Organic & Biomolecular Chemistry (v.15, #27)

Front cover (5645-5645).

Inside front cover (5646-5646).

Contents list (5647-5655).

Targeting heparin and heparan sulfate protein interactions by Ryan J. Weiss; Jeffrey D. Esko; Yitzhak Tor (5656-5668).
Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged glycans play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. These biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection.

Identification of new DNA i-motif binding ligands through a fluorescent intercalator displacement assay by Qiran Sheng; Joseph C. Neaverson; Tasnim Mahmoud; Clare E. M. Stevenson; Susan E. Matthews; Zoë A. E. Waller (5669-5673).
i-Motifs are quadruplex DNA structures formed from sequences rich in cytosine and held together by intercalated, hemi-protonated cytosine–cytosine base pairs. These sequences are prevalent in gene promoter regions and may play a role in gene transcription. Targeting these structures with ligands could provide a novel way to target genetic disease but there are very few ligands which have been shown to interact with i-motif DNA. Fluorescent intercalator displacement (FID) assays are a simple way to screen ligands against DNA secondary structures. Here we characterise how thiazole orange interacts with i-motif DNA and assess its ability for use in a FID assay. Additionally, we report FID-based ligand screening using thiazole orange against the i-motif forming sequence from the human telomere to reveal new i-motif binding compounds which have the potential for further development.

Copper-catalyzed decarboxylative methylthiolation of aromatic carboxylate salts with DMSO by Liang Hu; Dadian Wang; Xiang Chen; Lin Yu; Yongqi Yu; Ze Tan; Gangguo Zhu (5674-5679).
A novel copper-catalyzed decarboxylative methylthiolation of arenecarboxylate salts has been realized using DMSO as the methylthiolation source. Various potassium aryl carboxylates underwent decarboxylative methylthiolation under air to furnish the corresponding aryl methyl thioethers in moderate to excellent yields. The reaction tolerated a wide variety of functional groups. Notably, the synthesis of ethylthioethers was also successfully achieved directly from diethyl sulfoxide under similar reaction conditions.

There is currently an unmet need for reliable tools that allow for direct detection and quantification of modifications in genomic DNA. For example, in cancer research and clinical diagnostics, target DNA has to be amplified and sequenced in order to reveal mutations. For 5-methylcytosine detection, bisulfite treatment of DNA is applied for the analysis, which often leads to poor specificity and reproducibility of the results. Herein we describe a simple approach that specifically detects clinically significant modifications in the human oncogenes BRAF and KRAS. We prove that this can be done using a fast and reliable hybridization assay applying novel internally labelled oligonucleotide probes and optical detection methods.

Iron catalyzed diastereoselective hydrogenation of chiral imines by D. Brenna; S. Rossi; F. Cozzi; M. Benaglia (5685-5688).
Cyclopentadienone-based iron complexes were used for the first time to successfully catalyze the diastereoselective hydrogenation of enantiopure imines. Chiral amines, including valuable biologically active products, were obtained often as enantiomerically pure compounds. Computational studies helped to elucidate the chemical and stereochemical aspects of the iron-catalyzed reaction.

Enzymatic self-assembly of an immunoreceptor tyrosine-based inhibitory motif (ITIM) by Natsuko Yamagata; Xiaoyi Chen; Jie Zhou; Jie Li; Xuewen Du; Bing Xu (5689-5692).
Here we show the first example of an immunoreceptor tyrosine-based inhibitory motif (ITIM), LYYYYL, as well as its enantiomeric or retro-inverso peptide, to self-assemble in water via enzyme-instructed self-assembly. Upon enzymatic dephosphorylation, the phosphohexapeptides become hexapeptides, which self-assemble in water to result in supramolecular hydrogels. This work illustrates a new approach to design bioinspired soft materials from a less explored, but important pool of immunomodulatory peptides.

