Organic & Biomolecular Chemistry (v.9, #7)
Front cover (2009-2010).
Green oxidations of furans—initiated by molecular oxygen—that give key natural product motifs by Tamsyn Montagnon; Dimitris Noutsias; Ioanna Alexopoulou; Maria Tofi; Georgios Vassilikogiannakis (2031-2039).
In this article, we explore how changes in the positioning of pendant hydroxyl functionalities in the photooxygenation substrate dramatically alter the course of furan oxidations that are initiated by singlet oxygen; and, how these different reactivities can be harnessed through cascade reaction sequences to access, rapidly and effectively, a broad range of important natural product motifs.
Chemical synthesis of bacterial lipoteichoic acids: An insight on its biological significance by Richard R. Schmidt; Christian M. Pedersen; Yan Qiao; Ulrich Zähringer (2040-2052).
During infections caused by Gram-negative bacteria, lipopolysaccharide (LPS, endotoxin) has a dominant role leading to fulminant pro-inflammatory reactions in the host. As there is no LPS in Gram-positive bacteria, other microbial cell wall components have been identified to be the causative agent for the pro-inflammatory activity since also Gram-positive bacterial infections lead to comparable clinical symptoms and reactions. On search for the “Gram-positive endotoxin” a widely accepted hypothesis has been raised in that the lipoteichoic acids (LTAs) serve as pathogen-associated molecular patterns (PAMPs) during Gram-positive sepsis, although the amount necessary for a pro-inflammatory in vitro response is several orders of magnitude higher than that for LPS. Therefore, LTA cannot be considered to be “the (endo)toxin of Gram-positive bacteria”. Although LPS and LTA show structural relatedness (amphiphilic, negatively charged glycophospholipids), they are structurally quite different from each other and one might expect that they are also recognized by different receptors of the innate immune system, the so called toll-like receptors 4 and 2 (TLR4 and TLR2), respectively. Based on their chemical structure, the LTAs were classified into four types (type I–IV) of which we have carefully investigated the LTA of Staphylococcus aureus (type I), Lactococcus garvieae (type II) and Streptococcus pneumoniae (type IV). Hence, these LTAs have been synthesized in our group and biologically evaluated with respect to their potency to activate cytokines in transiently TLR2/CD14-transfected human endothelial kidney cells (HEK 293) or human macrophages and whole blood cells. Although LTA of type I and IV are structurally quite different, especially in their hydrophilic moiety, they originally were believed to interact with the same receptor (TLR2). Hence, the chemical syntheses leading to structurally defined, non-contaminated stimuli have a major impact on the outcome and interpretation of these biological studies of the innate immune system. With this material, it became evident that synthetic LTA from S. aureus and S. pneumoniae are not recognized by TLR2. Instead, another receptor of the innate immune system, the lectin pathway of the complement, known since many years to interact with LTA in quite a specific way, has gained increasing attractivity. With the help of synthetic LTA we obtained first evidences that this receptor is indeed the pathogen recognition receptor (PRR) for LTA.
Insights into the stereospecificity of ketoreduction in a modular polyketide synthase by David H. Kwan; Manuela Tosin; Nadin Schläger; Frank Schulz; Peter F. Leadlay (2053-2056).
Ketoreductase enzymes are responsible for the generation of hydroxyl stereocentres during the biosynthesis of complex polyketide natural products. Previous studies of isolated polyketide ketoreductases have shown that the stereospecificity of ketoreduction can be switched by mutagenesis of selected active site amino acids. We show here that in the context of the intact polyketide synthase multienzyme the same changes do not alter the stereochemical outcome in the same way. These findings point towards additional factors that govern ketoreductase stereospecificity on intact multienzymes in vivo.
Efficient iron-mediated approach to pyrano[3,2-a]carbazole alkaloids—first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine, first asymmetric synthesis and assignment of the absolute configuration of (−)-trans-dihydroxygirinimbine by Konstanze K. Gruner; Thomas Hopfmann; Kazuhiro Matsumoto; Anne Jäger; Tsutomu Katsuki; Hans-Joachim Knölker (2057-2061).
Iron-mediated oxidative cyclisation provides an efficient approach to pyrano[3,2-a]carbazole alkaloids. Thus, improved routes to girinimbine and murrayacine as well as the first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine are reported. Asymmetric epoxidation of girinimbine led to (−)-trans-dihydroxygirinimbine and the assignment of its absolute configuration.
Benzyl radical addition reaction through the homolytic cleavage of a benzylic C–H bond by Masafumi Ueda; Eiko Kondoh; Yuta Ito; Hiroko Shono; Maiko Kakiuchi; Yuki Ichii; Takahiro Kimura; Tetsuya Miyoshi; Takeaki Naito; Okiko Miyata (2062-2064).
Direct generation of a benzyl radical by C–H bond activation of toluenes and the addition reaction of the resulting radical to an electron deficient olefin were developed. The reaction of dimethyl fumarate with toluene in the presence of Et3B as a radical initiator at reflux afforded 2-benzylsuccinic acid dimethyl ester in good yield.
Microwave promoted C6-alkylation of purines through SNAr-based reaction of 6-chloropurines with 3-alkyl-acetylacetone by Hai-Ming Guo; Yu Zhang; Hong-Ying Niu; Dong-Chao Wang; Zhi-Liang Chu; Gui-Rong Qu (2065-2068).
C6-Alkylated purine analogues were obtained in good to excellent isolated yields by SNAr reaction of 6-chloropurine derivatives with 3-alkyl-acetylacetone. 3-Alkyl-acetylacetones were employed as alkylating agents and C6-alkylated purines were obtained highly selectively within short reaction time under microwave irradiation conditions. This work is complementary to the classical coupling reactions for the synthesis of C6-alkylated purine analogues.
N-Heterocyclic carbene-catalysed intermolecular Stetter reactions of acetaldehyde by Sun Min Kim; Ming Yu Jin; Mi Jin Kim; Yan Cui; Young Sug Kim; Liqiu Zhang; Choong Eui Song; Do Hyun Ryu; Jung Woon Yang (2069-2071).
A facile method for the intermolecular Stetter reaction of various Michael acceptors with acetaldehyde as a biomimetic acylanion source was realized using N-heterocyclic carbene catalysis. This catalytic system has also been applied to the enantioselective Stetter reaction and resulted in moderate to good enantioselectivities for the corresponding Stetter products.
Synthesis of (1R,2R)-DPEN-derived triazolium salts and their application in asymmetric intramolecular Stetter reactions by Min-Qiang Jia; Yi Li; Zi-Qiang Rong; Shu-Li You (2072-2074).
A series of novel chiral triazolium salts has been synthesized from readily available (1R,2R)-DPEN and found to be efficient for the enantioselective intramolecular Stetter reaction. With 10 mol% of the catalyst, the intramolecular Stetter reaction was realized in excellent yields with up to 97% ee.
Direct AFM observation of an opening event of a DNA cuboid constructed via a prism structure by Masayuki Endo; Kumi Hidaka; Hiroshi Sugiyama (2075-2077).
A cuboid structure was constructed using a DNA origami design based on a square prism structure. The structure was characterized by atomic force microscopy (AFM) and dynamic light scattering. The real-time opening event of the cuboid was directly observed by high-speed AFM.
Second-order NMR spectra at high field of common organic functional groups by Paul J. Stevenson (2078-2084).
The proton NMR spectra of aryl n-propyl sulfides gave rise to what may appear to be first-order proton NMR spectra. Upon oxidation to the corresponding sulfone, the spectra changed appearance dramatically and were clearly second-order. A detailed analysis of these second-order spectra, in the sulfone series, provided vicinal coupling constants which indicated that these compounds had a moderate preference for the anti-conformer, reflecting the much greater size of the sulfone over the sulfide. It also emerged, from this study, that the criterion for observing large second-order effects in the proton NMR spectra of 1,2-disubstituted ethanes was that the difference in vicinal coupling constants must be large and the difference in geminal coupling constants must be small. n-Propyl triphenylphosphonium bromide and 2-trimethylsilylethanesulfonyl chloride, and derivatives thereof, also exhibited second-order spectra, again due to the bulky substituents. Since these spectra are second-order due to magnetic nonequivalence of the nuclei in question, not chemical shifts, the proton spectra are perpetually second-order and can never be rendered first-order by using higher field NMR spectrometers.
