Organic & Biomolecular Chemistry (v.7, #23)
Front cover (4801-4801).
Inside front cover (4802-4802).
Contents and Highlights in Chemical Biology (4803-4816).
Cationic rhodium(I)/bisphosphine complex-catalyzed cyclization of 1,6-diynes with carboxylic acids by Ken Tanaka; Shunsuke Saitoh; Hiromi Hara; Yu Shibata (4817-4820).
A cationic rhodium(I)/bisphosphine complex catalyzes carboxylative cyclizations of 1,6-diynes, leading to cyclic dienyl carboxylates, in high yields with high chemo-, regio-, and stereoselectivities under mild reaction conditions.
Microwave-assisted versatile hydrogenation of carbonyl compounds using supported metal nanoparticles by Maria Jose Gracia; Juan Manuel Campelo; Elia Losada; Rafael Luque; Jose Maria Marinas; Antonio Angel Romero (4821-4824).
The efficient microwave-assisted transfer hydrogenation of carbonyl compounds was performed using supported Pt and Pd nanoparticles on Al-SBA-15 materials. Excellent conversions, with exceedingly higher TOF values (4,000-20,000 h−1) compared to any previous literature report, were achieved in very short times of reaction (5-30 min), together with complete selectivities to the hydrogenated product.
The pyridinone-methide elimination by Rotem Perry-Feigenbaum; Phil S. Baran; Doron Shabat (4825-4828).
The quinone-methide elimination is a common, efficient methodology used in linkers designed to undergo self-fragmentation. Here, for the first time, we demonstrate this elimination in a pyridine ring system. Under physiological conditions, a compound constructed of a pyridine core, a reporter, and an enzymatic trigger underwent significantly faster 1,4-elimination than its parent compound with a benzene core. In addition, an AB2 self-immolative dendron based on a pyridine core released its two reporter units upon activation through 1,6- and 1,4 pyridinone-methide elimination reactions, again faster than the analogous benzene system. Increased aqueous solubility was observed with compounds based on pyridine relative to those based on benzene. The pyridinone-methide elimination could be applied as an alternative tool in designing self-immolative linkers for release of active target molecules in an aqueous environment.
Stereodivergent syntheses at the glucose backbone by Jian Yin; Torsten Linker (4829-4831).
Both diastereomers of 2-C-branched carbohydrates with various functional groups are selectively available from the same malonate precursor in good yields in only a few steps.
Synthesis of unsaturated phosphatidylinositol 4,5-bisphosphate and analogues by Nitesh Panchal; Piers R. J. Gaffney (4832-4841).
A new approach for the synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] is described, compatible with unsaturated fatty acid esters, as well as phosphorothioate and acetylenic analogues. This strategy depends on masking the phosphate charges with base-labile cyanoethyl esters, and the hydroxyls of the target with mild acid-labile protecting groups. A two-step basic then acidic global unblocking of orthogonal protecting groups provides the target lipid. A xanthenylidene acetal was used for key temporary protection of the 4,5-diol, and the 6-O was protected with a 1-(4-chlorophenyl)-4-ethoxypiperidin-4-yl (Cpep) acetal.
Neighbouring group participation vs. addition to oxacarbenium ions: studies on the synthesis of mycobacterial oligosaccharides by Susanne A. Stalford; Colin A. Kilner; Andrew G. Leach; W. Bruce Turnbull (4842-4852).
Neighbouring group participation is frequently used to control the stereoselectivity of chemical reactions. Herein, we investigate the use of neighbouring group participation for the synthesis of disaccharides incorporating the mycobacterial sugar methylthioxylose. A bicyclic thioglycoside was activated by methylation to generate a methylsulfonium group that would act both as the anomeric leaving group, and also provide the methylsulfide group in the product. Model reactions indicated that the bicyclic intermediate would also act as a participating group to direct the acceptor alcohol to the lower α-face of the sugar. While the key sulfonium intermediate could be detected in the reaction mixture, the glycosylation reaction proceeded with moderate stereoselectivity, apparently via an SN1-type mechanism. Density functional theory calculations were used to compare our methylthioxylose sulfonium ion with a trans-decalin-like sulfonium ion described by Boons and co-workers to be an α-directing participating group (J. Am. Chem. Soc. 2005, 127, 12090). Our studies show that even where a bicyclic sulfonium ion can be detected in the reaction mixture, caution should be applied before invoking it as an intermediate on the reaction pathway.