Palladium-catalyzed geometrically selective hydrogenation of (Z)-trifluoromethyl alkenyl triflate: an efficient approach to (Z) or (E)-3,3,3-trifluoropropenyl derivatives by Yilong Zhao; Yuhan Zhou; Chunxia Zhang; Huan Wang; Jinfeng Zhao; Kun Jin; Jihong Liu; Jianhui Liu; Jingping Qu (5693-5700).
A Pd-catalyzed hydrogenation of (Z)-trifluoromethyl alkenyl triflate providing either (Z)- or (E)-3,3,3-trifluoropropenyl derivatives with excellent divergent geometric control in good yield is described. Catalyzed by Pd(OAc)2/PPh3, the reduction of (Z)-trifluoromethyl alkenyl triflates with HSiEt3 gave (E)-3,3,3-trifluoropropenyl derivatives, and while using HCOOH/Et3N as the reducing agent, the (Z)-isomers were obtained through an elimination/hydrogenation tandem pathway. Both transformations showed excellent geometrical selectivity.

Rhodium-catalyzed redox-neutral coupling of phenidones with alkynes by Zhoulong Fan; Heng Lu; Wei Li; Kaijun Geng; Ao Zhang (5701-5708).
A switchable synthesis of N-substituted indole derivatives from phenidones via rhodium-catalyzed redox-neutral C–H activation has been achieved. In this protocol, we firstly disclosed that the reactivity of Rh(iii) catalysis could be enhanced through employing palladium acetate as an additive. Some representative features include external oxidant-free, applicable to terminal alkynes, short reaction time and operational simplicity. The utility of this method is further showcased by the economical synthesis of potent anticancer PARP-1 inhibitors.

One-pot asymmetric synthesis of a spiro[dihydrofurocoumarin/pyrazolone] scaffold by a Michael addition/I2-mediated cyclization sequence by Ai-Bao Xia; Xiao-Long Zhang; Cheng-Ke Tang; Kai-Xiang Feng; Xiao-Hua Du; Dan-Qian Xu (5709-5718).
An asymmetric formal one-pot reaction of 4-hydroxycoumarins with unsaturated pyrazolones has been developed by merging a chiral bifunctional organocatalyst with molecular iodine, which furnished a series of optically active spiro[dihydrofurocoumarin/pyrazolone] heterocycles with spiro quaternary stereogenic centers in moderate to excellent yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1 dr) and good to excellent enantioselectivities (up to 99% ee). The application in the gram-scale synthesis of chiral spiro[dihydrofurocoumarin/pyrazolone] compounds was also successfully realized.

Exploiting the biosynthetic machinery of Streptomyces pilosus to engineer a water-soluble zirconium(iv) chelator by Tomas Richardson-Sanchez; William Tieu; Michael P. Gotsbacher; Thomas J. Telfer; Rachel Codd (5719-5730).
The water solubility of a natural product-inspired octadentate hydroxamic acid chelator designed to coordinate Zr(iv)-89 has been improved by using a combined microbiological-chemical approach to engineer four ether oxygen atoms into the main-chain region of a methylene-containing analogue. First, an analogue of the trimeric hydroxamic acid desferrioxamine B (DFOB) that contained three main-chain ether oxygen atoms (DFOB-O3) was generated from cultures of the native DFOB-producer Streptomyces pilosus supplemented with oxybis(ethanamine) (OBEA), which competed against the native 1,5-diaminopentane (DP) substrate during DFOB assembly. This precursor-directed biosynthesis (PDB) approach generated a suite of DFOB analogues containing one (DFOB-O1), two (DFOB-O2) or three (DFOB-O3) ether oxygen atoms, with the latter produced as the major species. Log P measurements showed DFOB-O3 was about 45 times more water soluble than DFOB. Second, a peptide coupling chain-extension reaction between DFOB-O3 and the synthetic ether-containing endo-hydroxamic acid monomer 4-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-4-oxobutanoic acid (PBH-O1) gave the water soluble tetrameric hydroxamic acid DFOB-O3–PBH-O1 as an isostere of sparingly water soluble DFOB–PBH. The complex between DFOB-O3–PBH-O1 and natZr(iv), examined as a surrogate measure of the radiolabelling procedure, analysed by LC-MS as the protonated adduct ([M + H]+, m/zobs = 855.2; m/zcalc = 855.3), with supporting HRMS data. The use of a microbiological system to generate a water-soluble analogue of a natural product for downstream semi-synthetic chemistry is an attractive pathway for developing new drugs and imaging agents. The improved water solubility of DFOB-O3–PBH-O1 could facilitate the synthesis and purification of downstream products, as part of the ongoing development of ligands optimised for Zr(iv)-89 immunological PET imaging.