Synthesis of arabinofuranose branched galactofuran tetrasaccharides, constituents of mycobacterial arabinogalactan by Lucía Gandolfi-Donadío; Malena Santos; Rosa M. de Lederkremer; Carola Gallo-Rodriguez (2085-2097).
Mycolyl-arabinogalactan (mAG) complex is a major component of the cell wall of Mycobacterium tuberculosis, the causative agent of tuberculosis disease. Due to the essentiality of the cell wall for mycobacterium viability, knowledge of the biosynthesis of the arabinogalactan is crucial for the development of new therapeutic agents. In this context, we have synthesized two new branched arabinogalactafuranose tetrasaccharides, decenyl β-d-Galf-(1→5)-β-d-Galf-(1→6)[α-d-Araf(1→5)]-β-d-Galf (1) and decenyl β-d-Galf-(1→6)-[α-d-Araf-(1→5)]-β-d-Galf-(1→5)-β-d-Galf (2), as interesting tools for arabinofuranosyl transferase studies. The aldonolactone strategy for the introduction of the internal d-Galf was employed, allowing the construction of oligosaccharides from the non-reducing to the reducing end. Moreover, a one-pot procedure was developed for the synthesis of trisaccharide lactone 21, precursor of 2, which involved a glycosylation-deprotection-glycosylation sequence, through the use of TMSOTf as catalyst of the trichloroacetimidate method as well as promoter of TBDMS deprotection.
A facile approach to highly functional trisubstituted furans via intramolecular Wittig reactions by Ko-Wei Chen; Siang-en Syu; Yeong-Jiunn Jang; Wenwei Lin (2098-2106).
An efficient and mild synthesis of trisubstituted furans, starting from α,β-unsaturated ketones, tributylphosphine, and acyl chlorides, is described. The strategy employs the intramolecular Wittig protocol as a key step to install the crucial furan ring, leading to a wide variety of highly functional furans in one step.
A new diversity oriented and metal-free approach to highly functionalized 3H-pyrimidin-4-ones by Renata Riva; Luca Banfi; Andrea Basso; Paola Zito (2107-2122).
A new synthesis of 3H-pyrimidin-4-ones, characterized by four different sets of decorations, is presented. The strategy is based on the synthetic elaboration of readily available α-substituted β-ketoesters that, upon transformation into the corresponding acyl enamines, have been cyclized to give 6H-1,3-oxazin-6-ones. These reactive intermediates have been in turn cleanly converted into highly functionalized pyirimidinones, by treatment with an appropriate primary amine. The whole sequence does not need the use of any metal mediator or catalyst.
Mechanism and electronic effects in nitrogen ylide-promoted asymmetric aziridination reaction by Ramanan Rajeev; Raghavan B. Sunoj (2123-2132).
The mechanism and stereoselectivity of the aziridination reaction between guanidinium ylide and a series of para-substituted benzaldehydes have been studied by using density functional theory methods. The mechanistic details and analyses of the key elementary steps involved in (a) the addition of nitrogen ylide to benzaldehydes and (b) subsequent fragmentation of the resulting oxaspirocyclic intermediate are presented. The relative energies of important transition states and intermediates are found to be useful toward rationalizing reported diastereoselective product formation. The relative energies of the key transition states could be rationalized on the basis of the differences in steric, electrostatic, and other stabilizing weak interactions. The deformation analysis of the transition state geometries exhibited good correlation with the predicted activation barriers. The changes in cis/trans diastereoselectivity preferences upon changes in the electron donating/withdrawing abilities of the para substituents on benzaldehyde are identified as arising due to vital differences in the preferred pathways. The large value of reaction constant (ρ > 4.8) estimated from the slope of good linear Hammett plots indicated high sensitivity to the electronic nature of substituents on benzaldehyde. The formation of trans-aziridine in the case of strong electron donating groups and cis-aziridines with weakly electron donating/withdrawing group has been explained by the likely changes in the mechanistic course of the reaction. In general, the predicted trends are found to be in good agreement with the earlier experimental reports.
Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates by Sabesan Yoganathan; Clarissa S. Sit; John C. Vederas (2133-2141).
The lantibiotic gallidermin was modified at lysine residues by regioselective attachment of derivatives of pyochelin, agrobactin and desferrioxamine B with the objective of having siderophore receptors of Gram-negative bacteria transport the antibiotic-iron chelator conjugate through the outer membrane. All of the conjugates retained activity against the Gram-positive indicator strain, Lactococcus lactis subsp. cremoris HP. However, testing of the conjugates against several Gram-negative strains yielded unexpected results. Bacteria treated with 100 μM of the conjugates complexed with Fe3+ grew better than bacteria grown in iron-free media but worse than bacteria grown in the same media supplemented with 10 μM FeCl3. Although these findings indicate that the conjugates are unable to inhibit the growth of Gram-negative bacteria, they indicate penetration of the outer membrane and provide structure–activity information for design of other lantibiotic conjugates. The synthetic strategy is applicable for linking biomarkers or fluorescence probes to gallidermin for studies on its localization and mode of action. As there are many lantibiotics that operate with unknown mechanisms of action, this chemical approach provides a means to modify such peptides with biomarkers for biological investigations.
Fluorescent neuroactive probes based on stilbazolium dyes by Adrienne S. Brown; Lisa-Marie Bernal; Teresa L. Micotto; Erika L. Smith; James N. Wilson (2142-2148).
A set of spectrally diverse stilbazolium dyes was identified in an uptake assay using cultured brainstem and cerebellum cells isolated from e19 chicks. Pretreatment of cells with indatraline, a monoamine reuptake inhibitor, allowed identification of dyes that may interact with monoamine transporters. Two structurally related, yet spectrally segregated, probes, (E)-1-methyl-4-[2-(2-naphthalenyl)ethenyl]-pyridinium iodide (NEP+, 3A) and (E)-4-[2-(6-hydroxy-2-naphthalenyl)ethenyl]-1-methyl-pyridinium iodide (HNEP+, 4A), were selected and further investigated using HEK-293 cells selectively expressing dopamine, norepinephrine or serotonin transporters. HNEP+ was selectively accumulated via catecholamine transporters, with the norepinephrine transporter (NET) giving the highest response; NEP+ was not transported, though possible binding was observed. The alternate modes of interaction enable the use of NEP+ and HNEP+ to image distinct cell populations in live brain tissue explants. The preference for HNEP+ accumulation via NET was confirmed by imaging uptake in the absence and presence of desipramine, a norepinephrine reuptake inhibitor.
Supramolecular hydrogels based on short peptides linked with conformational switch by Yucheng Huang; Zhenjun Qiu; Yanmei Xu; Junfeng Shi; Hongkun Lin; Yan Zhang (2149-2155).
Short peptides appropriately linked with an azobenzene conformational switch were found to be motif and pH dependant supramolecular hydrogelators. The hydrogelation properties of the short peptides linked with the conformational switch were studied in detail with respect to dependence on amino acid residue, pH and salt effect. The presence of amino acids with aromatic side chains such as Phe and Tyr was found to be favorable for the short peptides to gel water at an appropriate pH range. Cationic amino acid residues such as Arg and Lys in the short peptides were found to be unfavorable for hydrogelation. pH and salt effect were also found to be important factors for the hydrogelation properties of the short peptides. A series of short peptides with bioactive sequences were linked with the conformational switch and their hydrogelation properties were investigated. Photoresponsive supramolecular hydrogels were realized based on the E-/Z- transition of the conformational switch upon light irradiation. Proper combination of amino acid residues in the short peptides resulted in smart supramolecular hydrogels with responses to multiple stimuli.
