Organic & Biomolecular Chemistry (v.17, #9)

Front cover (2293-2293).

Inside front cover (2294-2294).

Contents list (2295-2304).

Microorganisms are remarkable chemists, with enzymes as their tools for executing multi-step syntheses to yield myriad natural products. Microbial synthetic aptitudes are illustrated by the structurally diverse 2,5-diketopiperazine (DKP) family of bioactive nonribosomal peptide natural products. Nonribosomal peptide synthetases (NRPSs) have long been recognized as catalysts for formation of DKP scaffolds from two amino acid substrates. Cyclodipeptide synthases (CDPSs) are more recently recognized catalysts of DKP assembly, employing two aminoacyl-tRNAs (aa-tRNAs) as substrates. CDPS-encoding genes are typically found in genomic neighbourhoods with genes encoding additional biosynthetic enzymes. These include oxidoreductases, cytochrome P450s, prenyltransferases, methyltransferases, and cyclases, which equip the DKP scaffold with groups that diversify chemical structures and confer biological activity. These tailoring enzymes have been characterized from nine CDPS-containing biosynthetic pathways to date, including four during the last year. In this review, we highlight these nine DKP pathways, emphasizing recently characterized tailoring reactions and connecting new developments to earlier findings. Featured pathways encompass a broad spectrum of chemistry, including the formation of challenging C–C and C–O bonds, regioselective methylation, a unique indole alkaloid DKP prenylation strategy, and unprecedented peptide-nucleobase bond formation. These CDPS-containing pathways also provide intriguing models of metabolic pathway evolution across related and divergent microorganisms, and open doors to synthetic biology approaches for generation of DKP combinatorial libraries. Further, bioinformatics analyses support that much unique genetically encoded DKP tailoring potential remains unexplored, suggesting opportunities for further expansion of Nature's biosynthetic spectrum. Together, recent studies of DKP pathways demonstrate the chemical ingenuity of microorganisms, highlight the wealth of unique enzymology provided by bacterial biosynthetic pathways, and suggest an abundance of untapped biosynthetic potential for future exploration.

An atom efficient synthesis of tamoxifen by Dorus Heijnen; Milan van Zuijlen; Filippo Tosi; Ben L. Feringa (2315-2320).
The direct carbolithiation of diphenylacetylenes and their cross-coupling procedure taking advantage of the intermediate alkenyllithium reagents are presented. By employing our recently discovered highly active palladium nanoparticle based catalyst, we were able to couple an alkenyllithium reagent with a high (Z/E) selectivity (10 : 1) and good yield to give the breast cancer drug tamoxifen in just 2 steps from commercially available starting materials and with excellent atom economy and reaction mass efficiency.

Efficient two-step synthesis of structurally diverse indolo[2,3-b]quinoline derivatives by Sandip Kundal; Baitan Chakraborty; Kartick Paul; Umasish Jana (2321-2325).
A general and efficient synthesis of diverse tetracyclic indolo[2,3-b]quinoline derivatives was achieved through palladium-catalyzed domino carboannulation/cross-coupling and DDQ-mediated double cross-dehydrogenative C–N bond formation. This approach provides a straightforward, atom-economical and concise route to easily access a diverse range of tetracyclic indolo[2,3-b]quinolines and their analogues in excellent yields with good tolerance of functional groups.

Copper-catalyzed carbene/alkyne metathesis terminated with the Buchner reaction: synthesis of dihydrocyclohepta[b]indoles by Qian Zeng; Kuiyong Dong; Jingjing Huang; Lihua Qiu; Xinfang Xu (2326-2330).
A copper-catalyzed selective cascade reaction of alkyne-tethered diazo compounds is reported for the direct and efficient construction of dihydrocyclohepta[b]indole skeletons under mild reaction conditions. A vinyl copper carbene is the key intermediate, which is generated in situ via carbene/alkyne metathesis (CAM) and terminated with the Buchner reaction.

