Organic & Biomolecular Chemistry (v.17, #22)

Front cover (5403-5403).

Inside front cover (5404-5404).

Contents list (5405-5412).

Recent progress in photochemical radical di- and mono-fluoromethylation by Takashi Koike; Munetaka Akita (5413-5419).
Recently, photoinduced radical difluoromethylation has emerged as a step-economical synthetic method of CHF2-containing compounds. In this article, difluoromethylation of alkenes, isonitriles and aryl bromides promoted by photoredox catalysis is described together with a non-catalytic photoinduced system. Representative reactions will be discussed for each highlighted difluoromethylating reagent. In addition, related monofluoromethylation with their corresponding monofluoromethylating reagents is also discussed.

The Lossen rearrangement from free hydroxamic acids by Mikaël Thomas; Jérôme Alsarraf; Nahla Araji; Isabelle Tranoy-Opalinski; Brigitte Renoux; Sébastien Papot (5420-5427).
The Lossen rearrangement, that allows the conversion of hydroxamic acids into isocyanates, was discovered almost 150 years ago. For more than a century, this transformation was supposed to occur exclusively in the presence of stoichiometric amounts of activating reagents devoted to promoting the dehydration of primary hydroxamic acids. Very recently, it was demonstrated that the Lossen rearrangement can take place directly from free hydroxamic acids offering a renewal of interest for such a reaction. This short review summarizes advances in this field by describing successively the metal-assisted, the self-propagative and the promoted self-propagative Lossen rearrangement with a special emphasis on their mechanisms.

Strategies towards the synthesis of anti-tuberculosis drugs by Haridas B. Rode; Dhanaji M. Lade; René Grée; Prathama S. Mainkar; Srivari Chandrasekhar (5428-5459).
Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resolution based strategies, microbial transformations, solid phase synthesis, and asymmetric synthesis. As stereochemistry is an important hallmark of many drugs, the strategies based on asymmetric synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.

Chemical ADP-ribosylation: mono-ADPr-peptides and oligo-ADP-ribose by Qiang Liu; Gijsbert A. van der Marel; Dmitri V. Filippov (5460-5474).
ADP-ribosylation is an important post-translational modification that plays a pivotal role in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Although chemical synthesis of mono- or poly-ADP-ribosylated biomolecules is extremely difficult due to the challenges in regio- and stereoselective glycosylation, suitable protective group manipulations and pyrophosphate construction, synthetic procedures towards these bio-related targets have been reported in recent years. Chemically synthesized well-defined ADP-ribose derivatives serve as useful tools in biological experiments aimed to further elucidate native ADP-ribosylation. In this review, we will discuss the synthetic studies on mono-ADP-ribosylated proteins and oligo-ADP-ribose chains. Future possible synthetic targets and upcoming new methods for the synthesis of these molecules are also included.

Visible light-mediated organophotocatalyzed C–H bond functionalization reactions by Mustafa Uygur; Olga García Mancheño (5475-5489).
Over the last decade, a variety of methodologies for the direct functionalization of C–H bonds have been developed. Among others, visible light photoredox reactions have recently emerged as one of the most efficient and highly selective processes for the direct introduction of a functionality into organic molecules. Easy reaction setups, as well as mild reaction conditions, make this approach superior to other methodologies applying transition metals or strong oxidants, in terms of both costs and substrate and functional group tolerance. In this review, the recent developments in organophotocatalyzed C–H bond functionalization reactions are presented.

C31-Selective substitution of cationic N-heteroaromatic groups into a 3-vinylated chlorophyll-a derivative by Tatsuya Takahashi; Shin Ogasawara; Shihoko Echizen; Yoshinao Shinozaki; Hitoshi Tamiaki (5490-5495).
A variety of N-containing heteroarenes were site-selectively introduced at the C31-position of a chlorophyll-a derivative possessing a 3-vinyl group through a C–N+ bond via oxidative reactions using iodine in the presence of a silver(i) salt. Electron-rich N-heteroarenes were effectively substituted, while electron-withdrawing or bulky nitrogen-neighboring substituents suppressed the reactivities. The cationic products formed were characterized by 1D/2D NMR, and their optical properties were also investigated.