Substrate specificity of Rv3378c, an enzyme from Mycobacterium tuberculosis, and the inhibitory activity of the bicyclic diterpenoids against macrophage phagocytosis by Tsutomu Hoshino; Chiaki Nakano; Takahiro Ootsuka; Yosuke Shinohara; Takashi Hara (2156-2165).
The Rv3378c gene product from Mycobacterium tuberculosis encodes a diterpene synthase to produce tuberculosinol (3), 13R-isotuberculosinol (4a), and 13S-isotuberculosinol (4b) from tuberculosinyl diphosphate (2). The product distribution ratios are 1 : 1 for 3 to 4 and 1 : 3 for 4a to 4b. The substrate specificity of the Rv3378c-encoded enzyme was examined. The 3 labdadienyl diphosphates, copalyl diphosphate (CDP) (7), ent-CDP (8), and syn-CDP (9), underwent the conversion reaction, with good yields (67–78%). Copalol (23) and manool (24) were produced from 7, ent-copalol (25) and ent-manool (26) from 8, and syn-copalol (27) and vitexifolin A (28) from 9. The ratio of 23 to 24 was 40 : 27, that of 25:26 was 22 : 50, and that of 27:28 was 16 : 62. Analysis on a GC-MS chromatograph equipped with a chiral column revealed that 24, 26, and 28 consisted of a mixture of 13R- (a) and 13S-stereoisomers (b) in the following ratio: ca. 1 : 1 for 24a to 24b, ca. 1 : 5 for 26a to 26b, and ca. 1 : 19 for 28a to 28b. The structures of these products indicate that the reactions of the 3 CDPs proceeded in the same fashion as that of 2. This is the first report on the enzymatic synthesis of natural diterpenes manool, ent-manool, and vitexifolin A. Both Rv3377c and Rv3378c genes are found in virulent Mycobacterium species, but not in avirulent species. We found that 3 and 4 inhibited the phagocytosis of opsonized zymosan particles by human macrophage-like cells. Interestingly, the inhibitory activity was synergistically increased by the coexistence of 3 and 4b. Other labdane-related diterpenes, 13–16 and 23–28, had little or no inhibitory activity. This synergistic inhibition by 3 and 4 may provide further advantage to the impairment of phagocyte function, which might contribute to pathogenicity of M. tuberculosis.
The multicomponent reaction of imidazo[1,5-a]pyridine carbenes with phthalaldehydes and dimethyl acetylenedicarboxylate: a facile construction of benzo[d]furo[3,2-b]azepines by Huan-Rui Pan; Xiao-Rong Wang; Cai-Xia Yan; Zhong-Xin Sun; Ying Cheng (2166-2174).
A study on the multicomponent reaction comprising both N-heterocyclic carbenes and substituted phthalaldehydes is reported. The imidazo[1,5-a]pyridine carbenes, namely imidazo[1,5-a]pyridine-3-ylidenes, reacted with phthalaldehydes and DMAD under very mild conditions to produce novel fused tricyclic benzo[d]furo[3,2-b]azepine derivatives. The resulting fused heterocyclic compounds are fluorescent and they give an emission around 500 nm with quantum yields (ΦF) being up to 0.81. This study provides not only a unique approach to fused azepine derivatives that are not easily accessible by other methods, but also opens a new avenue to complicated molecular skeletons. The fluorescence properties of long emission wavelength and high fluorescence quantum yields of some products predict their potential applications as optical sensors.
Highly stereoselective double (R)-phenylglycinol-induced cyclocondensation reactions of symmetric aryl bis(oxoacids) by Mercedes Amat; Carlos Arróniz; Elies Molins; Carmen Escolano; Joan Bosch (2175-2184).
The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol-derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled cyclocondensation reaction to phenyl bis-γ-oxoacid 4b provided 11, which was converted to the corresponding enantiopure di(pyrrolidinyl)benzene 22. The absolute configuration of the new stereogenic centers generated in the key cyclocondenstion step was unambiguously established by X-ray crystallographic analysis.
Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and -pyrimidines by Obaid-ur-Rahman Abid; Muhammad Nawaz; Muhammad Farooq Ibad; Rasheed Ahmad Khera; Viktor Iaroshenko; Peter Langer (2185-2191).
Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction.
An environmentally friendly Mukaiyama aldol reaction catalyzed by a strong Brønsted acid in solvent-free conditions by Margherita Barbero; Stefano Bazzi; Silvano Cadamuro; Stefano Dughera; Claudio Magistris; Alessandra Smarra; Paolo Venturello (2192-2197).
o-Benzenedisulfonimide, a new strong bench-stable Brønsted acid, has been shown to efficiently catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under mild solvent-free reaction conditions.
Total synthesis of C19 lipid diols containing a 2,5-disubstituted-3-oxygenated tetrahydrofuran by Caroline L. Nesbitt; Christopher S. P. McErlean (2198-2208).
The total synthesis of the C19 lipid diols 5 and 6, the enantiomers of the anthelmintic marine natural products 1 and 3, is described. Key steps in the divergent syntheses include a syn selective epoxidation of a homoallylic alcohol, a one-pot alkoxypalladation-carbonylation-lactonisation reaction sequence and a DMEAD promoted Mitsunobu inversion.
The design, synthesis and photochemical study of a biomimetic cyclodextrin model of Photoactive Yellow Protein (PYP) by Christina Loukou; Pascale Changenet-Barret; Marie-Noelle Rager; Pascal Plaza; Monique M. Martin; Jean-Maurice Mallet (2209-2218).
The design, synthesis and study of the photophysical and photochemical properties of the first biomimetic cyclodextrin (CD) model of photoactive yellow protein (PYP) are described. This model bears a deprotonated trans-p-coumaric acid chromophore, covalently linked via a cysteine moiety to a permethylated 6-monoamino β-CD. NMR and UV/Visible spectroscopy studies showed the formation of strong self-inclusion complexes in water at basic pH. Steady-state photolysis demonstrated that, unlike the free chromophore in solution, excitation of the model molecule leads to the formation of a photoproduct identified as the cis isomer by NMR spectroscopy. These observations provide evidence that the restricted CD cavity offers a promising framework for the design of biomimetic models of the PYP hydrophobic pocket.
Sugar-bearing tetraphenylethylene: novel fluorescent probe for studies of carbohydrate–protein interaction based on aggregation-induced emission by Jin-Xiang Wang; Qi Chen; Ning Bian; Fen Yang; Jing Sun; Ai-Di Qi; Chao-Guo Yan; Bao-Hang Han (2219-2226).
Neutral sugar-bearing tetraphenylethenes (TPE) are designed and prepared as “turn-on” luminescent sensors for lectins and glycosidases based on aggregation-induced emission. Through aggregation derived from carbohydrate–lectin binding, multivalent mannosyl-bearing TPE shows a good selectivity and sensitivity to Con A by switching on the fluorescence of water-soluble tetraphenylethylene-based glyco-conjugates in aqueous solution. Meanwhile, cellobiosyl-bearing TPE can be used to investigate enzymatic hydrolysis based on emission enhancing by glycosidase-induced aggregation.
7-Deazapurine biosynthesis: NMR study of toyocamycin biosynthesis in Streptomyces rimosus using 2-13C-7-15N-adenine by Ugo Battaglia; Jed E. Long; Mark S. Searle; Christopher J. Moody (2227-2232).
Although 7-deazapurines are well known and feature in the hypermodified RNA base queuosine, and in a range of nucleoside antibiotics such as toyocamycin, a mechanistic understanding of their biosynthesis is a longstanding problem. In particular, the obligatory loss of the N-7 nitrogen atom is puzzling, and in order to address this mechanistic conundrum a novel doubly labeled purine, [2-13C, 7-15N]-adenine, has been prepared and used as a biosynthetic precursor to toyocamycin in Streptomyces rimosus. NMR spectroscopy and mass spectrometry clearly showed incorporation of 13C but loss of 15N in the toyocamycin produced.