Catalytic asymmetric aza-Michael addition of fumaric monoacids with multifunctional thiourea/boronic acids by Kenichi Michigami; Hiroki Murakami; Takeru Nakamura; Noboru Hayama; Yoshiji Takemoto (2331-2335).
The first chemical enantioselective synthesis of N-hydroxyaspartic acid derivatives using chiral multifunctional thiourea/boronic acid organocatalysts was developed. A series of fumaric monoacids underwent an intermolecular asymmetric aza-Michael addition of O-alkyl hydroxylamines in excellent regioselectivity. The addition of another carboxylic acid raised the enantiomeric enrichment up to 97% ee. O-Deprotection of the aza-Michael adduct provided an aspartate-derived hydroxylamine fragment applicable for KAHA (α-keto acid-hydroxylamine) ligation.

A simple and efficient protocol for silver(i)-catalyzed tandem reaction of o-alkynylphenyl isothiocyanates with sodium azide has been developed, affording a series of 5H-benzo[d]tetrazolo[5,1-b][1,3]thiazines in moderate to good yields. In this transformation, a [3 + 2] cycloaddition reaction mechanism was involved and two new rings were formed in one pot.

Here, we present an unprecedented pathway to α-sulfenylated carbonyl compounds from commercially available thiols and universally employed TEMPO and its analogues, which act as C3 synthons through skeletal rearrangement under simple and metal-free conditions. Mechanism studies suggest that this reaction involves a consecutive radical oxidation and cation coupling process. TEMPO analogues and thiols serve as oxidants and reductive reagents, respectively, along the radical process, while in the coupling process, the former ones afford C3 synthons to couple with related sulfur sources.

Cytosporins A–D, novel benzophenone derivatives from the endophytic fungus Cytospora rhizophorae A761 by Hong-Xin Liu; Hai-Bo Tan; Kai Chen; Li-Yun Zhao; Yu-Chan Chen; Sai-Ni Li; Hao-Hua Li; Wei-Min Zhang (2346-2350).
Four novel benzophenone derivatives, cytosporins A–D (1–4), hemiterpene-conjugated phenolics with an unprecedented benzo[b][1,5]dioxocane skeleton, were isolated from Cytospora rhizophorae A761. The structures of the new compounds were fully characterized on the basis of extensive spectroscopic analysis. The deduced structure represents the first example of natural meroterpenoids which bear a benzo[b][1,5]dioxocane framework embodying hemiterpene and benzophenone moieties. Moreover, compounds 1–4 were evaluated for in vitro antimicrobial activity.

Enantioselective synthesis of chiral heterocyclic biaryls via asymmetric Suzuki–Miyaura cross-coupling of 3-bromopyridine derivatives by Wang Xia; Zhen-Wei Zhang; Yongsu Li; Xiaoding Jiang; Hao Liang; Yaqi Zhang; Rihui Cao; Liqin Qiu (2351-2355).
A series of chiral heterocyclic biaryls with a pyridyl moiety were prepared in moderate to good yields with up to 92% ee via asymmetric Suzuki–Miyaura coupling. The chiral-bridged biphenyl monophosphine ligand L1 was found to be much more effective in the reaction enantioselection than its counterpart binaphthyl monophosphine ligands.

Synthesis of quinazolin-4(1H)-ones via amination and annulation of amidines and benzamides by Fangpeng Hu; Xinfeng Cui; Zihui Ban; Guoqiang Lu; Nan Luo; Guosheng Huang (2356-2360).
Quinazolinones have broad applications in the biological, pharmaceutical and material fields. Studies on the synthesis of these compounds are therefore widely conducted. Herein, a novel and highly efficient copper-mediated tandem C(sp2)–H amination and annulation of benzamides and amidines for the synthesis of quinazolin-4(1H)-ones is proposed. This synthetic route can be useful for the construction of quinazolin-4(1H)-one frameworks.

Phosphine-catalyzed [4 + 2] cyclization of para-quinone methide derivatives with allenes by Fu-Ru Yuan; Fei Jiang; Ke-Wei Chen; Guang-Jian Mei; Qiong Wu; Feng Shi (2361-2369).
The first [4 + 2] cyclization of para-quinone methide (p-QM) derivatives with allenes has been established via phosphine catalysis, which afforded a series of chroman derivatives in high yields (up to 97%) and excellent (E/Z)-selectivities (all >95 : 5 E/Z). This reaction will not only enrich the research contents of cyclization reactions involving p-QM derivatives, but also provide a good example of the application of allenes and phosphine catalysis in cyclization reactions. In addition, this approach also offers a useful method for the construction of chroman scaffolds.

