Organic & Biomolecular Chemistry (v.13, #38)

Front cover (9711-9711).

Inside front cover (9712-9712).

Contents list (9713-9719).

The development of processes that streamline the synthesis of complex, functionalized carbocycles and heterocycles remains a hotly pursued topic because their scaffolds are present in a range of bioactive molecules and electronic materials. Although the Nazarov reaction has emerged to be useful in the synthesis of carbocycles and heterocycles, using an electrocyclization to trigger a migration remains underdeveloped. By constructing several bonds in one operation, domino reaction sequences are particularly effective at improving the efficiency of synthesis. The use of transition metal catalysts has the potential to render these processes stereoselective. This review examines the use of electrocyclization–[1,2] migrations to construct molecules and is organized by the type of ring constructed and the order of the two steps in this process.

Highly regioselective para-methylthiolation/bridging methylenation of arylamines promoted by NH4I by Yinfeng Xu; Tiantian Cong; Ping Liu; Peipei Sun (9742-9745).
Aryl methyl thioethers and methylene-bridged arylamines were synthesized via highly regioselective para-methylthiolation/bridging methylenation of arylamines using DMSO as the methylthio or methylene source in the presence of NH4I under metal-free conditions. For the substrates with both electron-donating and electron-withdrawing substituents, the reaction proceeded smoothly and gave moderate to good yields.

Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules by Shusuke Tomoshige; Mikihiko Naito; Yuichi Hashimoto; Minoru Ishikawa (9746-9750).
We have developed a protein knockdown technology using hybrid small molecules designed as conjugates of a ligand for the target protein and a ligand for ubiquitin ligase cellular inhibitor of apoptosis protein 1 (cIAP1). However, this technology has several limitations. Here, we report the development of a novel protein knockdown system to address these limitations. In this system, target proteins are fused with HaloTag to provide a common binding site for a degradation inducer. We designed and synthesized small molecules consisting of alkyl chloride as the HaloTag-binding degradation inducer, which binds to HaloTag, linked to BE04 (2), which binds to cIAP1. Using this system, we successfully knocked down HaloTag-fused cAMP responsive element binding protein 1 (HaloTag-CREB1) and HaloTag-fused c-jun (HaloTag-c-jun), which are ligand-unknown nuclear proteins, in living cells. HaloTag-binding degradation inducers can be synthesized easily, and are expected to be useful as biological tools for pan-degradation of HaloTag-fused proteins.

Bu4NI-catalyzed direct α-oxyacylation of diarylethanones with acyl peroxides by Zhou Zhou; Jiang Cheng; Jin-Tao Yu (9751-9754).
The Bu4NI-catalyzed α-oxyacylation of diarylethanones with acyl peroxides is developed. The reaction is conducted at room temperature without metal catalysts and tolerates a series of functional groups leading to α-oxyacylated diarylethanones in moderate to good yields.

An efficient aldol-type direct reaction of isatins with TMSCH2CN by V. U. Bhaskara Rao; Krishna Kumar; Ravi P. Singh (9755-9759).
Cesium fluoride catalyzed direct cyanomethylation of various isatins by using trimethylsilyl acetonitrile (TMSAN) as a nucleophile has been developed. The reaction has been explored for a number of isatins, with various substitutions on its aromatic ring. Further, the versatility of the reaction is demonstrated by converting the direct aldol adducts to the corresponding intermediates of natural products and medicinally important compounds.

A fluorescent turn-on H2S-responsive probe: design, synthesis and application by Yufeng Zhang; Haiyan Chen; Dan Chen; Di Wu; Xiaoqiang Chen; Sheng Hua Liu; Jun Yin (9760-9766).
Hydrogen sulfide (H2S) is considered as the third signaling molecule in vivo and it plays an important role in various physiological processes and pathological processes in vivo, such as vasodilation, apoptosis, neurotransmission, ischemia/reperfusion-induced injury, insulin secretion and inflammation. Developing a highly selective and sensitive method that can detect H2S in the biological system is very important. In this work, a colorimetric and “turn-on” fluorescent probe is developed. Furthermore, this probe displays a highly selective response to H2S in aqueous solution and possesses good capability for bioimaging H2S without interference in living cells. The results suggest that a H2S-selective probe has good water-solubility, biocompatibility and cell-penetrability and can serve as an efficient tool for probing H2S in the cell level.