An S–S bond containing maleimide-conjugated closo-dodecaborate (SSMID) was synthesised for identification of albumin binding sites. Three Lys residues, Lys221, Lys413 and Lys431, were identified as SSMID modification sites in addition to Cys34 in bovin serum albumin (BSA). Fluorescent-labelled MID-BSA was found to be accumulated in the cytosol of HeLa cells.

Planarized B,N-phenylated dibenzoazaborine with a carbazole substructure: electronic impact of the structural constraint by Mikinori Ando; Mika Sakai; Naoki Ando; Masato Hirai; Shigehiro Yamaguchi (5500-5504).
A B,N-diphenyl-5,10-dihydro-dibenzo-1,4-azaborine, in which both phenyl groups on the boron and nitrogen atoms are planarized to generate a carbazole substructure, was synthesized. The structral constraint around the boron and nitrogen atoms alters the π-conjugation mode and thus the photophysical and electrochemical properties. Specifically, this structurally constrained dibenzoazaborine showed an intense blue emission with a narrow full width at half maximum. One of its derivatives exhibited near infrared absorption in the one-electron-oxidized state.

Chemodivergent reaction of azomethine imines and 2H-azirines for the synthesis of nitrogen-containing scaffolds by Yufeng Wu; Bing Tian; Chao Hu; Kohei Sekine; Matthias Rudolph; Frank Rominger; A. Stephen K. Hashmi (5505-5508).
The metal-free reactions of 2H-azirines with C,N-cyclic azomethine imines were investigated. N-Bridged strained ring-fused triazole derivatives or 1,2,4-triazine derivatives are obtained, and the chemoselectivity is dependent on the protecting group on the azomethine dipole. Although benzoyl-protected starting materials give access to strained polycyclic compounds, a ring-opening occurs in the case of a tosyl protecting group that is cleaved during the process with elimination of sulfinic acid. 1,2,4-Triazine can be prepared on a mmol-scale and concomitantly oxidized with air as an oxidant to form the corresponding ketone, which is an interesting structural motif that can be found in bioactive scaffolds.

Copper nitrate-mediated synthesis of 3-aryl isoxazolines and isoxazoles from olefinic azlactones by Yifan Lin; Ke Zhang; Mingchun Gao; Zheyi Jiang; Jiajie Liu; Yurui Ma; Haoyu Wang; Qitao Tan; Junjie Xiao; Bin Xu (5509-5513).
A copper nitrate-mediated [2 + 2 + 1] cycloaddition reaction was developed for the expedient synthesis of pharmacologically interesting 3-aryl substituted isoxazolines and isoxazoles through CC bond cleavage. Copper nitrate is employed as a reaction promoter and precursor of nitrile oxides. The given approach features a new mode of cycloaddition from olefinic azlactones, copper nitrate and unsaturated compounds with wide substrate scope, good functional group tolerance and operational simplicity.

The catalytic asymmetric synthesis of CF3-containing spiro-oxindole–pyrrolidine–pyrazolone compounds through squaramide-catalyzed 1,3-dipolar cycloaddition by Cui Wang; Dongwa Wen; Hui Chen; Yabo Deng; Xueting Liu; Xin Liu; Li Wang; Fengyun Gao; Yifei Guo; Mengmeng Sun; Kairong Wang; Wenjin Yan (5514-5519).
Pharmaceutically important compounds were synthesized through the organocatalytic 1,3-dipolar cycloaddition reaction. In the presence of a cinchonine-derived squaramide catalyst, the cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with α,β-unsaturated pyrazolones gave a spiro-pyrrolidine-linked oxindole and pyrazolone compound bearing four consecutive stereocenters and two vicinal spiroquaternary chiral centers, in excellent yields and stereoselectivities.

