaction is described. A variety of functionalized indole derivatives were prepared by conducting this four step reaction under Pd/C–Cu catalysis. The methodology involved coupling of (trimethylsilyl)acetylene with iodoarenes in the presence of 10% Pd/C–CuI–PPh3 and triethylamine in MeOH, followed by treating the reaction mixture with K2CO3 in aqueous MeOH, and finally coupling with o-iodoanilides. The single crystal X-ray data of a synthesized indole derivative is presented. Application of the methodology, in vitro pharmacological properties of the synthesized compound, along with a docking study is described.

Total synthesis and absolute configuration of malyngamide W by Xian-Liang Qi; Jun-Tao Zhang; Jian-Peng Feng; Xiao-Ping Cao (3817-3824).
A concise enantioselective synthesis of malyngamide W (1) and its 2′-epimer was described. The strategy was based on three key steps: (1) ozonolysis of compound 11 which was derived from (R)-(−)-carvone 8, followed by copper-iron-catalyzed rearrangement to give the key cyclohex-2-enone intermediate 5, (2) Nozaki–Hiyama–Kishi coupling reaction between aldehyde 4 and iodide 14 to afford alcohol 3, and (3) asymmetric (R)-CBS reduction of the ketone functionality in compound 21 to establish the C-2′ chiral center in the target compound 1. The absolute configuration of malyngamide W (1) was thus confirmed via the synthesis of 1 and 2′-epi-1.

Total synthesis of spiruchostatin B aided by an automated synthesizer by Shinichiro Fuse; Kumiko Okada; Yusuke Iijima; Asami Munakata; Kazuhiro Machida; Takashi Takahashi; Motoki Takagi; Kazuo Shin-ya; Takayuki Doi (3825-3833).
The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.

A new rapid multicomponent domino reaction for the formation of functionalized benzo[h]pyrazolo[3,4-b]quinolines by Bo Jiang; Ge Zhang; Ning Ma; Feng Shi; Shu-Jiang Tu; Parminder Kaur; Guigen Li (3834-3838).
A new multicomponent domino reaction for rapid and regioselective synthesis of highly functionalized benzo[h]pyrazolo[3,4-b]quinolines has been established. The reaction can be conducted by using readily available and inexpensive substrates under microwave irradiation within short periods of 10–26 min. Good to excellent chemical yields (61–91%) and complete regioselectivity have been achieved for 22 examples. Tedious work-up procedure can be avoided due to the direct precipitation of products from the reaction solution. The resulting benzoquinolines have been readily converted into quinoxaline-fused benzo[h]isoxazolo[5,4-b]quinoline analogues by treating with benzene-1,2-diamine under microwave irradiation. The structural assignment has been ambiguously confirmed by X-ray analysis. A new mechanism has been proposed for this new multicomponent domino process.

Dirhodium acetate catalyzed three-component reactions of aryl diazoacetates, alcohols or water, and 2-alkynals are reported to afford β-alkynyl α,β-dihydroxyl acid esters in good yield with high diastereoselectivity. Synthetic utility of the reaction was demonstrated in the conversion of the versatile alkynyl functionality to other synthetically useful compounds, including efficient synthesis of 2-aryl-2,3-dihydroxyl enelactones.

Highly selective fluorescent OFF–ON thiol probes based on dyads of BODIPY and potent intramolecular electron sink 2,4-dinitrobenzenesulfonyl subunits by Huimin Guo; Yingying Jing; Xiaolin Yuan; Shaomin Ji; Jianzhang Zhao; Xiaohuan Li; Yanyan Kan (3844-3853).
Two highly selective OFF–ON green emitting fluorescent thiol probes (1 and 2) with intense absorption in the visible spectrum (molar extinction coefficient ε is up to 73 800 M−1 cm−1 at 509 nm) based on dyads of BODIPY (as electron donor of the photo-induced electron transfer, i.e.PET) and 2,4-dinitrobenzenesulfonyl (DNBS) (as electron acceptor of the PET process) were devised. The single crystal structures of the two probes were determined. The distance between the electron donor (BODIPY fluorophore) and the electron acceptor (DNBS) of probe 2 is larger than that of probe 1, as a result the contrast ratio (or the PET efficiency) of probe 2 is smaller than that of probe 1. However, fluorescence OFF–ON switching effects were observed for both probe 1 and probe 2 in the presence of cysteine (the emission enhancement is 300-fold for probe 1 and 54-fold for probe 2). The fluorescence OFF–ON sensing mechanism is rationalized by DFT/TDDFT calculations. We demonstrated with DFT calculations that DNBS is ca. 0.76 eV more potent to accept electrons than the maleimide moiety. The probes were used for fluorescent imaging of cellular thiols.

Preparation of fluoxetine by multiple flow processing steps by Batoul Ahmed-Omer; Adam J. Sanderson (3854-3862).
Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.