Rapid synthesis and zebrafish evaluation of a phenanthridine-based small molecule library by Lauren R. Donaldson; Stephen Wallace; David Haigh; E. Elizabeth Patton; Alison N. Hulme (2233-2239).
A Heck cyclisation approach is described for the rapid synthesis of a library of natural product-like small molecules, based on the phenanthridine core. The synthesis of a range of substituted benzylamine building blocks and their incorporation into the library is reported, together with a highly selective cis-dihydroxylation protocol that enables access to the target compounds in an efficient manner. Biological evaluation of the library using zebrafish phenotyping has led to the discovery of compound 20c, a novel inhibitor of early-stage zebrafish embryo development.
Degenerate rotaxanes with electrostatic barriers by Hao Li; Yan-Li Zhao; Albert C. Fahrenbach; Soo-Young Kim; Walter F. Paxton; J. Fraser Stoddart (2240-2250).
A synthetic approach to the preparation of rotaxanes (1–5·6PF6) incorporating bispyridinium derivatives and two 1,5-dioxynaphthalene (DNP) units situated in the rod portions of their dumbbell components that are encircled by a single cyclobis(paraquat-p-phenylene) tetracationic (CBPQT4+) ring has been developed. Since the π-electron-deficient bispyridinium units are introduced into the dumbbell components of the rotaxanes 1–5·6PF6, there are Coulombic charge–charge repulsions between these dicationic units and the CBPQT4+ ring in the rotaxanes. Thus, the CBPQT4+ rings in the degenerate rotaxanes exhibit slow shuttling between two DNP recognition sites on the 1H NMR time-scale on account of the electrostatic barrier posed by the bispyridinium units, as demonstrated by variable-temperature 1H NMR spectroscopy. Electrochemical experiments carried out on the rotaxanes 1·6PF6 and 2·6PF6 indicate that the one-electron reduced bipyridinium radical cation in the dumbbell components of the rotaxanes serves as an additional recognition site for the two-electron reduced CBPQT2(˙+) diradical cationic ring. Under appropriate conditions, the ring components in the degenerate rotaxanes 1·6PF6 and 2·6PF6 can shuttle along the recognition sites – two DNP units and one-electron reduced bipyridinium radical cation – under redox control.
An straightforward entry to new pyrazolo-fused dibenzo[1,4]diazepines by Susana Hernández; Isabel Moreno; Raul SanMartin; María Teresa Herrero; Esther Domínguez (2251-2257).
A series of novel pyrazolodibenzo[1,4]diazepines has been synthesized with good overall yields. The diarylpyrazole intermediates, with structure similarity to biologically relevant compounds such as currently marketed drugs like rimonabant or celecoxib, were prepared by a tandem sequence amine-exchange/heterocyclization starting from readily available enaminones and arylhydrazines. The key step of this efficient methodology was Caryl–N bond construction, accomplished by a palladium-catalyzed intramolecular N-arylation reaction, which was conducted in both homogeneous and polymer-supported versions. Reaction scope of such protocols and recycling of the heterogeneous catalyst were also examined.
Effective oxidation of benzylic and alkane C–H bonds catalyzed by sodium o-iodobenzenesulfonate with Oxone as a terminal oxidant under phase-transfer conditions by Li-Qian Cui; Kai Liu; Chi Zhang (2258-2265).
Catalytic oxidation of benzylic C–H bonds could be efficiently realized using IBS as a catalyst which was generated in situ from the oxidation of sodium 2-iodobenzenesulfonate (1b) by Oxone in the presence of a phase-transfer catalyst, tetra-n-butylammonium hydrogen sulfate, in anhydrous acetonitrile at 60 °C. Various alkylbenzenes, including toluenes and ethylbenzenes, several oxygen-containing functionalities substituted alkylbenzenes, and a cyclic benzyl ether could be efficiently oxidized. And, the same reagent system of cat. 1b/Oxone/cat. n-Bu4NHSO4 could be applied to the effective oxidation of alkanes as well.
Protein-inspired modified DNAzymes: dramatic effects of shortening side-chain length of 8-imidazolyl modified deoxyadenosines in selecting RNaseA mimicking DNAzymes by Christopher J. Hipolito; Marcel Hollenstein; Curtis H. Lam; David M. Perrin (2266-2273).
The discovery of imidazole/amine-functionalized DNAzymes that efficiently cleave RNA independently of divalent metal cations (M2+) and cofactors underscores the importance of expanding the catalytic repertoire with modified nucleosides. Considerable effort has gone into defining polymerase tolerances of various modified dNTPs for synthesizing and amplifying modified DNA. While long linkers are generally found to enhance incorporation and therefore increase sequence space, shorter linkers may reduce the entropic penalty paid for orienting catalytic functionality. Catalytic enhancement ultimately depends on both the functional group and appropriate linkage to the nucleobase. Whether a shorter linker provides enough catalytic enhancement to outweigh the cost of reduced polymerizability can only be determined by the outcome of the selection. Herein, we report the selection of DNAzyme 20–49 (Dz20–49), which depends on amine, guanidine, and imidazole-modified dNTPs. In contrast to previous selections where we used dAimeTP (8-(4-imidazolyl)e̲t̲h̲y̲l̲amino-2′-dATP), here we used dAimmTP (8-(4-imidazolyl)m̲e̲t̲h̲y̲l̲amino-2′-dATP), in which the linker arm is shortened by one methylene group. Although the most active clone, Dz20–49, was absolutely dependent on the incorporation of either dAimmp or dAimep, it catalyzed cofactor independent self-cleavage with a rate constant of 3.1 ± 0.3 × 10−3 min−1, a value not dissimilar from unmodified catalysts and strikingly inferior to modified catalysts selected with dAimeTP. These results demonstrate that very subtle differences in modified nucleotide composition may dramatically effect DNAzyme selection.
Straightforward preparation of biologically active 1-aryl- and 1-heteroarylpropan-2-amines in enantioenriched form by María Rodríguez-Mata; Vicente Gotor-Fernández; Javier González-Sabín; Francisca Rebolledo; Vicente Gotor (2274-2278).
Because of the importance of developing stereoselective syntheses for single enantiomers, a selected panel of racemic biologically active 1-aryl- and 1-heteroarylpropan-2-amines has been prepared, followed by a study of their behavior in enzymatic kinetic resolution (KR) processes. For this purpose, lipase B from Candida antarctica (CAL-B) proved to be an ideal biocatalyst allowing the preparation of the corresponding enantioenriched (R)-amides and (S)-amines by aminolysis reactions. Likewise, dynamic kinetic resolutions (DKR) have been successfully achieved combining the use of CAL-B and Shvo's catalyst. This research constitutes the first example of a lipase-catalyzed DKR process of β-substituted isopropylamines.
Synthesis of a family of 3-alkyl- or 3-aryl-substituted 1,2-dihydroquinazolinium salts and their isomerization to 4-iminium-1,2,3,4-tetrahydroquinolines by José Vicente; María Teresa Chicote; Antonio Jesús Martínez-Martínez; Delia Bautista; Peter G. Jones (2279-2285).
A straightforward synthesis of substituted 1,2-dihydroquinazolinium triflates (3) is reported by reaction of 2-imino-substituted anilines with a range of carbonyl compounds in the presence of triflic acid via intermediate iminium salts. Similar reactions with di- or trialdehydes and triflic acid give bis- or tris-(1,2-dihydroquinazolinium) salts. Some 4-methyl substituted 1,2-dihydroquinazolinium salts rearrange, under various conditions, to their corresponding 4-iminium-1,2,3,4-tetrahydroquinolinium isomers (7). Most of salts 3 derived from ketones are rather unstable, which prevents their isolation or full characterization. The crystal structures of various 3 and 7 salts have been determined.
Aromatic A-ring analogues of orobanchol, new germination stimulants for seeds of parasitic weeds by Heetika Malik; Wouter Kohlen; Muhammad Jamil; Floris P. J. T. Rutjes; Binne Zwanenburg (2286-2293).