Palladium-catalysed ortho-arylation of carbamate-protected phenols by Robin B. Bedford; Ruth L. Webster; Charlotte J. Mitchell (4853-4857).
The carbamate (–O2CNR2) function is an excellent directing group for palladium-catalysed direct arylation reactions giving both protected or free mono- or di-substituted phenols, as well as an example of a dibenzopyranone, depending on coupling partners (aryl iodides or diaryliodonium salts) and conditions.
Lewis acid InBr3-catalyzed arylation of diorgano diselenides and ditellurides with arylboronic acids by Kai Ren; Min Wang; Lei Wang (4858-4861).
A novel Lewis acid InBr3-catalyzed direct cross-coupling reaction of arylboronic acids with diorgano diselenides and ditellurides without any additive has been developed. The reactions generated the corresponding unsymmetrical diorgano monoselenides and monotellurides in good to excellent yields. The method has advantages of broad substrate scope, simple operation, mild reaction conditions and high effectiveness. A possible reaction mechanism was proposed.
The coumarin→indole transformation—a method for preparing 4-halo-5-hydroxyindoles from coumarins by Elia J. L. Stoffman; Derrick. L. J. Clive (4862-4870).
Readily accessible 3-alkoxycarbonyl-6-hydroxy-5-halocoumarins can be converted into 4-halo-5-hydroxyindoles by a sequence whose essential steps are conjugate reduction or conjugate addition, decarboxylation, lactone opening with ammonia, phenolic oxygen protection, Hofmann rearrangement to an N-Boc ethylamine, oxidation to a quinone and deprotection of the nitrogen. The resulting β-aminoethyl quinone cyclizes to a mixture of quinone imine and indole, and the imine tautomerizes to the indole spontaneously or on treatment with rhodium on alumina.
Direct synthesis of sulfonated azacalixarenes in water by Jonathan Clayden; Stephen J. M. Rowbottom; Warren J. Ebenezer; Michael G. Hutchings (4871-4880).
Successive treatment of cyanuric chloride with two aromatic diamines, at least one of them sulfonated, yields water-soluble sulfonated azacalixarenes which may be isolated by crystallisation. Functionalised azacalixarenes may be made by first displacing two chloro substituents from the cyclisation precursor. Attempted formation of an azacalixarene led to a dimeric species for which two structures may be proposed, one of them an azacalixarene catenane.
Synthesis and X-ray structural analysis of platinum and ethynyl-platinum corannulenes: supramolecular tectons by Roman Maag; Brian H. Northrop; Anna Butterfield; Anthony Linden; Oliver Zerbe; Young Min Lee; Ki-Whan Chi; Peter J. Stang; Jay S. Siegel (4881-4885).
The synthesis and characterization of two direct platinum (1 and 6a/b) and three ethynyl-platinum corannulene derivatives (2, 8 and 9), bearing 2, 4, or 5 square planar platinum centers, are presented. The structure of the bowl bearing substituents remains comparable to corannulene and the dynamic behavior of the bowl inversion as assessed by VT NMR supports a persistent bowl structure in solution. These platinum-corannulenes are well-structured tectons for the future assembly of coordination Platonic polyhedra.
Evaluation of the pharmacophoric motif of the caged Garcinia xanthones by Oraphin Chantarasriwong; Woo Cheal Cho; Ayse Batova; Warinthorn Chavasiri; Curtis Moore; Arnold L. Rheingold; Emmanuel A. Theodorakis (4886-4894).