Based on the strategy of the development of phosphine-free palladium-catalyzed direct C–H arylation, a series of camphyl-based α-diimine palladium complexes bearing sterically bulky substituents were synthesized and characterized. The palladium complexes were applied for the cross-coupling of thiazole derivatives with aryl bromides. The effect of the sterically bulky substituent on the N-aryl moiety as well as the reaction conditions was screened. Under the optimal protocols, a wide range of aryl bromides can be smoothly coupled with thiazoles in good to excellent yields in the presence of a low palladium loading of 0.2 mol% under open-air conditions.

Direct access to isoxazolino and isoxazolo benzazepines from 2-((hydroxyimino)methyl)benzoic acid via a post-Ugi heteroannulation by Saeed Balalaie; Mohammad Shamakli; Ali Nikbakht; Nahid S. Alavijeh; Frank Rominger; Shahnaz Rostamizadeh; Hamid Reza Bijanzadeh (5737-5742).
A diversity-oriented access to isoxazolino and isoxazolo benzazepines is elaborated via a post-Ugi heteroannulation involving intramolecular 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes and alkynes. This sequence offers an interesting multicomponent entry to a library of isoxazolino and isoxazolo benzazepines under mild reaction conditions in good to excellent yields.

Synthesis and biological evaluation of novel acyclic and cyclic glyoxamide based derivatives as bacterial quorum sensing and biofilm inhibitors by Shashidhar Nizalapur; Onder Kimyon; Eugene Yee; Mohan M. Bhadbhade; Mike Manefield; Mark Willcox; David StC. Black; Naresh Kumar (5743-5755).
Bacteria regulate the expression of various virulence factors and processes such as biofilm formation through a chemically-mediated communication mechanism called quorum sensing. Bacterial biofilms contribute to antimicrobial resistance as they can protect bacteria embedded in their matrix from the effects of antibiotics. Thus, developing novel quorum sensing inhibitors, which can inhibit biofilm formation, is a viable strategy to combat antimicrobial resistance. We report herein the synthesis of novel acyclic and cyclic glyoxamide derivatives via ring-opening reactions of N-acylisatins. These compounds were evaluated for their quorum sensing inhibition activity against P. aeruginosa MH602 and E. coli MT102. Compounds 20, 21 and 30 displayed the greatest quorum sensing inhibition activity against P. aeruginosa MH602, with 71.5%, 71.5%, and 74% inhibition, respectively, at 250 μM. Compounds 18, 20 and 21 exhibited the greatest QSI activity against E. coli MT102, with 71.5%, 72.1% and 73.5% quorum sensing inhibition activity, respectively. In addition, the biofilm inhibition activity was also investigated against P. aeruginosa and E. coli at 250 μM. The glyoxamide compounds 16, 18 and 19 exhibited 71.2%, 66.9%, and 66.5% inhibition of P. aeruginosa biofilms, respectively; whereas compounds 12, 20, and 22 showed the greatest inhibitory activity against E. coli biofilms with 87.9%, 90.8% and 89.5%, respectively. Finally, the determination of the in vitro toxicity against human MRC-5 lung fibroblast cells revealed that these novel glyoxamide compounds are non-toxic to human cells.

Palladium-catalyzed allylation of tautomerizable heterocycles with alkynes by Chuan-Jun Lu; Dong-Kai Chen; Hong Chen; Hong Wang; Hongwei Jin; Xifu Huang; Jianrong Gao (5756-5763).
A method for the allylic amidation of tautomerizable heterocycles was developed by a palladium catalyzed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted heterocycles can be synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions.