Strigolactones are signaling compounds in plants of increasing importance. In this paper the focus is on their activity as germinating agents for seeds of parasitic weeds. The syntheses of aromatic A-ring analogues of the germination stimulant orobanchol have been described. Starting substrate is the ABC unit of the stimulant GR24. Oxidation at the C-4 position gives a 4-oxo derivative which on subsequent reduction produces two C-4 epimeric alcohols, syn and anti in a ratio of 82 : 3. For practical access of the C-4 anti alcohol, the predominant syn epimer is inverted by a Mitsunobu procedure. The anti C-4 alcohol is then coupled with the D-ring in a one-pot two-step process involving a formylation and a reaction with bromobutenolide to give a mixture of the diastereomeric aromatic A-ring analogues of orobanchol. In contrast, the syn C-4 alcohol cannot be coupled directly with the D-ring. Protection of the C-4 syn OH is a prequisite. The best protecting function is the SEM group as deprotection after coupling with the D-ring can then readily be achieved. The structures of these new analogues have been ascertained by X-ray analyses. Both diastereomers of the C-4 syn as well as the C-4 anti orobanchol analogues have been tested as germination agents of seeds of Striga hermonthica and Orobanche ramosa. In addition, the acetates of both epimeric C-4 alcohols have been prepared and tested. Both diastereomers of the 4-oxo derivative have been prepared and bioassayed as well. The bioassays reveal that the diastereomers having the natural relative configuration are most active. The data also suggest that hydrogen bonding is not an important factor in the binding of the stimulant molecules in the receptor.
Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides by Julia Ponce González; Mark Edgar; Mark R. J. Elsegood; George W. Weaver (2294-2305).
Lithium–bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated benzofurans or benzothiophenes respectively by SNAr substitution of the adjacent fluorine in the perfluoroaryl substituent. The structures of the new compounds were confirmed by NMR spectroscopy and single crystal X-ray diffraction analysis. In the case of 2-bromophenyl tetrafluoropyrid-4-yl ether, lithiation promoted a Smiles-type rearrangement which led to formation of 4-(2-hydroxyphenyl)tetrafluoropyridine, for which the structure was confirmed by X-ray crystallography.
Unexpected hydroxylamine-induced ring-closure reactions of meso-tetraphenylsecochlorin bisaldehyde by Joshua Akhigbe; Gretchen Peters; Matthias Zeller; Christian Brückner (2306-2313).
Reaction of meso-tetraphenylsecochlorin bisaldehyde with hydroxylamine results in the formation of the known meso-tetraphenyl-2-nitroporphyrin and the novel meso-tetraphenylimidazolophorphyrin. The products are the result of two diverging pathways of the presumed intermediate monooxime monoaldehyde that are unusual and surprising, but fully rationalized. The structures of both products were confirmed by spectroscopic techniques and single crystal X-ray diffractometry. This reaction represents the first reaction in which a pyrrole in a porphyrin was formally replaced by an imidazole moiety. The optical properties of the free base and metalloimidazoloporphyrin under neutral and acidic conditions are discussed. Further, an alternative synthesis of the imidazoloporphyrin Ni(ii) based on meso-tetraphenyl-1-formyl-chlorophin is presented.
An efficient biomaterial supported bifunctional organocatalyst (ES-SO3− C5H5NH+) for the synthesis of β-amino carbonyls by Sanny Verma; Suman L. Jain; Bir Sain (2314-2318).
A biomaterial supported organocatalyst, readily synthesized by the reaction of chemically modified sulfonic group containing expanded corn starch with pyridine exhibited excellent catalytic activity for the synthesis of β-amino carbonyls in excellent yields via aza-Michael addition of amines to electron deficient alkenes. A remarkable enhancement in the reaction rates was observed with the prepared bifunctional organocatalyst in comparison to the either starch grafted sulfonic acid or the corresponding homogeneous pyridinium p-toluenesulfonate.
8-Hydroxyquinoline as a building block for artificial receptors: binding preferences in the recognition of glycopyranosides by Monika Mazik; Christoph Geffert (2319-2326).
8-Hydroxyquinoline-based receptors 1–3, containing a trisubstituted triethylbenzene core, were prepared and their binding properties towards glycosides were evaluated. 1H NMR and fluorescence titrations as well as binding studies in two-phase systems, such as dissolution of solid carbohydrates in apolar media and phase transfer of sugars from aqueous into organic solvents, revealed β- vs.α-anomer binding preferences in the recognition of glycosides. Compared to the previously described three-armed aminopyridine-based receptor, compounds 1 and 2 showed significantly increased affinity to β-galactoside. Receptor 2, incorporating two 8-hydroxyquinoline units, was shown to be the most effective receptor for β-galactoside. Compound 3, bearing one 8-hydroxyquinoline group, was found to be a highly effective receptor for β-glucoside and shown to be a more powerful receptor than the quinoline-based compound 4, indicating an important role of the quinoline hydroxy group in the complex formation.
Peptide bond formation by aminolysin-A catalysis: A simple approach to enzymatic synthesis of diverse short oligopeptides and biologically active puromycins by Hirokazu Usuki; Yukihiro Yamamoto; Jiro Arima; Masaki Iwabuchi; Shozo Miyoshi; Teruhiko Nitoda; Tadashi Hatanaka (2327-2335).
A new S9 family aminopeptidase derived from the actinobacterial thermophile Acidothermus cellulolyticus was cloned and engineered into a transaminopeptidase by site-directed mutagenesis of catalytic Ser491 into Cys. The engineered biocatalyst, designated aminolysin-A, can catalyze the formation of peptide bonds to give linear homo-oligopeptides, hetero-dipeptides, and cyclic dipeptides using cost-effective substrates in a one-pot reaction. Aminolysin-A can recognize several C-terminal-modified amino acids, including the l- and d-forms, as acyl donors as well as free amines, including amino acids and puromycin aminonucleoside, as acyl acceptors. The absence of amino acid esters prevents the formation of peptides; therefore, the reaction mechanism involves aminolysis and not a reverse reaction of hydrolysis. The aminolysin system will be a beneficial tool for the preparation of structurally diverse peptide mimetics by a simple approach.
In search of a new class of stable nitroxide: synthesis and reactivity of a peri-substituted N,N-bissulfonylhydroxylamine by Bhaven Patel; Julie Carlisle; Steven E. Bottle; Graeme R. Hanson; Benson M. Kariuki; Louise Male; John C. McMurtrie; Neil Spencer; Richard S. Grainger (2336-2344).
Acyclic bissulfonylnitroxides have never been isolated, and degrade through fragmentation. In an approach to stabilising a bissulfonylnitroxide radical, the cyclic, peri-substituted N,N-bissulfonylhydroxylamine, 2-hydroxynaphtho[1,8-de][1,3,2]dithiazine 1,1,3,3-tetraoxide (1), has been prepared by formal nitrogen insertion into the sulfur–sulfur bond of a sulfinylsulfone, naphtho[1,8-cd][1,2]dithiole 1,1,2-trioxide. The heterocyclic ring of 1 is shown to adopt a sofa conformation by X-ray crystallography, with a pseudo-axial hydroxyl group. N,N-Bissulfonylhydroxylamine 1 displays high thermal, photochemical and hydrolytic stability compared to acyclic systems. EPR analysis reveals formation of the corresponding bissulfonylnitroxide 2 upon oxidation of 1 with the Ce(iv) salts CAN and CTAN. Although 2 does not undergo fragmentation, it cannot be isolated, since hydrogen atom abstraction to reform 1 occurs in situ. The stability and reactivity of 1 and 2 are compared with the known cyclic benzo-fused N,N-bissulfonylhydroxylamine, N-hydroxy-O-benzenedisulfonimide (6), for which the X-ray data, and EPR of the corresponding nitroxide 10, are also reported for the first time.