Chiral hexamine macrocycle derived from trans-1,2-diaminocyclohexane (DACH) in a complex with diethylzinc efficiently catalyzes the asymmetric hydrosilylation of N-phosphorylated aryl-alkyl or aryl-aryl ketimines in protic media with enantiomeric excess of the product approaching 100%. The cyclic structure of the trianglamine ligand increases the enantioselectivity and/or the yield of the reaction, in comparison to the catalysis by acyclic N,N′-dibenzyl-DACH ligands. Density functional theory (DFT) computations on the structure of the model ligand-zinc complex and on the structures of the pre-organized reactants together with the calculations of possible transition states allow rationalization of the direction of the asymmetric induction of the hydrosilylation reaction. This is the first example of asymmetric catalysis of the hydrosilylation reaction of ketimines with the use of a readily available and inexpensive macrocyclic trianglamine ligand.

Energy transfer cassettes in silica nanoparticles target intracellular organelles by Jiney Jose; Aurore Loudet; Yuichiro Ueno; Liangxing Wu; Hsiang-Yun Chen; Dong Hee Son; Rola Barhoumi; Robert Burghardt; Kevin Burgess (3871-3877).
Lipophilic energy transfer cassettes like 1 and 2 are more conveniently synthesized than the corresponding hydrophilic compounds, but they are not easily used in aqueous media. To overcome the latter issue, cassettes 1 and 2 were separately encapsulated in silica nanoparticles (ca. 22 nm) which freely disperse in aqueous media. Photophysical properties of the encapsulated dyes 1–SiO2 and 2–SiO2 were recorded. The nanoparticles 1–SiO2 permeated into Clone 9 rat liver cells and targeted only the ER. A high degree of energy transfer was observed in this organelle such that most of the light fluoresced from the acceptor part, i.e. the particles appeared red. Silica nanoparticles 2–SiO2 also permeated into Clone 9 rat liver cells and they targeted mitochondria but were also observed in endocytic vesicles (lysosomes or endosomes). In these organelles they fluoresced red and red/green respectively. Thus the cargo inside the nanoparticles influences where they localize in cells, and the environment of the nanoparticles in the cells changes the fluorescent properties of the encapsulated dyes. Neither of these findings were anticipated given that silica nanoparticles of this type are generally considered to be non-porous.

A cascade process for the synthesis of gem-difluoromethylene compounds by Zixian Chen; Jiangtao Zhu; Haibo Xie; Shan Li; Yongming Wu; Yuefa Gong (3878-3885).
An efficient strategy for the synthesis of 2,2-difluoro-2,3-dihydrofuran derivatives from β-fluoroalkyl-β-enaminoketones is described. The reaction occurred via an intramolecular halophilic attack-initiated cascade process. A series of 2,3-dihydrofurans were prepared in high yields. And an intermolecular domino process achieved providing polysubstituted furans. The mechanism of the reaction is discussed.

An efficient approach to azirino and pyrrolo-fused dibenzazepines. Conformations of substituted dibenzo[c,f]pyrrolo[1,2-a]azepines by Alexander F. Khlebnikov; Mikhail S. Novikov; Maria V. Golovkina; Petr P. Petrovskii; Alexander S. Konev; Dmitry S. Yufit; Helen Stoeckli-Evans (3886-3895).
An effective approach to azepino-fused heterocycles is described. trans-1-Aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines were synthesised via a domino sequence: isomerization of gem-dichloroaziridine–intramolecular Friedel–Crafts acylation of the tethered benzene ring catalysed by SnCl4 and subsequent hydride induced intramolecular cyclization. Cycloaddition of dibenzazepinium ylides, generated by heating these aziridines, to activated CC, CC dipolarophiles and fullerene C60, leads to derivatives of dibenzo[c,f]pyrrolo[1,2-a]azepine. The reaction proceeds with complete stereoselectivity via cycloaddition of only W-ylide, which due to the high barrier does not undergo E,Z-isomerization under the reaction conditions. It was found that 2,3,9,13b-tetrahydro-1H-dibenzo[c,f]pyrrolo[1,2-a]azepine systems can exist in conformations of two types depending on the substituents at the pyrrolidine carbons in β-position with respect to nitrogen. Details of cycloaddition reactions and the conformational behavior of cycloadducts were studied by DFT calculations at the B3LYP/6-31G(d) level.

Effective 1,5-, 1,6- and 1,7-remote stereocontrol in reactions of alkoxy- and hydroxy-substituted allylstannanes with aldehydes by John S. Carey; Somhairle MacCormick; Steven J. Stanway; Aphiwat Teerawutgulrag; Eric J. Thomas (3896-3919).
Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated stereoselectively with tin(iv) halides to generate allyltin trihalides which react with aldehydes to give (Z)-alk-3-enols with useful levels of 1,5-, 1,6- and 1,7-stereocontrol. Alk-2-enylstannanes with a stereogenic centre bearing a hydroxy or alkoxy group at the 4-, 5- or 6-position, react with overall (Z)-1,5-, 1,6- and 1,7-syn-stereoselectivity with respect to the hydroxy and alkoxy substituents. The analogous reactions of alkoxy- and -hydroxyalk-2-enylstannanes with a methyl bearing stereogenic centre at the 4- or 5-position react with overall (Z)-1,5- and 1,6-anti-stereoselectivity with respect to the hydroxy and methyl substituents.