Platinated porphyrin as a new organelle and nucleus dual-targeted photosensitizer for photodynamic therapy by Sizhe Zhu; Si Yao; Fengshou Wu; Lijun Jiang; Ka-Leung Wong; Ji Zhou; Kai Wang (5764-5771).
Organelle and nucleus dual-targeted anticancer drugs are being increasingly used for efficient cancer therapy as they can attack the double vital sites of tumor cells. In this work, we synthesized and characterized two new porphyrin compounds Pt-Por-RB and Me-Por-RB. The spectral titration results suggest that both Pt-Por-RB and Me-Por-RB bind to DNA efficiently in an intercalation binding mode. Upon irradiation, Pt-Por-RB with low dark-cytotoxicity can rapidly generate singlet oxygen to damage the tumor cells through the process of photodynamic therapy. Compared with Me-Por-RB, Pt-Por-RB was not only internalized in the organelles, but also in the nuclei of HeLa cells, probably due to the presence of platinum complexes, as analyzed using the confocal laser scanning microscope. Thus, with the combination of organelle and nucleus dual-targeting property and high efficiency of singlet oxygen generation, Pt-Por-RB showed a significant therapeutic activity against tumor cells.

Pyrene-tagged carbohydrate-based mixed P/S ligand: spacer effect on the Rh(i)-catalyzed hydrogenation of methyl α-acetamidocinnamate by Juan Francisco Moya; Christian Rosales; Inmaculada Fernández; Noureddine Khiar (5772-5780).
The post-functionalization of a chiral catalyst offers the advantage of providing it with additional physical characteristics that, together with its enantioselective capacity, increase its overall synthetic value. Taking advantage of the modularity and polyfunctionality of carbohydrate-derived ligands, herein we report the synthesis of two mixed P/S catalysts functionalized with a pyrene group through the 6 position of the sugar by carbon chains of different lengths. Using the hydrogenation of methyl (Z)-α-acetamidocinnamate as the model reaction has shown that the proximity of the pyrenyl group to the catalytic center is detrimental to the activity and enantioselectivity of the hydrogenation process, the most efficient catalyst being the complex derived from pyrenebutyric acid 12. The study of the supramolecular π–π interaction of the most active complex 12 with SWCNTs by UV-Vis spectroscopy shows, that in ethyl acetate complex 12 is totally adsorbed onto the SWCNT surface, while in methylene chloride there is an equilibrium between the adsorbed and the free form of the complex, allowing the use of complex 12 and SWCNTs in a catch and release process. Interestingly, it has been determined that the nanocatalyst 12/SWCNT is more enantioselective than complex 12 alone, affording (S)-N-acetylphenyl alanine 16 in quantitative yield and 96% ee.

A novel approach to construct 2-aryl/heteroaryl quinazolines was developed through an iron-catalyzed cascade reaction of 2-aminobenzyl alcohols with benzylamines under aerobic oxidative conditions. The reaction proceeds via the formation of N-benzylidenebenzylamines followed by oxidative trapping of ammonia/intramolecular cyclization in a one-pot manner. This method exhibits a broad substrate scope and a high tolerance level for sensitive functional groups, and is amenable to gram scale synthesis.

Tricyclic biaryls are important scaffold structures in many natural products and lead compounds in drug discovery. The formation of a biaryl unit is often the key step for the synthesis of tricyclic biaryls. Despite significant progress toward the synthesis of biaryl compounds in recent years, the direct cross-coupling of two different aryl halides is still challenging and robust methods are lacking. Herein we report a direct cross-coupling of two different aryl halides in the presence of a palladium catalyst and boron ester, which provides a new and useful complementary method to synthesize tricyclic biaryls.

The effect of l-DOPA hydroxyl groups on the formation of supramolecular hydrogels by Nicola Zanna; Debora Iaculli; Claudia Tomasini (5797-5804).
Fmoc-l-DOPA-d-Oxd-OH was prepared starting from commercially available l-DOPA. Its gelation ability was tested by comparison with Fmoc-l-Tyr-d-Oxd-OH and Fmoc-l-Phe-d-Oxd-OH using ten different triggers. Among them, only GdL, CaCl2 and ZnCl2 form strong hydrogels with the three gelators. The analysis of the aerogels obtained by freeze drying the hydrogels show that the three gelators always induce the formation of dense networks, which strongly depend on the nature of the gelator. Rheological analysis of these samples demonstrates that stronger gels were obtained using the l-Tyr containing gelator, while the l-DOPA containing hydrogels were characterized by a storage modulus approximately one order of magnitude lower. Finally, the l-Phe containing gelators show a different trend with respect to the other samples depending on the trigger used. All the hydrogels show a thixotropic behaviour at the molecular level. These results indicate that hydrogel formation is sensitive to both the number of the hydroxyl moieties on the aromatic rings and trigger used.