An 2-(2′-aminophenyl)benzoxazole-based OFF–ON fluorescent chemosensor for Zn2+ in aqueous solution by Maliang Chen; Xin Lv; Yunlong Liu; Yun Zhao; Jing Liu; Pi Wang; Wei Guo (2345-2349).
A water-soluble fluorescent sensor, 1, based on the “receptor-spacer-fluorophore” [2-(2′-aminophenyl)benzoxazole-amide-2-picolylamine] sensor platform, demonstrates the high sensitivity for Zn2+ with a 25-fold fluorescence enhancement upon chelation to Zn2+ and also exhibits high selectivity to Zn2+ over other metal ions. X-ray crystal structure of Zn2+ complex reveals that the amide oxygen (O2) cooperates with 2-picolylamine unit (N3, N4) as a receptor bind Zn2+.
A methionine-based turn-on chemical sensor for selectively monitoring Hg2+ ions in 100% aqueous solution by Mi-Hwa Yang; Chuda Raj Lohani; Hyeongjin Cho; Keun-Hyeung Lee (2350-2356).
Dansyl-labeled methionine is synthesized by solid-phase synthesis, and found to be a highly sensitive and selective sensor for Hg2+. The sensor sensitively detects Hg2+ ions in aqueous solution by a turn-on response; however, the sensor detects Hg2+ ions by a turn-off response in organic and mixed aqueous–organic solutions. We investigated the binding stoichiometry, binding constant, and binding mode of the sensor under various solvent conditions. In 100% aqueous solution, 2 : 1 complexation of the sensor with Hg2+ ions is more favorable than 1 : 1 complexation, whereas the sensor preferentially forms a 1 : 1 complex in 100% CH3CN or in 50% CH3CN–aqueous solutions. Results reveal that the stoichiometry of the sensor–Hg2+ complex plays an important role in the type of response to Hg2+ ions, and that 2 : 1 complexation is required for a turn-on response to Hg2+ ions in aqueous solution.
Synthesis and luminescence properties of new red-shifted absorption lanthanide(iii) chelates suitable for peptide and protein labelling by Nicolas Maindron; Séverine Poupart; Maxime Hamon; Jean-Baptiste Langlois; Nelly Plé; Ludovic Jean; Anthony Romieu; Pierre-Yves Renard (2357-2370).
The synthesis and photo-physical properties of an original bis-pyridinylpyrazine chromophore efficiently sensitising europium(iii) and samarium(iii) are described. The corresponding lanthanide(iii) complexes display in aqueous solutions a maximum excitation wavelength which is significantly red-shifted compared to the usual terpyridine-based chelates, and a valuable luminescence brightness above 2 000 dm3 mol−1 cm−1 at 345 nm was obtained with a europium(iii) derivative. Further functionalisation with three different bioconjugatable handles was also investigated and their ability to efficiently label a model hexapeptide was evaluated and compared. Finally, the best bioconjugatable europium(iii) chelate was used in representative labelling experiments involving monoclonal antibodies and the luminescence features of the corresponding bioconjugates remained satisfactory.
“In silico” mechanistic studies as predictive tools in microwave-assisted organic synthesis by A. M. Rodriguez; P. Prieto; A. de la Hoz; A. Díaz-Ortiz (2371-2377).
Computational calculations can be used as a predictive tool in Microwave-Assisted Organic Synthesis (MAOS). A DFT study on Intramolecular Diels–Alder reactions (IMDA) indicated that the activation energy of the reaction and the polarity of the stationary points are two fundamental parameters to determine “a priori” if a reaction can be improved by using microwave irradiation.
Synthesis of fluorinated pseudopeptides: metal mediated reversal of stereochemistry in diastereoselective addition of organometallic reagents to N-(tert-butanesulfinyl)-α-fluoroenimines by Camille Pierry; Dominique Cahard; Samuel Couve-Bonnaire; Xavier Pannecoucke (2378-2386).
The addition reaction of organometallic reagents to N-(tert-butanesulfinyl)-α-fluoroenimines was studied. Depending of the nature of the organometallic species (Grignard reagents or zincate complexes), we were able to control the configuration of the newly created stereogenic centers in high yields with good to high diastereomeric ratios. The chiral β-fluoro allylamines are key synthons toward the synthesis of fluorinated pseudopeptides bearing a fluoroolefin moiety as a peptide bond mimic.
Allosterically driven self-assemblies of interlocked calixarene receptors by Stéphane Le Gac; Jean-François Picron; Olivia Reinaud; Ivan Jabin (2387-2396).
The construction of self-assembled receptors based on flexible concave subunits is a challenging task and constitutes an interesting approach to mimic binding processes occurring in biological systems. The receptors studied herein are based on flexible calixarene skeletons bearing three (or more) acid–base functionalities at their narrow rim. When complementary, they self-assemble in a tail-to-tail manner to give a diabolo-like complex, provided that each calixarene subunit hosts a guest. The allosterically-driven multi-recognition pattern is highly selective and leads to stable quaternary adducts. In order to evaluate the scope of this system, various polyamino and polyacidic calixarenes have been studied. It is shown that modifications of the nature of the wide rim substituents do not alter the efficiency of the quaternary self-assembling process, even with the more flexible macrocycles that lack tBu substituents. On the contrary, the replacement of the latter by smaller groups led to receptors with broader scope, as larger guests such as tryptamine and dopamine derivatives were stabilized in the cavities. Implementation of extra-functionalities at the narrow rim were revealed also to be of high interest. Indeed, it is shown that secondary interactions take place between the two calix-subunits when they present additional and complementary functions such as carboxylate and ureido moieties. The ureido arms are also capable of binding the counter anion Cl− of the ammonium guest, thus leading to a quinternary neutral complex. Such remarkable behavior is due to the versatility of the calixarene platform, which allows the implementation of a high number of functions, leading to multiple non-covalent attractive interactions, whereas the macrocycle remains flexible, thus allowing induced-fit processes to occur.
Switching of the enzymatic activity synchronized with signal recognition by an artificial DNA receptor on a liposomal membrane by Yoshihiro Sasaki; Masaru Mukai; Akihiro Kawasaki; Kazuma Yasuhara; Jun-ichi Kikuchi (2397-2402).
We constructed a supramolecular system on a liposomal membrane that is capable of activating an enzyme via DNA hybridization. The design of the system was inspired by natural signal transduction systems, in which enzymes amplify external signals to control signal transduction pathways. The liposomal membrane, providing a platform for the system, was prepared by the self-assembly of an oligonucleotide lipid, a phospholipid and a cationic synthetic lipid. The enzyme was immobilized on the liposomal surface through electrostatic interactions. Selective recognition of DNA signals was achieved by hybridizing the DNA signals with the oligonucleotide lipid embedded in the liposome. The hybridized DNA signal was sent to the enzyme by a copper ion acting as a mediator species. The enzyme then amplified the event by the catalytic reaction to generate the output signal. In addition, our system demonstrated potential for the discrimination of single nucleotide polymorphisms.
Aggregation behaviour of peptide–polymer conjugates containing linear peptide backbones and multiple polymer side chains prepared by nitroxide-mediated radical polymerization by Michael Möller; Carsten Hentschel; Lifeng Chi; Armido Studer (2403-2412).
A series of peptides with an alternating sequence of alkoxyamine conjugated lysine and glycine residues were synthesized by classical solution phase peptide coupling. The resulting peptides containing up to eight alkoxyamine moieties were used as initiators in nitroxide-mediated polymerization (NMP) to obtain peptide–polymer conjugates with well defined linear peptide backbones and a defined number of polymeric side chains. Polymerization of styrene and N-isopropylacrylamide (NIPAM) occurred in a highly controlled fashion. Molecular weight and polydispersity index (PDI) were determined by gel permeation chromatography (GPC). Aggregation behaviour of these hybrid materials was investigated by dynamic light scattering (DLS) and atomic force microscopy (AFM). Depending on composition, number and length of the polymer side chains, the conjugates aggregate to different topologies. Whereas peptide–polystyrene conjugates may aggregate to so called honeycomb structures, peptide–poly-N-isopropylacrylamide conjugates show differentiated aggregation behaviour.