Expanding the chiral pool: oxidation of meta-bromobenzoic acid by R. eutrophus B9 allows access to new reaction manifolds by Julia A. Griffen; Amélie M. Le Coz; Gabriele Kociok-Köhn; Monika Ali Khan; Alan J. W. Stewart; Simon E. Lewis (3920-3928).
Metabolism of meta-bromobenzoic acid by the blocked mutant Ralstonia eutrophus B9 affords an enantiopure dearomatised halodiene-diol which we demonstrate is a versatile chiron for organic synthesis. The presence of the halogen leads to reactivity that is distinct to that observed for the non-halogenated analogue and also serves as a synthetic handle for further functionalisation.

Ready access to 3-amino-2,3-dideoxysugars via regio- and stereo-selective tandem hydroamination–glycosylation of glycals by Feiqing Ding; Ronny William; Siming Wang; Bala Kishan Gorityala; Xue-Wei Liu (3929-3939).
A highly stereoselective BF3·OEt2-promoted tandem hydroamination–glycosylation on a glycal scaffold has been developed to form 3-amino-2,3-dideoxysugars in a one-pot procedure. This efficient multicomponent reaction protocol offers simplicity and general applicability to a broad range of variations on each component.

A novel acid-catalyzed C5-alkylation of oxindoles using alcohols by Chada Raji Reddy; Enukonda Jithender; Gaddam Krishna; Gunreddy Venkat Reddy; Bharatam Jagadeesh (3940-3947).
A novel C5-alkylation of oxindoles using alcohols as alkylating agents under acid catalysis is described for the first time. The reactions of various benzylic, allylic and propargylic alcohols are studied to obtain the corresponding 5-substituted oxindoles in good yields.

Chemoselective reduction of 2-acyl-N-sulfonylpyrroles: Synthesis of 3-pyrrolines and 2-alkylpyrroles by Hai Tao You; Andrew C. Grosse; James K. Howard; Christopher J. T. Hyland; Jeremy Just; Peter P. Molesworth; Jason A. Smith (3948-3953).
The partial reduction of pyrroles is not a common practice even though it offers a potential route to pyrroline building blocks, commonly used for synthesis. We have investigated the reduction of 2-acyl-N-sulfonylpyrroles and by varying the hydride source and solvent, achieved a chemoselective reduction, leading to 3-pyrrolines and alkyl pyrroles in high yield.

Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position by Hiroshi Saitoh; Takayuki Chida; Kenichiro Takagi; Kyohei Horie; Yoshiyuki Sawai; Yuko Nakamura; Yoshifumi Harada; Kazuya Takenouchi; Atsushi Kittaka (3954-3964).
In order to obtain vitamin D derivatives, which have strong activity for enhancing bone growth, we designed vitamin D derivatives with various substitutions at the C-2 position. Novel 2 α-substituted vitamin D derivatives were synthesized starting from d-glucose as a chiral template of the A-ring with a CD-ring bromoolefin unit using the Trost coupling method. We evaluated these compounds by two in vitro assays, affinity to VDR and transactivation assays, using human osteosarcoma (Hos) cells, and demonstrated the SAR of the C-2 position of VD3. Furthermore, by using the OVX model, we found that compound 5c, which has a hydroxypropoxy side chain at C-2 and 2,2-dimethyl cyclopentanone in the CD-ring side chain, has a strong activity for enhancing bone growth, same as the reported compound, 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D31d, and this derivative shows a possibility that calcemic activity is less than 1din vivo.

Structure–activity relationships in hydroxy-2,3-diarylxanthone antioxidants. Fast kinetics spectroscopy as a tool to evaluate the potential for antioxidant activity in biological systems by Clementina M. M. Santos; Artur M. S. Silva; Paulo Filipe; René Santus; Larry K. Patterson; Jean-Claude Mazière; José A. S. Cavaleiro; Patrice Morlière (3965-3974).
A structure–activity relationship has been established for eight hydroxy-2,3-diarylxanthones (XH) bearing hydroxy groups on the two aryl rings. One-electron oxidation by superoxide radical-anions (˙O2) and ˙Trp radicals as well as reaction with ˙CCl3O2 and ˙CHCl2O2 radicals demonstrates that two OH groups are required for efficient antioxidant reactivity in cetyltrimethylammonium bromide micelles. Hydroxy groups at the meta and para positions on either of the two phenyl rings confer enhanced reactivity, but XH bearing an OH at the para position of either phenyl ring is unreactive. While oxidation is favoured by OH in both meta and para positions of 2-aryl xanthone substituents, addition of a third and/or fourth OH enhances electron-donating capacity. In Cu2+-induced lipid peroxidation of human LDL, the lag period preceding the commencement of lipid peroxidation in the presence of XH bearing OH at meta and para positions on the 3-phenyl ring is extended to twice that observed with a comparable concentration of quercetin, a reference antioxidant. These antioxidants are also superior to quercetin in protecting human skin keratinocytes against tert-butylhydroperoxide-induced oxidative stress. While XH antioxidant activity in model biological systems is consistent with the structure–activity relationship, their response is also modulated by the localization of XH and by structural factors.

Back cover (3975-3976).