Identification of the common biosynthetic gene cluster for both antimicrobial streptoaminals and antifungal 5-alkyl-1,2,3,4-tetrahydroquinolines by Taro Ozaki; Ryosuke Sugiyama; Morito Shimomura; Shinichi Nishimura; Shumpei Asamizu; Yohei Katsuyama; Hideaki Kakeya; Hiroyasu Onaka (2370-2378).
5-Alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs) and streptoaminals (STAMs) are natural products isolated from the combined-culture of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596. Despite their unique structures, their biosynthetic pathway has yet to be elucidated. In the present study, we conducted a feeding experiment using 13C-labeled acetates and demonstrated that 5aTHQs are likely synthesized by the action of polyketide synthase (PKS). Based on this observation, we identified the biosynthetic gene cluster for 5aTHQs. Interestingly, the same gene cluster was also responsible for the structurally-distinct STAMs. The gene cluster contains nine genes encoding one acyl carrier protein, two sets of ketosynthases (KSs) and chain length factors (CLFs), one aminotransferase/reductase bifunctional protein, two ketoreductases, and one thioesterase. KSs and CLFs are classified into the phylogenetically distinct clades from those of known type II PKSs. Heterologous expression of the biosynthetic genes and subsequent gene inactivation clearly indicated that all of the nine genes were required for the biosynthesis of both compounds. In the proposed biosynthetic pathway, chain elongation by PKS, reductive cleavage of a thioester bond, and subsequent transamination generate the core skeleton of both compounds. Differences in the oxidation states of the products result in a distinct cyclization mode to yield 5aTHQs and STAMs.

K2CO3-catalyzed thio-Michael addition using quinoline-2-thiones and α,β-unsaturated carbonyl compounds was used to assess the chemoselective construction of C–S and S–S bonds under mild reaction conditions in different solvents. The C–S bond showed a better chemoselective construction in EtOH whereas the S–S bond showed a better chemoselective construction in 1,4-dioxane. The corresponding products, generated from the reaction, presented a significant solvent-controlling effect.

Chemo- and regioselective reactions of 5-bromo enones/enaminones with pyrazoles by Paulo A. Moraes; Marcio M. Lobo; Mário A. Marangoni; Alexandre R. Meyer; Clarissa P. Frizzo; Helio G. Bonacorso; Marcos A. P. Martins; Nilo Zanatta (2384-2392).
Reaction of 5-bromo enones with pyrazoles provided a series of unexpected N,O-aminal derivatives, through a 1,4-conjugated addition at the β-carbon of the 5-bromo enones instead of the expected nucleophilic substitution of the bromine. This reaction also furnished the 1,3-regioisomer of the pyrazole. A similar reaction of pyrazoles using 5-bromo enaminones furnished only N-alkylated pyrazoles—with high regioselectivity and at good yields—through nucleophilic substitution of the bromine.

(18R)- and (18S)-stereoisomers of resolvin E3 (RvE3), potent anti-inflammatory mediators, were synthesized stereo- and enantioselectively through the Wittig reaction of the carbonate of 6R,7R- and 6R,7S-dihydroxynona-2E,4E-dienal, a C12–C20 part, with the phosphonium salt corresponding to the C1–C11 part. The stereoisomeric carbonate was prepared by the Swern oxidation of 3-(AcO)-6R,7R- or 3-(AcO)-6R,7S-(dihydroxy-carbonate)-4-nonen-1-ol followed by the spontaneous elimination of the AcO group in one pot. The (6R,7R)-(dihydroxy-carbonate)-alcohol for (18R)-RvE3 was, in turn, provided by stereoselective epoxidation of 9-(TBS-oxy)nona-4Z,6E-dien-3R-ol with m-CPBA and the subsequent Pd-catalyzed addition of AcOH to the resulting syn vinyl epoxy alcohol followed by carbonate formation of the vic-syn-diol and TBS desilylation. The Mitsunobu inversion of the syn vinyl epoxy alcohol gave the anti isomer, which was converted to 3-(AcO)-6R,7S-(dihydroxy-carbonate)-4-nonen-1-ol, the intermediate to (18S)-RvE3, by the same set of reactions.