The combination of unique structure and potent bioactivity exhibited by several family members of the caged Garcinia xanthones, led us to evaluate their pharmacophore. We have developed a Pd(0)-catalyzed method for the reverse prenylation of catechols that, together with a Claisen/Diels–Alder reaction cascade, provides rapid and efficient access to various caged analogues. Evaluation of the growth inhibitory activity of these compounds leads to the conclusion that the intact ABC ring system containing the C-ring caged structure is essential to the bioactivity. Studies with cluvenone (7) also showed that these compounds induce apoptosis and exhibit significant cytotoxicity in multidrug-resistant leukemia cells. As such, the caged Garcinia xanthone motif represents a new and potent pharmacophore.
Synthesis and kinetic studies of a low-molecular weight organocatalyst for phosphate hydrolysis in water by Michael Merschky; Carsten Schmuck (4895-4903).
Kinetic studies of a low-molecular weight organocatalyst 1 are presented. Compound 1 contains two histidines and one cationic side chain attached to a central aromatic core. In aqueous solution 1 accelerates the hydrolysis of a prototypal phosphodiester with rate enhancements of up to two orders of magnitude. A detailed HPLC analysis of hydrolysis experiments in Bis-Tris-buffer showed that the buffer itself can act as a nucleophile at least with the cyclic phosphate 16. Compound 1 is also an efficient host for the binding of bis-(para-nitrophenyl)-phosphate 14 with extraordinary high affinity of Kass = 24 400 M−1 in buffered water.
Calixarenes featuring a direct lower rim attachment of dansyl groups. Synthesis, fluorescence properties and first report on crystal structures by Tobias Gruber; Conrad Fischer; Marika Felsmann; Wilhelm Seichter; Edwin Weber (4904-4917).
A series of new fluorescent calixarenes (2–7; 5 has been isolated as two not yet described conformational isomers) featuring two directly lower rim attached dansyl moieties besides other lower or upper rim site substituents have been synthesized and investigated with reference to their fluorescence properties including potential sensing capability for metal ions. Except for the nitro substituted compound 7, which showed a moderate fluorescence quenching on the addition of Hg2+ in acetonitrile, the calixarenes 2–6 were found to selectively recognize Cu2+ in the 10−6 mol L−1 concentration range detectable by the nearly total quenching of their intrinsic fluorescence. Using fluorescence titration experiments, the ideal complexation ratio [metal ion]/[ligand] for three exemplarily investigated calixarenes (3, 5a and 7) was determined to be 2:1. For 5a, a new red shifted signal was observed by the complexation of Cu2+ while the addition of Hg2+ only yields a moderate quenching of the parent signal, indicating a different binding mode for both metal ions. This finding enables the calixarene 5a to be used as a suitable chemosensor for the simultaneous determination of copper and mercury. In this paper we also present the first crystal structures of dansylated calixarenes having the dansyl groups directly attached to the lower rim site. They involve the unsolvated calixarene 5b and the two solvent inclusion compounds 2·CH2(OH)CN and 3·3CH3CN, each showing an extensive pattern of non-covalent interactions. In both solvates, the calixarenes are fixed in a cone conformation while the unsolvated calixarene 5b adopts the partial cone conformation. A solution 1H NMR study in CDCl3 reveals also the cone conformation for all dansylated calixarenes, except the more conformationally flexible upper rim unsubstituted calixarene 5 which showed cone and partial cone conformers 5a and 5b, respectively, in an approximate 2:3 ratio.
Peptide thioester synthesis through N→S acyl-transfer: application to the synthesis of a β-defensin by Jaskiranjit Kang; Natalie L. Reynolds; Christine Tyrrell; Julia R. Dorin; Derek Macmillan (4918-4923).
Peptide thioesters readily prepared through N→S acyl transfer of a specific C-terminal motif provide access to biologically active mini-proteins using native chemical ligation.
4-Aminoproline-based arginine-glycine-aspartate integrin binders with exposed ligation points: practical in-solution synthesis, conjugation and binding affinity evaluation by Lucia Battistini; Paola Burreddu; Paola Carta; Gloria Rassu; Luciana Auzzas; Claudio Curti; Franca Zanardi; Leonardo Manzoni; Elena M. V. Araldi; Carlo Scolastico; Giovanni Casiraghi (4924-4935).