Borylative cyclisation of diynes using BCl3 and borocations by Andrew J. Warner; Kieron M. Enright; John M. Cole; Kang Yuan; John S. McGough; Michael J. Ingleson (5520-5525).
The borylative cyclisation of 1,2-dialkynyl benzenes with BCl3 leads to dibenzopentalenes (via intramolecular SEAr) or benzofulvenes (via chloride addition) depending on substituents, with stabilised vinyl cation intermediates (e.g. with a p-MeO-C6H4-group) favouring the latter. The use of borocations leads to more selective dibenzopentalene formation, while other diyne frameworks undergo intramolecular SEAr selectively even with p-MeO groups.

Fusaresters A–E, new γ-pyrone-containing polyketides from fungus Fusarium sp. Hungcl and structure revision of fusariumin D by Jiaojiao Gong; Chunmei Chen; Shuyuan Mo; Junjun Liu; Wenjing Wang; Yi Zang; Huaqiang Li; Chenwei Chai; Hucheng Zhu; Zhengxi Hu; Jianping Wang; Yonghui Zhang (5526-5532).
Marine-derived fungi have been regarded as an under-explored and promising reservoir of structurally novel and bioactive natural products. In this study, five new γ-pyrone-containing polyketides, fusaresters A–E (1–5), were isolated and identified from the culture extracts of a marine-derived fungus Fusarium sp. Hungcl. The structures of compounds 1–5 were elucidated on the basis of their HRESIMS and NMR spectroscopic data as well as 13C NMR calculation and electronic circular dichroism (ECD) analyses. Remarkably, the structure of fusariumin D was revised to (9S*,11S*)-3. All these isolates were tested for the cytotoxicity against seven human cancer cell lines, including SW480, HL-60, A549, MCF-7, HepG2, HeLa and SMMC-7721, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). The results revealed that only compound 2 showed a weak inhibition rate of 56% at 40 μM.

Solid-phase synthesis of biocompatible N-heterocyclic carbene–Pd catalysts using a sub-monomer approach by Durgadas Cherukaraveedu; Paul T. Cowling; Gavin P. Birch; Mark Bradley; Annamaria Lilienkampf (5533-5537).
Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC–palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and ‘switch-on’ an anticancer prodrug in 3D cell culture.

Manganese(iii) acetate-mediated direct C(sp2)–H-sulfonylation of enamides with sodium and lithium sulfinates by Philipp Kramer; Sara-Cathrin Krieg; Harald Kelm; Georg Manolikakes (5538-5544).
A Mn(OAc)3 mediated oxidative C(sp2)–H sulfonylation of enamides and encarbamates with sodium and lithium sulfinates is reported. This operationally simple transformation provides a straightforward and highly stereoselective access to (E)-β-amidovinyl sulfones in moderate to excellent yields. The reaction proceeds readily under mild conditions at room temperature and tolerates various sensitive functional groups. This process affords exclusively (E)-configurated β-amidovinyl sulfones independent of the starting material configuration. Moreover, a direct transformation of organolithium reagents and sulfur dioxide into β-amidovinyl sulfones is described.

Platinum-catalyzed reactions between Si–H groups as a new method for cross-linking of silicones by Konstantin V. Deriabin; Ekaterina K. Lobanovskaia; Alexander S. Novikov; Regina M. Islamova (5545-5549).
The platinum-catalyzed self-cross-linking of polymethylhydrosiloxane at RT in air was performed for the first time and proved by 1H, 13C, and 29Si SSNMR and swelling measurements. Quantum chemical modeling of possible structures was investigated. Platinum (0) and (ii) complexes were used as catalysts between the Si–H groups of polymethylhydrosiloxane. Karstedt's catalyst leads to Si–O–Si and Si–Si bond formation, but cis-[PtCl2(BnCN)2] generates predominantly Si–O–Si cross-links. cis-[PtCl2(BnCN)2] allows creating high-quality silicone rubbers without visible mechanical defects. This cross-linking approach can be used to obtain new Si–H-containing silicone materials.