Diol glycidyl ether-bridged cyclens: preparation and their applications in gene delivery by Wen-Jing Yi; Zhi-Hua Feng; Qin-Fang Zhang; Ji Zhang; Ling-Dong Li; Wen Zhu; Xiao-Qi Yu (2413-2421).
Polymeric 1,4,7,10-tetraazacyclododecanes (cyclens) using diol glycidyl ether with different chain length as bridges (5a–e) were designed and synthesized from various diols, 1,7-diprotected cyclen and epichlorohydrin. The molecular weights of the title polymers were measured by GPC with good polydispersity. Agarose gel retardation and fluorescent titration using ethidium bromide showed good DNA-binding ability of 5. They could retard plasmid DNA (pDNA) at an N/P ratio of 4–6 and form polyplexes with sizes around 100–250 nm from an N/P ratio of 10 to 60 and relatively low zeta-potential values (5–22 mV). The cytotoxicity of 5 assayed by MTT is much lower than that of 20 kDa PEI. In vitro transfection against A549 and 293 cells showed that the transfection efficiency (TE) of 5c/DNA polyplexes is close to that of 20 kDa PEI at an N/P ratio of 5. Structure–activity relationship (SAR) of 5 was discussed in their DNA-binding, cytotoxicity, and transfection studies. The TE of 5c/DNA polyplexes could be improved by the introduction of 50 μM of chloroquine, the endosomolytic agents, to pretreated cells. These studies may extend the application areas of macrocyclic polyamines, especially for cyclen.
Cationic lipo-thiophosphoramidates for gene delivery: synthesis, physico-chemical characterization and gene transfection activity – comparison with lipo-phosphoramidates by Aurore Fraix; Tristan Montier; Nathalie Carmoy; Damien Loizeau; Laure Burel-Deschamps; Tony Le Gall; Philippe Giamarchi; Hélène Couthon-Gourvès; Jean-Pierre Haelters; Pierre Lehn; Paul-Alain Jaffrès (2422-2432).
The synthesis of cationic lipo-thiophosphoramidates, a new family of cationic lipids designed for gene delivery, is reported herein. This new class of lipids is less polar than its oxygenated equivalent the lipo-phosphoramidates. Fluorescence anisotropy and FRET were used to determine the fluidity and fusogenicity of the lipo-phosphoramidates 3a–b and lipo-thiophosphoramidates 7a–b. The determination of both the size and the zeta potential of the nano-objects (liposomes and lipoplexes) and the determination of the DNA binding ability of the liposomes have completed the physico-chemical characterizations of the cationic lipids studied. Finally, the cationic lipids 3a–b and 7a–c have been evaluated as synthetic vectors for gene transfection into a variety of mammalian cell lines. The lipo-thiophosphoramidate 7a proved to be an efficient and low toxicity synthetic vector even when used at low lipid to DNA charge ratios.
A stereoselective, Sm(ii)-mediated approach to decorated cis-hydrindanes: synthetic studies on faurinone and pleuromutilin by Thomas J. K. Findley; David Sucunza; Laura C. Miller; Matthew D. Helm; Madeleine Helliwell; David T. Davies; David J. Procter (2433-2451).
The cis-hydrindane motif is found in a number of natural products that display important biological activity. A flexible, stereoselective approach to the framework has been developed that features highly diastereoselective, SmI2-mediated cyclisations. The strategy has been exploited in the first synthesis of the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural product, pleuromutilin.
Addition-substitution reactions of 2-thio-3-chloroacrylamides with carbon, nitrogen, oxygen, sulfur and selenium nucleophiles by Marie Kissane; Maureen Murphy; Elisabeth O'Brien; Jay Chopra; Linda Murphy; Stuart G. Collins; Simon E. Lawrence; Anita R. Maguire (2452-2472).
Synthetically versatile conjugate addition of a range of carbon, nitrogen, oxygen, sulfur and selenium nucleophiles to the highly functionalised 2-thio-3-chloroacrylamides is described. The stereochemical and synthetic features of this transformation are discussed in detail. In most instances, the nucleophile replaces the chloro substituent with retention of stereochemistry. With the oxygen nucleophiles, a second addition can occur leading to acetals, while with the nitrogen nucleophiles, E-Z isomerism occurs in the resulting enamine derivatives. The ratio of the E/Z isomers can be rationalised on the basis of the substituent and the level of oxidation.
DEPMPO: an efficient tool for the coupled ESR-spin trapping of alkylperoxyl radicals in water by Hakim Karoui; Florence Chalier; Jean-Pierre Finet; Paul Tordo (2473-2480).
Peroxidation is an important process both in chemistry and biology, and peroxyl radicals play a crucial role in various pathological situations involving lipid and protein peroxidation. A few secondary and tertiary peroxyl radicals can be detected directly by Electron Spin Resonance (ESR). However, primary and secondary alkylperoxyl radicals have extremely short lifetimes and their direct observation is impossible in biological samples. DMPO has been used to trap alkylperoxyl radicals generated in biological systems and the characterization of DMPO–alkylperoxyl spin adducts has been claimed by different authors. However, it was then clearly shown that all the assignments made previously to DMPO–OOR adducts were actually due to DMPO–OR adducts. We have investigated the potential of DEPMPO to characterize the formation of alkylperoxyl radicals in biological milieu. Various DEPMPO–OOR (R = Me, primary or secondary alkyl group) spin adducts were unambiguously characterized and the formation of DEPMPO–OOCH3 was clearly established during the reaction of tert-butylhydroperoxide with chloroperoxidase and cytochrome c.
Alkoxyl- and carbon-centered radicals as primary agents for degrading non-phenolic lignin-substructure model compounds by Yasunori Ohashi; Yukiko Uno; Rudianto Amirta; Takahito Watanabe; Yoichi Honda; Takashi Watanabe (2481-2491).
Lignin degradation by white-rot fungi proceeds via free radical reaction catalyzed by oxidative enzymes and metabolites. Basidiomycetes called selective white-rot fungi degrade both phenolic and non-phenolic lignin substructures without penetration of extracellular enzymes into the cell wall. Extracellular lipid peroxidation has been proposed as a possible ligninolytic mechanism, and radical species degrading the recalcitrant non-phenolic lignin substructures have been discussed. Reactions between the non-phenolic lignin model compounds and radicals produced from azo compounds in air have previously been analysed, and peroxyl radical (PR) is postulated to be responsible for lignin degradation (Kapich et al., FEBS Lett., 1999, 461, 115–119). However, because the thermolysis of azo compounds in air generates both a carbon-centred radical (CR) and a peroxyl radical (PR), we re-examined the reactivity of the three radicals alkoxyl radical (AR), CR and PR towards non-phenolic monomeric and dimeric lignin model compounds. The dimeric lignin model compound is degraded by CR produced by reaction of 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH), which under N2 atmosphere cleaves the α–β bond in 1-(4-ethoxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-1,3-propanediol to yield 4-ethoxy-3-methoxybenzaldehyde. However, it is not degraded by the PR produced by reaction of Ce4+/tert-BuOOH. In addition, it is degraded by AR produced by reaction of Ti3+/tert-BuOOH. PR and AR are generated in the presence and absence of veratryl alcohol, respectively. Rapid-flow ESR analysis of the radical species demonstrates that AR but not PR reacts with the lignin model compound. Thus, AR and CR are primary agents for the degradation of non-phenolic lignin substructures.
Synthesis of serine-based glycolipids as potential TLR4 activators by Li-De Huang; Hong-Jyune Lin; Po-Hsiung Huang; Wei-Chen Hsiao; L. Vijaya Raghava Reddy; Shu-Ling Fu; Chun-Cheng Lin (2492-2504).