An expedient and practical in-solution synthesis of three new 4-aminoproline-based arginine-glycine-aspartate integrin binders – compounds 15, 17 and 19– is presented. Two candidates carrying exposed azide and amine functional points were further advanced to trimeric platform 21 as well as fluorescein- and DOTA-conjugates 23 and 25. The new compounds were assayed for their binding affinity towards human αVβ3 and αVβ5 integrin receptors. Both monomeric candidates and covalent conjugates revealed potent ligand competence for the αVβ3 receptor in the one-digit nanomolar range (IC50αVβ3 = 0.2–8.0 nM; IC50αVβ5 = 5.0–1621 nM), thus demonstrating that conjugation does not impair the exquisite binding profile of this new generation of integrin ligands.
Synthetic routes to pyrrolizine-1,5-dione derivatives by flash vacuum pyrolysis of amidomethylene derivatives of Meldrum's acid by Hamish McNab; Mark Morrow; Simon Parsons; David A. Shannon; Kirsti Withell (4936-4942).
Methoxymethylene Meldrum's acid 1 reacts with 5- and 6-membered lactams in refluxing acetonitrile to give the N-substituted products 9–15. If the reactions are continued for extended times, the Meldrum's acid derivatives decompose to provide enamidoesters e.g.22–24. Flash vacuum pyrolysis of the 5-membered ring products 9–13 provides reasonable yields of the fused pyrrolones 31–35. The constitution of the products is supported by X-ray crystal structures of 10, 12, 19, 32 and 34.
l-Proline-catalyzed synthesis of highly functionalized multisubstituted 1,4-dihydropyridines by Huanfeng Jiang; Ronghuan Mai; Hua Cao; Qiuhua Zhu; Xiaohang Liu (4943-4953).
Highly functionalized multisubstituted 1,4-dihydropyridines 5 have been concisely synthesized in moderate to good yields vial-proline-catalyzed one-pot multicomponent reactions (MCRs) of alkynoates or alkynones 1, amines 2, β-dicarbonyl compounds 3 and aldehydes 4 under mild conditions. The MCR process involves hydroamination/Knoevenagel condensation/Michael-type addition/intramolecular cyclization processes and leads to the formation of 1,4-dihydropyridines 5. The molecular structure of 5ckaa was confirmed by single-crystal X-ray diffraction. This method is energy saving and environmentally friendly, providing easy access to diverse multisubstituted polyfunctional 1,4-dihydropyridines.
Synthesis of a photo-caged aminooxy alkane thiol by Rock J. Mancini; Ronald C. Li; Zachary P. Tolstyka; Heather D. Maynard (4954-4959).
A photo-caged aminooxy alkane thiol synthesized in 7 steps and 15% overall yield was used to form a self-assembled monolayer (SAM). Photo-deprotection on the surface was confirmed by FT-IR spectroscopy and contact angle goniometry. Conjugation of a small molecule ketone, ethyl levulinate, further confirmed the presence of aminooxy groups on the surface.
Expedient synthesis of 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones via one-pot aryne acyl-alkylation/condensation by Kevin M. Allan; Boram D. Hong; Brian M. Stoltz (4960-4964).
A convenient method is disclosed for the synthesis of both 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones from β-ketoesters using a one-pot aryne acyl-alkylation/condensation procedure. When performed in conjunction with a one-step method for the synthesis of the β-ketoester substrates, this method provides a new route to these polyaromatic structures in only two steps from commercially available carboxylic acid starting materials. The utility of this approach is demonstrated in the synthesis of the atropisomeric P,N-ligand, QUINAP.
Photolabile N-hydroxypyrid-2(1H)-one derivatives of guanine nucleosides: a new method for independent guanine radical generation by Panagiotis Kaloudis; Cecilia Paris; Despoina Vrantza; Susana Encinas; Raul Pérez-Ruiz; Miguel A. Miranda; Thanasis Gimisis (4965-4972).