TBA loop mapping with 3′-inverted-deoxythymidine for fine-tuning of the binding affinity for α-thrombin by Zhilong Chai; Lei Guo; Hongwei Jin; Yang Li; Shanshan Du; Yucong Shi; Chuhan Wang; Weiguo Shi; Junlin He (2403-2412).
TBA is a 15-mer DNA aptamer for human α-thrombin, and its three T-rich loops are involved in the binding interactions with thrombin differently. In order to clarify their specific spatial locations in the binding interactions and search for more favourable positions, here a systematic investigation of all the loop residues was conducted with 3′-inverted thymidine (iT), by which both unnatural 3′–3′- and 5′–5′-linkages for each incorporation were introduced in the tertiary structure. The changes in Tm values and CD spectra revealed that motifs T3T12 and T4T13 are structurally distinct. Longer anti-clotting time was obtained for the T3 and T12 modifications, respectively, while T4 and T13 were completely intolerant with such changes, in terms of stability and binding to thrombin. In particular, the increased affinity bindings and longer anti-clotting time were obtained with the replacement on the central loop T7G8T9, which were closely related to the existence of a monovalent ion, K+ or Na+, consistently with the supposed binding site of these ions in TBA. It is worthwhile to note that both the subtle variations of the loop residues induced by iT and the monovalent ions determined the interacting residues of TBA and the binding strength rather than the thermal stability of the TBA structure.

FRET-based nanosensors for monitoring and quantification of alcohols in living cells by Neha Soleja; Ovais Manzoor; Preeti Nandal; Mohd. Mohsin (2413-2422).
Odorants constitute a small and chemically diverse group of molecules with ethanol functioning as a key odorant that induces reproductive toxicity and adverse chronic effects on the liver. Analytical tools designed so far for the detection of odorant molecules are relatively invasive. Therefore, a tool that can measure the corresponding rate changes of ethanol concentration in real-time is highly desirable. Here in this work, we report a genetically encoded fluorescence resonance energy transfer (FRET)-based nanosensor for in vivo quantification of ethanol at the cellular level with high spatial and temporal resolution. A human odorant-binding protein (hOBPIIa) was flanked by fluorescent proteins ECFP (Enhanced Cyan Fluorescent Protein) and Venus at the N- and C-terminus respectively. The constructed FRET nanosensor was named the fluorescent indicator protein for odorants (FLIPO). FLIPO allows in vitro and in vivo determination of FRET changes in a concentration-dependent manner. The developed nanosensor is highly specific to ethanol, stable to pH changes and provides rapid detection rate response. FLIPO-42 is the most efficient nanosensor created that measures ethanol with an apparent affinity (Kd) of 4.16 μM and covers the physiological range of 500 nM to 12 μM ethanol measurement. FLIPO-42 can measure ethanol dynamics in bacterial, yeast and mammalian cells non-invasively in real time which proves its efficacy as a sensing device in both prokaryotic and eukaryotic systems. Taken together, a prototype for a set of nanosensors was established, potentially enabling the monitoring of dynamic changes of ethanol and investigate its uptake and metabolism with subcellular resolution in vivo and ex vivo. Furthermore, the advent of a set of novel nanosensors will provide us with the tools for numerous medical, scientific, industrial and environmental applications which would help to illuminate their role in biological systems.