An efficient solvent-free protocol for the Buchwald–Hartwig cross-coupling reaction of aryl and heteroaryl chlorides with primary and secondary amines using the Pd(dba)2/ligand 1 catalytic system has been developed. Notably, the catalytic system also efficiently catalyzed the reaction under aqueous conditions.

One-pot strategy of copper-catalyzed synthesis of 1,2-disubstituted benzimidazoles by Caixia Xie; Xushuang Han; Jian Gong; Danyang Li; Chen Ma (5811-5819).
A simple, one-pot and copper-catalyzed coupling reaction for the construction of 1,2-disubstituted benzimidazole derivatives is described. A low-cost copper salt and a weak base K3PO4 were utilized in this reaction. A variety of 1,2-disubstituted benzimidazoles were obtained in moderate to excellent yields.

A DABCO-promoted three-component reaction of β-ketothioamides (KTAs), arylglyoxals and 2-cyanoacetates to construct disulfides tethered pyrroles by using air as an oxidant has been disclosed. Importantly, this protocol involves a tandem sequence that includes Knoevenagel condensation, Michael addition, N-cyclization, O-cyclization, ring-opening and oxidative coupling.

A highly efficient protocol for the synthesis of 3-(2-thiopyridyl)indoles via the ruthenium(ii) catalyzed [2 + 2 + 2] cycloaddition reaction of α,ω-diynes with 3-thiocyanatoindoles under mild reaction conditions has been developed. A variety of 3-(2-thiopyridyl)indole derivatives were prepared by the reaction of the aforesaid substrates in the presence of a readily available chloro(pentamethylcyclopentadienyl)(cyclooctadiyne)ruthenium(ii) catalyst in ethanol with good to excellent yields. This atom economical methodology provides us efficient access to 3-(2-thiopyridyl)indole skeletons with close structural similarity to other pyridyl indole thioethers that have potential medicinal value.

A reductive approach for carbamoyl radical generation from N-hydroxyphthalimido oxamides under photoredox catalysis is outlined. This strategy was applied to the synthesis of 3,4-dihydroquinolin-2-ones via the intermolecular addition/cyclization of carbamoyl radicals with electron deficient olefins in a mild, redox-neutral manner. Under a general set of reaction conditions, diversely substituted 3,4-dihydroquinolin-2-ones, including spirocyclic systems can be prepared. By using chlorine-substituted olefins, aromatic quinolin-2-ones can also be accessed.

A novel ratiometric ESIPT fluorescent probe, which is specific for palladium species of all the typical oxidation states (0, +2, and +4), has been designed. Notably, based on the excited state intramolecular proton transfer (ESIPT) process, the probe exhibits a ratiometric fluorescent response to palladium species with a low detection limit (9.0 nM, 0.96 ppb) in about 1.5 min at room temperature. Moreover, it has been successfully used as a two-photon ratiometric fluorescent palladium probe for in vivo and three-dimensional imaging with low cytotoxicity and autofluorescence. Compared with other reported palladium probes, the probe displays a shorter ratiometric response time and lower detection limit in milder test conditions. All of the results indicate that the probe may be favorable for environmental and biological applications.

Expression of concern for ‘A general and concise asymmetric synthesis of sphingosine, safingol and phytosphingosines via tethered aminohydroxylation’ by Pradeep Kumar et al., Org. Biomol. Chem., 2010, 8, 5074–5086.

Expression of concern for ‘Organocatalytic stereoselective synthesis of passifloricin A’ by Pradeep Kumar et al., Org. Biomol. Chem., 2012, 10, 1820–1825.

Expression of concern for ‘Enantio- and diastereocontrolled conversion of chiral epoxides to trans-cyclopropane carboxylates: application to the synthesis of cascarillic acid, grenadamide and l-(−)-CCG-II’ by Pradeep Kumar et al., Org. Biomol. Chem., 2012, 10, 6987–6994.

Back cover (5855-5856).