A new series of monosaccharide-based glycolipids devoid of phosphate groups and with two lipid chains were rationally designed by varying the lipid chain lengths and saccharide structure of a α-GalCer-derived lead compound (CCL-34) that is a potent TLR4 agonist. The NF-κB activity of a 60-membered galactosyl serine-based synthetic library containing compounds with various lipid chain lengths was measured in a HEK293 cell line that stably expressed human TLR4, MD2, and CD14 (293-hTLR4/MD2-CD14). The results showed that the optimal carbon chain lengths for the lipid amine and fatty acid to activate TLR4 were 10–11 and 12, respectively. Evaluation of a 20-membered synthetic glycosyl serine-based lipid library containing compounds with various saccharide moieties and fixed lipid chain lengths revealed that the galactose moiety in CCL-34 could be replaced by glucose without loss of activity (CCL-34-S3 and CCL-34-S16). Changing the orientation of the anomeric glycosidic bond of CCL-34 resulted in a complete loss of activity (β-CCL34). Surprisingly, a change in configuration of the anomeric glycosidic bond in a glucosyl glycolipid is tolerable (CCL-34-S14). Another noteworthy observation is that the activity of a l-fucosyl derived glycolipid (CCL-34-S13) was comparable to that of CCL-34. In sum, this study determines the structural features that are crucial for an optimal TLR4-stimulating activity. It also provides several molecules with immunostimulating potential.
Catalytic asymmetric Michael addition with curcumin derivative by Wenjun Li; Wenbin Wu; Feng Yu; Huicai Huang; Xinmiao Liang; Jinxing Ye (2505-2511).
Catalytic asymmetric Michael additions with curcumin derivatives were achieved by a new series of tertiary amine–thiourea organocatalysts to afford the Michael adducts in high yields and excellent enantioselectivities.
Total synthesis of (−)-indolactam V by Zhengren Xu; Fengying Zhang; Lihe Zhang; Yanxing Jia (2512-2517).
The total synthesis of protein kinase C activator (−)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from l-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.
Electrophilic chemistry of propargylic alcohols in imidazolium ionic liquids: Propargylation of arenes and synthesis of propargylic ethers catalyzed by metallic triflates [Bi(OTf)3, Sc(OTf)3, Yb(OTf)3], TfOH, or B(C6F5)3 by Gopalakrishnan Aridoss; Viorel D. Sarca; James F. Ponder Jr; Jessica Crowe; Kenneth K. Laali (2518-2529).
Metallic triflates M(OTf)3 (M = Bi, Sc, Yb), immobilized in imidazolium ionic liquids [BMIM][BF4], [BMIM][PF6] and [BMIM][OTf] are efficient systems for one-pot reactions of propargylic alcohols 1,3-diphenyl-2-propyn-1-ol Ia, 1-methyl-3-phenyl-2-propyn-1-ol Ib, and 2-pentyn-1-ol Ic, with a wide range of arenes bearing activating substituents, under mild conditions. The [BMIM][PF6]/B(C6F5)3 and [BMIM][PF6]/TfOH systems were superior in propargylation with Ib and Ic, while reaction of 3-phenyl-2-propyn-1-ol Id with activated aromatics resulted in the formation of diaryl-propanones instead. Propargylation of anisole with Ib under M(OTf)3 catalysis is highly para selective, but with TfOH or B(C6F5)3 as catalyst the ortho isomer was also formed. Steric influence of the propargylic moiety on substrate selectivity is reflected in the lack of ortho propargylation for phenol and ethylbenzene by using propargylic alcohol Ia, and notable formation of the ortho isomer employing alcohol Ib. In the later case para selectivity could be increased by running the reaction at r. t. for 10 h. The Bi(OTf)3-catalyzed reaction of 1,3-dimethoxybenzene with Ia led to minor formation of dipropargylated derivative, along with the monopropargyl product. Propargylation of the less reactive arenes (mesitylene, ethylbenzene, toluene), using Sc(OTf)3 as catalyst, led increasingly to the formation of dipropargylic ethers and propargyl ketones, with no ring propargylation product with toluene. Concomitant formation of dipropargylic ether was also observed in Yb(OTf)3-catalyzed propargylation of β-naphthol, whereas propargylation of 2-nitro and 4-nitro-aniline led to N-propargylation. The recycling/reuse of the IL was demonstrated in representative cases with no appreciable decrease in the conversions over 3 cycles. It was also shown that recycled IL could be used to propargylate a different aromatic compound. The efficacy of IL/M(OTf)3 and IL/TfOH systems for cross-breeding two propargylic alcohols or a propargylic alcohol with a non-propargylic alcohol and/or self-coupling, to form a wide variety of functionalized ethers is also demonstrated.
A new synthesis of fully phosphorylated flavones as potent pancreatic cholesterol esterase inhibitors by Guoping Peng; Yidan Du; Yingling Wei; Jingming Tang; Ai-Yun Peng; Liqun Rao (2530-2534).
Five flavones possessing one to four phenolic groups were fully phosphorylated efficiently and the obtained compounds showed excellent pancreatic cholesterol esterase (CEase) inhibitory activities with IC50 in the nanomolar range, which were much more potent than their parent compounds. The inhibition mechanism and kinetic characterization studies indicate that they are irreversible competitive inhibitors.
Superbase promoted synthesis of dienamides as useful intermediates for the synthesis of α-ketoamides, γ-lactams and cyclic imino ethers by Marco Blangetti; Annamaria Deagostino; Giuliana Gervasio; Domenica Marabello; Cristina Prandi; Paolo Venturello (2535-2538).
Alkoxydienamides 2 have been synthesized exploiting the reactivity of α,β-unsaturated acetals 1 with isocyanates in the presence of Schlosser's superbase LIC–KOR. In a mild acidic medium, 2 can then be promptly converted both into α-ketoamides 3 and into substituted 2-pyrrolidinones 4 or imino ethers 5 by choosing the appropriate experimental conditions.
First total synthesis of Papilistatin by Meng Wu; Ling Li; An-Zheng Feng; Bo Su; De-min Liang; Yu-xiu Liu; Qing-min Wang (2539-2542).
Papilistatin has been isolated recently and found to have good anticancer and antibacterial activity. Papilistatin is a unique phenanthrene-1,10-dicarboxylic acid. The first total synthesis of papilistatin is described here with radical cyclisation as the key step.
Stereoselective rearrangement of guaianolides to tricyclic δ-valerolactones by Martin Schanderl; Won Boo Jeong; Michael Schwarz; Oliver Reiser (2543-2547).
An unprecedented, highly stereoselective rearrangement of guaianolides, bearing a double bond at the C-6/C-6a position, to tricyclic δ-valerolactones is described.
An atom efficient route to N-aryl and N-alkyl pyrrolines by transition metal catalysis by Supaporn Sawadjoon; Joseph S. M. Samec (2548-2554).
The synthesis of N-aryl, N-tosyl, and N-alkyl pyrrolines from allyl alcohols and amines has been developed. The reaction sequence includes a palladium-catalyzed allylation step in which non-manipulated allyl alcohol is used to generate the diallylated amine in good to excellent yield. An excess of allyl alcohol was necessary for efficient diallylation of the amine, where the excess alcohol could be recycled three times. For aryl and tosyl amines, Pd[P(OPh)3]4 was used and for benzyl and alkyl amines a catalytic system comprising Pd(OAc)2, PnBu3, and BEt3 was used. Both the electronic properties and the steric influence of the amine affected the efficiency of the allylation. The isolated diallylated amines were transformed into their corresponding pyrrolines by ring-closing metathesis catalyzed by (H2IMes)(PCy3)Cl2RuCHPh in good to excellent yield. A one-pot reaction was developed in which aniline was transformed into the corresponding pyrroline without isolating the diallylated intermediate. This one-pot reaction was successfully scaled-up to 1 mL of aniline in which the N-phenyl pyrroline was isolated in 95% yield. The versatility of the reaction in which 3-methyl-1-phenyl pyrroline was prepared in two-steps was demonstrated.
Back cover (2555-2556).