One-electron oxidized guanine is an important reactive intermediate in the formation of oxidatively generated damage in DNA and a variety of methods have been utilized for the abstraction of a single electron from the guanine moiety. In this study, an alternative approach for the site specific, independent generation of the guanine radical, utilizing N-hydroxypyrid-2(1H)-one as a photolabile modifier of guanine, is proposed. Novel photolabile 6-[(1-oxido-2-pyridinyl)oxo]-6-deoxy- and 2′,6-dideoxy-guanosine derivatives capable of generating the neutral guanine radical (G(-H)˙) upon photolysis were synthesized and characterized. The generation of G(-H)˙ proceeds through homolysis of the N–O bond and was confirmed through continuous photolysis product analysis and trapping studies, as well as laser flash photolysis experiments.
Synthesis of new, UV-photoactive dansyl derivatives for flow cytometric studies on bile acid uptake by Jana Rohacova; M. Luisa Marin; Alicia Martínez-Romero; José-Enrique O'Connor; M. Jose Gomez-Lechon; M. Teresa Donato; Jose V. Castell; Miguel A. Miranda (4973-4980).
Four new fluorescent derivatives of cholic acid have been synthesized; they incorporate a dansyl moiety at 3α-, 3β-, 7α- or 7β- positions. These cholic acid analogs are UV photoactive and also exhibit green fluorescence. In addition, they have been demonstrated to be suitable for studying the kinetics of bile acid transport by flow cytometry.
Structural analysis of the DNA target site and its interaction with Mbp1 by Anna V. Chernatynskaya; Lynn Deleeuw; John O. Trent; Tom Brown; Andrew N. Lane (4981-4991).
The solution structure of a 14 base-pair non-self complementary DNA duplex containing the consensus-binding site of the yeast transcription factor Mbp1 has been determined by NMR using a combination of scalar coupling analysis, time-dependent NOEs, residual dipolar couplings and 13C-edited NMR spectroscopy of a duplex prepared with one strand uniformly labeled with 13C-nucleotides. As expected, the free DNA duplex is within the B-family of structures, and within experimental limits is straight. However, there are clear local structural variations associated with the consensus CGCG element in the binding sequence that are important for sequence recognition. In the complex, the DNA bends around the protein, which also undergoes some conformational rearrangement in the C-terminal region. Structural constraints derived from paramagnetic perturbation experiments with spin-labeled DNA, chemical shift perturbation experiments of the DNA, previous cross-saturation, chemical shift perturbation experiments on the protein, information from mutational analysis, and electrostatics calculations have been used to produce a detailed docked structure using the known solution conformation of the free protein and other spectroscopic information about the Mbp1:DNA complex. A Monte Carlo-based docking procedure with restrained MD in a fully solvated system subjected to available experimental constraints produced models that account for the available structural data, and can rationalize the extensive thermodynamic data about the Mbp1:DNA complex. The protein:DNA interface is closely packed and is associated with a small number of specific contacts. The structure shows an extensive positively charged surface that accounts for the high polyelectrolyte contribution to binding.
Thermal melting studies of alkyne- and ferrocene-containing PNA bioconjugates by Anna M. Sosniak; Gilles Gasser; Nils Metzler-Nolte (4992-5000).