Aggregation-induced emission behavior of a pH-controlled molecular shuttle based on a tetraphenylethene moiety by Xie Han; Meijiao Cao; Zhiqiang Xu; Di Wu; Zhao Chen; Anxin Wu; Sheng Hua Liu; Jun Yin (9767-9774).
Tetraphenylethene (TPE) with aggregation-induced emission (AIE) behavior as a popular backbone is applied widely in the construction of functional supramolecular systems. In this work, a TPE-based linear molecule having amide and amine units is synthesized. Its ammonium template is used to construct the N-hetero crown ether-based [2]rotaxane by the template-directed clipping approach. Their structures are well-characterized by NMR, MALDI-TOF-MS and elemental analysis. Owing to the existence of the amide unit, [2]rotaxane possesses the function of a molecular shuttle. The shuttling motion of the macrocycle component between the ammonium station and the amide station can be driven by external acid–base stimuli in solution, accompanied by changes in visual behavior. Investigation on their AIE behavior shows that (1) ammonium reaches the aggregation state almost in the presence of same water with the deprotonated form of ammonium; (2) the [2]rotaxane that the macrocycle component locates at the site of ammonium forms the aggregation state in the presence of less water than the deprotonated [2]rotaxane that the macrocycle component locates at the site of the amide, attributed to stronger interaction between the crown ether component and the TPE unit of the template component when the distance between the two is shorter. The result indicates that the shuttling motion of the macrocycle component can adjust the aggregation state of AIE molecules.

Differential detergent sensitivity of extracellular vesicle subpopulations by Xabier Osteikoetxea; Barbara Sódar; Andrea Németh; Katalin Szabó-Taylor; Krisztina Pálóczi; Krisztina V. Vukman; Viola Tamási; Andrea Balogh; Ágnes Kittel; Éva Pállinger; Edit Irén Buzás (9775-9782).
Extracellular vesicles (including exosomes, microvesicles and apoptotic bodies) are currently attracting rapidly increasing attention from various fields of biology due to their ability to carry complex information and act as autocrine, paracrine and even endocrine intercellular messengers. In the present study we investigated the sensitivity of size-based subpopulations of extracellular vesicles to different concentrations of detergents including sodium dodecyl sulphate, Triton X-100, Tween 20 and deoxycholate. We determined the required detergent concentration that lysed each of the vesicle subpopulations secreted by Jurkat, THP-1, MiaPaCa and U937 human cell lines. We characterized the vesicles by tunable resistive pulse sensing, flow cytometry and transmission electron microscopy. Microvesicles and apoptotic bodies were found to be more sensitive to detergent lysis than exosomes. Furthermore, we found evidence that sodium dodecyl sulphate and Triton X-100 were more effective in vesicle lysis at low concentrations than deoxycholate or Tween 20. Taken together, our data suggest that a combination of differential detergent lysis with tunable resistive pulse sensing or flow cytometry may prove useful for simple and fast differentiation between exosomes and other extracellular vesicle subpopulations as well as between vesicular and non-vesicular structures.

Substrate-controlled product-selectivity in the reaction of the Bestmann–Ohira reagent with N-unprotected isatin-derived olefins by Ashis Kumar Gupta; Shakir Ahamad; Ekta Gupta; Ruchir Kant; Kishor Mohanan (9783-9788).
A mild and efficient reaction of the Bestmann–Ohira reagent with N-unprotected isatin-derived olefins has been developed for the selective synthesis of spiro-pyrazoline-oxindoles and tricyclic pyrazoles. The reaction features an attractive product-selectivity depending on the substituent on isatin-derived olefin. Treatment of 3-aryl/alkylideneoxindoles with BOR afforded spiropyrazoline-oxindoles, whereas 3-phenacylideneoxindoles furnished pyrazoloquinazolinones via a unique ring expansion reaction.

The interface makes a difference: lanthanide ion coated vesicles hydrolyze phosphodiesters by Michal Poznik; Uday Maitra; Burkhard König (9789-9792).
Lanthanide ions are strong Lewis acids. Their complexation to a variety of ligands can further enhance their Lewis acidity allowing the hydrolysis of phosphoesters and even DNA. We show that the interaction of lanthanide ions with vesicles from zwitterionic phosphatidylcholine lipids gives supramolecular structures in which the metal ion is loosely coordinated to the surface. This assembly provides a high density of Lewis-acidic metal centres, which hydrolyze phosphodiesters with enhanced rates.