Catalytic mechanism of mevalonate kinase revisited, a QM/MM study by James McClory; Jun-Tang Lin; David J. Timson; Jian Zhang; Meilan Huang (2423-2431).
Mevalonate Kinase (MVK) catalyses the ATP-Mg2+ mediated phosphate transfer of mevalonate to produce mevalonate 5-phosphate and is a key kinase in the mevalonate pathway in the biosynthesis of isopentenyl diphosphate, the precursor of isoprenoid-based biofuels. However, the crystal structure in complex with the native substrate mevalonate, ATP and Mg2+ has not been resolved, which has limited the understanding of its reaction mechanism and therefore its application in the production of isoprenoid-based biofuels. Here using molecular docking, molecular dynamics (MD) simulations and a hybrid QM/MM study, we revisited the location of Mg2+ resolved in the crystal structure of MVK and determined a catalytically competent MVK structure in complex with the native substrate mevalonate and ATP. We demonstrated that significant conformational change on a flexible loop connecting the α6 and α7 helix is induced by the substrate binding. Further, we found that Asp204 is coordinated to the Mg2+ ion. Arg241 plays a crucial role in organizing the triphosphoryl tail of ATP for in-line phosphate transfer and stabilizing the negative charge that accumulates at the β,γ-bridging oxygen of ATP upon bond cleavage. Remarkably, we revealed that the phosphorylation of mevalonate catalyzed by MVK occurs via a direct phosphorylation mechanism, instead of the conventionally postulated catalytic base mechanism. The catalytically competent complex structure of MVK as well as the mechanism of reaction will pave the way for the rational engineering of MVK to exploit its applications in the production of biofuels.

Salts accelerate the switching kinetics of a cyclobis(paraquat-p-phenylene) [2]rotaxane by Sissel S. Andersen; Afaf W. Saad; Rikke Kristensen; Teis S. Pedersen; Luke J. O'Driscoll; Amar H. Flood; Jan O. Jeppesen (2432-2441).
The rate at which the macrocyclic cyclobis(paraquat-p-phenylene) ring of a bistable [2]rotaxane moves from a tetrathiafulvalene station to an oxyphenylene station upon oxidation of the tetrathiafulvalene station is found to be increased in the presence of added salts. Compared to the salt-free case, 0.1 M solutions of a series of tetraalkylammonium hexafluorophosphate salts (R4N·PF6, R = H, Me, Et or n-Bu) and of tetrabutylammonium perchlorate (n-Bu4N·ClO4) all afford an increased switching rate, which is largest in the case of n-Bu4N·ClO4 with smaller anions. Variation in the size of the ammonium cation has no significant effect. These results indicate that the addition of excess ions can be used as an accelerator to speed up shuttling processes in rotaxanes and catenanes based on the mobile cyclobis(paraquat-p-phenylene) ring, and that the choice of anion offers a convenient means of controlling the extent of this effect.

A self-templation strategy was used to synthesise isophthalamide [2]catenanes of various sizes in up to 51% yield without the need for metal ions as templates or mediators of covalent bond formation. Using this strategy a bis-monodentate catenane was prepared incorporating exohedral pyridine units. Upon complexation of this ligand with AgOTf a one-dimensional coordination polymer was obtained in the solid state in which both macrocycles of the catenane are involved in binding to the metal nodes, resulting in a rare example of a coordination assembly in which mechanical bonds are incorporated into the structure backbone.

In-flow photooxygenation of aminothienopyridinones generates iminopyridinedione PTP4A3 phosphatase inhibitors by Nikhil R. Tasker; Ettore J. Rastelli; Isabella K. Blanco; James C. Burnett; Elizabeth R. Sharlow; John S. Lazo; Peter Wipf (2448-2466).
A continuous flow photooxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones to produce 7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-diones has been developed, utilizing ambient air as the sole reactant. N-H Imines are formed as the major products, and excellent functional group tolerance and conversion on gram-scale without the need for chromatographic purification allow for facile late-stage diversification of the aminothienopyridinone scaffold. Several analogs exhibit potent in vitro inhibition of the cancer-associated protein tyrosine phosphatase PTP4A3, and the SAR supports an exploratory docking model.