The preparation of new metal-containing Peptide Nucleic Acids (PNAs) is currently a field of research intensively studied for various purposes, e.g. DNA biosensors. The role played by the metal centre, notably on the stability of the PNA·DNA hybrid, is obviously crucial, but has not yet been fully investigated. In this work, UV-Vis spectroscopic measurements of solutions of DNA·PNA hybrids, whose 11/12-mer PNA oligomers contained either one or two alkyne- (1) or ferrocene-containing (2) PNA monomers, were carried out to determine the effect of these monomers on the thermal stability of the hybrids (PNA: H-Gly-X-gggtc-Y-agctt-X-Lys-NH2 with X = 1 or 2 and Y = 1 or 2 or blank position). Supplementary CD spectroscopic measurements were performed to gain insight into the structures of the PNA·DNA duplexes formed. The effect of both modified monomers was found to depend on their actual positions within the PNA sequences. Insertions at the N- or C-termini of a PNA oligomer did not change the melting temperatures (Tm values of about 72 °C) of the DNA·PNA hybrids significantly. Insertion of monomers 1 or 2 in the middle of a PNA sequence induced a substantial decrease in the Tm of the hybrids (by about 23 °C) when bound to the same DNA oligomer. Interestingly, it was found that the type of modification, namely alkyne or ferrocene, did not significantly influence the Tm values in these cases. However, the thermal stability of hybrids with the DNA oligomers containing one to four additional thymines and the PNA oligomers containing the ferrocene moiety in its middle, varied significantly with the number of thymines added compared to its alkyne analogues (ΔTm up to −13 °C). The presence of the ferrocene moiety induced a significant decrease in thermal stability of the hybrids, probably due to its bulkiness. In order to assess the effect of PNA backbone rigidity on the stability of DNA·PNA hybrids, PNA oligomers with an internal amino acid, propargylglycine (Pgl) or the dipeptide glycine-propargylglycine (Gly-Pgl), were synthesised. It was assumed that the orientation of the alkyne moiety in the Pgl-containing PNA sequence is not identical to an alkyne-containing PNA sequence, as a significantly higher Tm value (ΔTm = +10 °C) was measured. It is anticipated that the alkyne moiety in Pgl is not facing the DNA base and therefore does not disturb as much the neighbouring nucleobases and base-stacking of the complementary DNA, in contrast to the alkyne moiety of 1. Interestingly, no significant differences in the thermal stability of the hybrids was observed between Pgl-containing and dipeptide-containing PNA oligomers, although the former contracts the PNA backbone by three atoms.
Synthesis and stereochemical determination of batzelladine C methyl ester by Michael Butters; Christopher D. Davies; Mark C. Elliott; Joseph Hill-Cousins; Benson M. Kariuki; Li-ling Ooi; John L. Wood; Stuart V. Wordingham (5001-5009).
Batzelladine C (3) is a tricyclic guanidine alkaloid of unknown stereochemistry at one centre as well as unknown absolute stereochemistry. The two possible diastereoisomers of the methyl ester corresponding to this compound have been synthesised, permitting the relative and absolute stereochemistry of this compound to be assigned.
Synthesis of novel synthetic intermediates from the reaction of benzimidazole and triazole carbenes with ketenimines and their application in the construction of spiro-pyrroles by Jun-Ming Mo; Yang-Guang Ma; Ying Cheng (5010-5019).
2-(2-Alkoxycarbonyl-1-arylamino-1-propenyl)benzimidazolium and 5-(2-alkoxycarbonyl-1-arylamino-1-propenyl)triazolium salts were synthesized in good yields from the reaction of benzimidazole and triazole carbenes with ketenimines. Upon treatment with a base, both salts were converted into novel 1,3-dipoles which underwent [3+2] cycloaddition reactions with electron-deficient alkynes and allenes to produce benzimidazole-spiro-pyrroles or triazole-spiro-pyrroles. This work provides novel synthons for the construction of multifunctional spiro-pyrrole derivatives that are not easy accessible by other synthetic methods and are potentially amenable to further transformations.
Synthesis of non-proteinogenic phenylalanine derivatives by rhodium-catalyzed [2+2+2] cycloaddition reactions by Lídia Garcia; Anna Pla-Quintana; Anna Roglans (5020-5027).
Non-proteinogenic phenylalanine derivatives were efficiently prepared by Rh(I)-catalyzed [2+2+2] cycloaddition reactions between enantiopure and racemic propargylglycine amino acids, with different protective groups, and diynes. Diverse substituents, including tags such as dansyl or dabsyl, were introduced onto the aromatic ring of the amino acid derivatives by selecting the most appropriate diyne reacting partners.
Component match in rhodium catalyzed three-component reactions of ethyl diazoacetate, H2O and aryl imines: a highly diastereoselective one-step synthesis of β-aryl isoserine derivatives by Zhenqiu Guo; Taoda Shi; Jun Jiang; Liping Yang; Wenhao Hu (5028-5033).
Water and ethyl diazoacetate were found to be matched components for generating highly reactive nucleophilic oxonium ylide in the presence of a dirhodium acetate catalyst. Simultaneous trapping of the oxonium ylide intermediate with aryl imines gave β-aryl isoserine derivatives with high diastereoselectivity.
Back matter (5034-5034).
Back cover (5035-5036).