Design of CID-cleavable protein cross-linkers: identical mass modifications for simpler sequence analysis by Wynne V. Kandur; Athit Kao; Danielle Vellucci; Lan Huang; Scott D. Rychnovsky (9793-9807).
The cross-linking Mass Spectrometry (XL-MS) technique has enormous potential for studying the interactions between proteins, and it can provide detailed structural information about the interaction interfaces in large protein complexes. Such information has been difficult to obtain by conventional structural methods. One of the primary impediments to the wider use of the XL-MS technique is the extreme challenge in sequencing cross-linked peptides because of their complex fragmentation patterns in MS. A recent innovation is the development of MS-cleavable cross-linkers, which allows direct sequencing of component peptides for facile identification. Sulfoxides are an intriguing class of thermally-cleavable compounds that have been shown to fragment selectively during low-energy collisional induced dissociation (CID) analysis. Current CID-cleavable cross-linkers create fragmentation patterns in MS2 of multiple peaks for each cross-linked peptide. Reducing the complexity of the fragmentation pattern in MS2 facilitates subsequent MS3 sequencing of the cross-linked peptides. The first authentic identical mass linker (IML) has now been designed, prepared, and evaluated. Multistage tandem mass spectrometry (MSn) analysis has demonstrated that the IML cross-linked peptides indeed yield one peak per peptide constituent in MS2 as predicted, thus allowing effective and sensitive MS3 analysis for unambiguous identification. Selective fragmentation for IML cross-linked peptides from the 19S proteasome complex was observed, providing a proof-of-concept demonstration for XL-MS studies on protein complexes.

A dual functional peptide carrying in vitro selected catalytic and binding activities by Liping Zhu; Wei Wang; Haixu Zhao; Muye Xu; Seiichi Tada; Takanori Uzawa; Mingzhe Liu; Yoshihiro Ito (9808-9812).
When minimal functional sequences are used, it is possible to integrate multiple functions on a single peptide chain, like a “single stroke drawing”. Here a dual functional peptide was designed by combining in vitro selected catalytic and binding activities. For catalytic activity, we performed in vitro selection for a peptide aptamer binding to hemin by using ribosome display and isolated a peptide that had peroxidase activity in the presence of hemin. By combining the selected catalytic peptide with a peptide antigen, which can be recognized by an antibody, an enzyme–antibody conjugate-like peptide was obtained. This study demonstrates a successful strategy to create dual functionalized peptide chains for use in immunoassays.

Diastereoselective synthesis of pitavastatin calcium via bismuth-catalyzed two-component hemiacetal/oxa-Michael addition reaction by Fangjun Xiong; Haifeng Wang; Lingjie Yan; Lingjun Xu; Yuan Tao; Yan Wu; Fener Chen (9813-9819).
An efficient and concise asymmetric synthesis of pitavastatin calcium (1) starting from commercially available (S)-epichlorohydrin is described. A convergent C1 + C6 route allowed for the assembly of the pitavastatin C7 side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C6-formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of (S)-α,β-unsaturated ketone 4 with acetaldehyde.

Rolling Circle Amplification (RCA) is an isothermal enzymatic method generating single-stranded DNA products consisting of concatemers containing multiple copies of the reverse complement of the circular template precursor. Little is known on the compatibility of modified nucleoside triphosphates (dN*TPs) with RCA, which would enable the synthesis of long, fully modified ssDNA sequences. Here, dNTPs modified at any position of the scaffold were shown to be compatible with rolling circle amplification, yielding long (>1 kb), and fully modified single-stranded DNA products. This methodology was applied for the generation of long, cytosine-rich synthetic mimics of telomeric DNA. The resulting modified oligonucleotides displayed an improved resistance to fetal bovine serum.

Metal/organo relay catalysis in a one-pot synthesis of methyl 4-aminopyrrole-2-carboxylates from 5-methoxyisoxazoles and pyridinium ylides by Ekaterina E. Galenko; Olesya A. Tomashenko; Alexander F. Khlebnikov; Mikhail S. Novikov (9825-9833).
Methyl 4-aminopyrrole-2-carboxylates were synthesized in one-pot mode by the relay catalytic cascade reaction of 5-methoxyisoxazoles with pyridinium ylides by the use of a FeCl2/Et3N binary catalytic system leading to 1-(5-methoxycarbonyl-1H-pyrrol-3-yl)pyridinium salts followed by hydrazinolysis. The approach permits the introduction of a substituent at the pyrrole nitrogen via a nucleophilic reaction of the pyrrolylpyridinium ylide derived from the salt. Catalytic reduction of the ylides gives methyl 4-piperidinopyrrole-2-carboxylates.