Photochromic peptidic NPY Y4 receptor ligands by D. Lachmann; A. Konieczny; M. Keller; B. König (2467-2478).
The neuropeptide Y (NPY) Y4 receptor is a G protein coupled receptor, which is targeted by pancreatic polypeptide, a homologue of NPY. Selective Y4R agonists were suggested as potential therapeutics for the treatment of obesity. Highly potent dimeric peptidic Y4R agonists, constituting two pentapeptide moieties connected through an aliphatic linker, represent an interesting class of Y4R ligands. Based on this compound class, photoresponsive Y4R ligands, containing an azobenzene, azopyrazole, diethienylethene or a fulgimide chromophore were prepared to explore structural requirements of such Y4R agonists on Y4R binding. The synthesized Y4R ligands, containing a non-aliphatic rigid photochromic linker, switch reversibly in aqueous buffer and exhibited high Y4R affinity throughout. This demonstrated that the replacement of the highly flexible aliphatic linker by a considerably less flexible photochromic linker was well tolerated with respect to Y4R binding. Differences in Y4R affinity and activity between the individual photoisomers (varying in spatial orientation and flexibility) were marginal suggesting that the linking element in the dimeric ligands is less critical for the adaptation of high-affinity binding modes at the receptor.

The systematic influence of solvent on the conformational features of furanosides by Karolina Gaweda; Wojciech Plazinski (2479-2485).
The endo- and exo-anomeric effects are the two most recognizable stereoelectronic effects exhibited by carbohydrates. Their presence relies on the interactions between ring substituent(s) and ring oxygen atoms. Here, we report the finding of a new effect that partially controls the conformational properties of furanose rings and can be ascribed to the influence of the solvent on the electronic structure of a molecule. In contrast to anomeric effects, it is not dependent on either presence or absence of ring substituents. Its origins lie in a solvent-induced flux of atomic charges that involves atoms forming the furanose ring. This systematically changes the energy of the whole molecular system and alters the ring-distortion free energies by ∼2.5–6.5 kJ mol−1, favoring the geometries close to the twist 3T2/2T3 conformers and disfavoring the envelope OE/EO-like shapes. This intriguing effect has never been reported before, although it is expected to exist in all furanose rings. Along with more recognized stereoelectronic effects, this phenomenon contributes to a wide applicability of the two-state (north vs. south) model of pseudorotation in furanosides and, in the case of extremely flexible furanose rings, may change the preferred conformation type in comparison with the gas-phase-oriented predictions.

A 4,5-dithienylimidazolium salt outfitted with pendant styrenyl groups was synthesized and studied. The salt was found to undergo reversible electrocyclization upon UV irradiation; subsequent exposure to visible light reversed the reaction. Acyclic diene metathesis (ADMET) polymerization of the salt afforded a novel fluorescent polyelectrolyte.

A smart molecular probe for selective recognition of nitric oxide in 100% aqueous solution with cell imaging application and DFT studies by Ananya Dutta; Abu Saleh Musha Islam; Debjani Maiti; Mihir Sasmal; Chandradoy Pradhan; Mahammad Ali (2492-2501).
Herein, a simple, least-cytotoxic as well as an efficient fluorescent sensor HqEN480 was prepared from (quinolin-8-yloxy)-acetic acid ethyl ester (L1) and N,N-dimethylethylene diamine to recognize NO in 100% aqueous solution. Its marked selectivity and sensitivity towards NO, makes it a highly suitable probe for nitric oxide under in vitro conditions with the possibility of in vivo monitoring of NO. Upon addition of 3.5 equivalents of NO, there is an approximately 7 fold enhancement in fluorescence intensity in aqueous solution with a corresponding Kf value of (1.75 ± 0.07) × 104 M−1. Quantum yields of HqEN480 and [HqEN480-NO] compounds are determined to be 0.04 and 0.22, respectively, using acidic quinine sulphate as a standard. In terms of the 3σ method, the LOD for nitric oxide was found to be 53 nM thus, making the probe suitable for tracking NO in biological systems.

Promotion of the collagen triple helix in a hydrophobic environment by Vladimir Kubyshkin; Nediljko Budisa (2502-2507).
In contrast to many other water-soluble peptide arrangements, the formation of a triple helix in collagen proceeds inside out: polar glycyl residues form the interior, whereas nonpolar prolyl side chains constitute the exterior. In our work, we decided to exploit this aspect of the peptide architecture in order to create hyperstable collagen mimicking peptides (CMPs). The key element of this study is the environment. Given that the peptide assembles in a nonpolar medium, the collapse of the polar peptide backbone into the triple helix should become more favorable. Following this idea, we prepared CMPs based on hydrophobic proline analogues. The synthesis was performed by a combination of liquid- and solid-phase approaches: first, hexapeptides were prepared in solution, and then these were launched into conventional Fmoc-based peptide synthesis on a solid support. The resulting peptides showed an excellent signal of the triple helix in the model nonpolar solvent (octanol) according to circular dichroism observations. In a study of a series of oligomers, we found that the minimal length of the peptides required for triple helical assembly is substantially lower compared to water-soluble CMPs. Our results suggest further explorations of the CMPs in hydrophobic media; in particular, we highlight the suggestion that collagen could be converted into a membrane protein.