4′-C-Trifluoromethyl modified oligodeoxynucleotides: synthesis, biochemical studies, and cellular uptake properties by Yifei Zhou; Chuanlong Zang; Huawei Wang; Jiajun Li; Zenghui Cui; Qiang Li; Fengmin Guo; Zhiguo Yan; Xin Wen; Zhen Xi; Chuanzheng Zhou (5550-5560).
Herein, we report the synthesis of 4′-C-trifluoromethyl (4′-CF3) thymidine (T4′-CF3) and its incorporation into oligodeoxynucleotides (ODNs) through solid-supported DNA synthesis. The 4′-CF3 modification leads to a marginal effect on the deoxyribose conformation and a local helical structure perturbation for ODN/RNA duplexes. This type of modification slightly decreases the thermal stability of ODN/RNA duplexes (−1 °C/modification) and leads to improved nuclease resistance. Like the well-known phosphorothioate (PS) modification, heavy 4′-CF3 modifications enable direct cellular uptake of the modified ODNs without any delivery reagents. This work highlights that 4′-CF3 modified ODNs are promising candidates for antisense-based therapeutics, which will, in turn, inspire us to develop more potent modifications for antisense ODNs and siRNAs.

We report the synthesis of three new triazole functionalized acyclic CB[n]-type receptors (2–4) by click chemistry. The compounds have good solubility in water (≥8 mM) and do not undergo strong self-association (Ks≤ 903 M−1). We measured the binding constants of 2–4 toward guests 9–24 and compared the results to those obtained for the prototypical acyclic CB[n]-type receptor 1. The X-ray crystal structure of 4 is also described.

H2O2-responsive polymeric micelles with a benzil moiety for efficient DOX delivery and AIE imaging by Yan-Dong Dai; Xue-Yi Sun; Wan Sun; Jing-Bo Yang; Rui Liu; Yi Luo; Tao Zhang; Yu Tian; Zhong-Lin Lu; Lan He (5570-5577).
Nano drug delivery is a promising domain in biomedical theranostics and has aroused more and more attention in recent years. We report here an amphiphilic polymer TPG1, bearing a H2O2-sensitive benzil and an AIE fluorophore tetraphenylethene (TPE) unit, which is able to self-assemble into spherical nanosized micelles in aqueous solution. Doxorubicin (DOX) can be encapsulated into TPG1 micelles efficiently with the loading capability of up to 59% by weight. The benzil moiety could be cleaved via the Baeyer–Villiger type reaction in the presence of H2O2, leading to the decomposition of TPG1 micelles and release of DOX. In vitro studies indicated that DOX-loaded TPG1 micelles can be internalized by cancer cells, followed by unloading encapsulated DOX under the stimulation of H2O2. The drug release process can be monitored by the AIE fluorescence from the degradation products containing a TPE moiety. MTT assays against HeLa and HepG2 cancer cells demonstrated that DOX-loaded micelles showed good anticancer efficacy. The polymer TPG1 and the corresponding decomposed products showed great biocompatibility. Our data suggest that TPG1 has the potential to be employed for the controlled drug delivery system.

A visible-light-induced decarboxylative sulfonylation of cinnamic acids with sodium sulfinates for the synthesis of vinyl sulfones was developed. The reaction proceeded smoothly in the presence of Merrifield resin supported Rose Bengal ammonium salt as a photocatalyst and tert-butyl hydroperoxide (70% in water) as an oxidant in aqueous DMSO solution at room temperature under green LED (530–535 nm) irradiation under an air atmosphere, generating the desired products in good yields. Notably, the supported catalyst can easily be separated from the reaction mixture by filtration and can be recycled at least six times without any significant loss of activity.

Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain by Yanbo Yu; Qianwa Liang; Hui Liu; Zonghua Luo; Hongzheng Hu; Joel S. Perlmutter; Zhude Tu (5586-5594).
The transient receptor potential channel subfamily member 5 (TRPC5) is a calcium permeable cation channel widely expressed in the brain. Accumulating evidence indicates that it plays a crucial role in psychiatric disorders including depression and anxiety. Positron emission tomography (PET) combined with a TRPC5 specific radioligand may provide a unique tool to investigate the functions of TRPC5 in animal disease models to guide drug development targeting TRPC5. To develop a TRPC5 PET radiotracer, the potent TRPC5 inhibitor HC608 was chosen for C-11 radiosynthesis through the N-demethyl amide precursor 7 reacting with [11C]methyl iodide. Under optimized conditions, [11C]HC608 was achieved with good radiochemical yield (25 ± 5%), high chemical and radiochemical purity (>99%), and high specific activity (204–377 GBq μmol−1, decay corrected to the end of bombardment, EOB). The in vitro autoradiography study revealed that [11C]HC608 specifically binds to TRPC5. Moreover, initial in vivo evaluation of [11C]HC608 performed in rodents and the microPET study in the brain of non-human primates further demonstrated that [11C]HC608 was able to penetrate the blood brain barrier and sufficiently accumulate in the brain. These results suggest that [11C]HC608 has the potential to be a PET tracer for imaging TRPC5 in vivo.

2-(Methylthio)aniline (MTA) directed C(sp3)–H functionalisations are efficient and straightforward protocols for the selective β-modification of N-methylated amino acids. The decreased reactivity of MTA in comparison with the 8-aminoquinoline (AQ) directing group allows for selective monoarylations in high yields without the formation of side products. The protocol is also suitable for the introduction of highly functionalised side chains onto the C-terminal alanines of dipeptides. The MTA directing group can easily be removed, providing free carboxylic acids as valuable building blocks.

Total synthesis and stereochemical revision of relgro and 10′-oxorelgro by Janardhan Gaddam; G. Sudhakar Reddy; Kanakaraju Marumudi; Ajit C. Kunwar; Jhillu S. Yadav; Debendra K. Mohapatra (5601-5614).
The first asymmetric total synthesis and stereochemical assignments of 10-membered macrolactones relgro and 10′-oxorelgro are disclosed. To this end, palladium-catalyzed Stille coupling, the Mitsunobu reaction, ring-closing metathesis, EDCI promoted coupling and the Jacobsen hydrolytic kinetic resolution are used as key steps. The total synthesis followed by thorough evaluation of the optical rotation and CD spectral data led to the revision of the absolute configuration at C-6′ for both relgro and 10′-oxorelgro. Moreover, the 1H as well as 13C NMR data are reported for the first time for relgro.

Functionalised bicyclic tetramates derived from cysteine as antibacterial agents by Tharindi D. Panduwawala; Sarosh Iqbal; Amber L. Thompson; Miroslav Genov; Alexander Pretsch; Dagmar Pretsch; Shuang Liu; Richard H. Ebright; Alison Howells; Anthony Maxwell; Mark G. Moloney (5615-5632).
Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300–600, clog D7.4 of −2.5 to 4 and rel. PSA of 11–22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.

Triaminopyrimidine derivatives as transmembrane HCl transporters by Petr Motloch; Ana Guerreiro; Carolina Q. Azeredo; Gonçalo J. L. Bernardes; Christopher A. Hunter; Istvan Kocsis (5633-5638).
Small synthetic molecules capable of inducing transmembrane anion transport have received a lot of attention as potential anti-cancer agents due to their ability to interfere with intracellular pH homeostasis. A series of triaminopyrimidine-based anion transporters have been synthesised, and they are found to diminish proton gradients across lipid bilayers at physiologically relevant pH. The compounds have pKa values (≈7.2) that allow protonation/deprotonation processes coupled with anion binding/unbinding events in physiologically relevant conditions. Synthetic vesicle transport experiments as well as solid state structures indicate synergistic binding of HCl. Cell assays show that the transporters induce apoptosis in various cancerous cell lines.

Back cover (5639-5640).