A new approach to the 8b-azaacenaphthylene ring system by Anushree Kamath; Charles-Henry Fabritius; Christian Philouze; Philippe Delair (9834-9843).
A stereoselective approach to the 8b-azaacenaphthylene ring system is described. This new route features a dichloroketene–enol ether [2 + 2] cycloaddition, a vinylogous Mannich reaction, and an aza-Prins cyclization as key stereoselective transformations.

A series of neutral anion receptors with one to three thiourea arms were synthesized and their binding to tetrabutylammonium chloride, acetate, and dihydrogen phosphate salts in aqueous DMSO mixtures was examined. The three-armed thiourea host was found to strongly and selectively bind H2PO4 even in DMSO solutions containing up to 30% water. This enabled the dihydrogen phosphate salt to be extracted from water into chloroform in its dibasic form despite the high heat of the hydration of HPO42−.

Hybrids of acylated homoserine lactone and nitric oxide donors as inhibitors of quorum sensing and virulence factors in Pseudomonas aeruginosa by Samuel K. Kutty; Nicolas Barraud; Kitty K. K. Ho; George M. Iskander; Renate Griffith; Scott A. Rice; Mohan Bhadbhade; Mark D. P. Willcox; David StC Black; Naresh Kumar (9850-9861).
Pseudomonas aeruginosa is an opportunistic pathogen causing a variety of life-threatening diseases such as cystic fibrosis and nosocomial infections in burn victims. The ability of P. aeruginosa to cause infection is attributed to the production of virulence factors such as pyocyanin and elastases. These virulence factors are under the control of quorum sensing (QS) a cell to cell communication process controlled by small diffusible signalling molecules based on N-acyl-homoserine lactones (AHLs) known as autoinducers. The inhibition of QS and thereby virulence factors is seen as a potential new anti-infective strategy. Additionally, the role of nitric oxide (NO) in downstream processes in bacteria such as biofilm dispersal, motility, virulence and antimicrobial defence systems is gaining attention and could be used to control bacterial. Herein we report the design and synthesis of hybrid compounds based on AHL signalling molecules and NO donors as anti-infective agents. A series of AHL-NO hybrids were synthesised and potent inhibitors of QS and virulence factors of P. aeruginosa were identified. This research has led to conversion of agonist AHLs to antagonist AHLs with dual properties of QS inhibition and NO release.

Imidazoles from nitroallylic acetates and α-bromonitroalkenes with amidines: synthesis and trypanocidal activity studies by Elumalai Gopi; Tarun Kumar; Rubem F. S. Menna-Barreto; Wagner O. Valença; Eufrânio N. da Silva Júnior; Irishi N. N. Namboothiri (9862-9871).
Cascade reactions of amidines with nitroallylic acetates and α-bromonitroalkenes provide potentially bioactive imidazoles in good to excellent yields in most cases. While 2,4-disubstituted imidazol-5-yl acetates are formed in the first case, 2,4-disubstituted imidazoles, bearing no substituent at position 5, are the products in the second case. These two series of imidazoles, viz. 2,4,5-trisubstituted and 2,4-disubstituted, were screened for their activity against the protozoan parasite Trypanosoma cruzi which is responsible for Chagas disease. As many as three compounds were as active as the standard benznidazole and two others were 2–3-fold more active highlighting the potential of substituted imidazoles, easily accessible from nitroalkenes, as possible anti-parasitic agents.

A three-component synthesis of aryl(heteroaryl)acylamides by Rafał Loska; Patrycja Bukowska (9872-9882).
A three-component reaction of azole or azine N-oxides, 1,1-difluorostyrenes and amines gives amides of α-aryl-α-heteroarylacetic or propionic acids. The key step is 1,3-dipolar cycloaddition between N-oxide and difluorostyrene leading to the acyl fluoride intermediate, which has been identified and characterized by NMR spectroscopy. The whole process is an example of selective functionalization of C–H bonds in both 5- and 6-membered heterocyclic systems.

Back cover (9883-9884).