Encapsulation of inuloxin A, a plant germacrane sesquiterpene with potential herbicidal activity, in β-cyclodextrins by Arash Moeini; Marco Masi; Maria C. Zonno; Angela Boari; Alessio Cimmino; Oreste Tarallo; Maurizio Vurro; Antonio Evidente (2508-2515).
Inuloxin A is a promising plant phytotoxic sesquiterpene that deserves further studies to evaluate its potential as a bioherbicide. However, its low solubility in water and its bioavailability could hamper its practical applications. For this reason, inuloxin A was complexed with β-cyclodextrins by using three different methods, i.e., kneading, co-precipitation and grinding. The resulted complexes were fully characterized by different techniques such as 1H NMR, UV-vis, XRD, DSC and SEM, and they were biologically assayed in comparison with the pure compound in several biological systems. The efficacy of the kneading and grinding complexes was similar to that of inuloxin A and these complexes almost completely inhibit Phelipanche ramosa seed germination. The complete solubility in water and the preservation of the biological properties of these two complexes could allow further studies to develop a novel natural herbicide for parasitic plant management based on these formulations.

A metal- and base-free domino protocol for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines and related scaffolds by V. P. Rama Kishore Putta; Raghuram Gujjarappa; Ujjawal Tyagi; Prasad P. Pujar; Chandi C. Malakar (2516-2528).
Efficient protocols have been described for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines, 2-aryl thiazin-4-ones and diaryl[b,f][1,5]diazocine-6,12(5H,11H)-diones. These transformations were successfully driven towards the product formation under mild acid catalyzed reaction conditions at room temperature using 2-amino aryl/hetero-aryl alkyl alcohols and amides as substrates. The merits of the present methods also rely on the easy access of rarely explored bioactive scaffolds like 1,3-benzoselenazine derivatives, for which well-documented methods are rarely known in the literature. A broad range of substrates with both electron-rich and electron-deficient groups were well-tolerated under the developed conditions to furnish the desired products in yields up to 98%. The scope of the devised method is not only restricted to the synthesis of 1,3-benzoselenazines, but it was also further extended towards the synthesis of 1,3-benzothiazines, 1,3-benzothiazinones and the corresponding eight membered N-heterocycles such as diaryl[b,f][1,5]diazocine-6,12(5H,11H)-diones.

A new method for the synthesis of 2,4,5-trisubstituted pyridines from N-propargylic β-enaminothiones is reported. β-Enaminothiones were prepared by thionation of the corresponding β-enaminones with Lawesson's reagent. When treated with diisopropylamine in DMF at room temperature, N-propargylic β-enaminothiones yielded 2,4,5-trisubstituted pyridines in moderate to high yields, along with small amounts of 2-methylene-2,3-dihydro-1,4-thiazepines. The reaction was found to be general for a broad range of N-propargylic β-enaminothiones and tolerated the presence of aromatic, heteroaromatic and aliphatic groups with electron-withdrawing and electron-donating substituents. The method could be widened to the internal alkyne-tethered N-propargylic β-enaminothiones. This operationally simple method may provide rapid access to a library of functionalized pyridines of pharmacological interest.

The synthesis of 1H-isothiochromenes by oxidative coupling of benzyl(tert-butyl)thioethers with internal alkynes, catalysed by Ru(ii), has been achieved. The reaction occurs by S-directed C–H activation at the ortho position of the aryl ring, promoted by ruthenium, migratory insertion of the alkyne, 1,2-thio-Wittig rearrangement of the tert-butyl group and reductive elimination by C–S coupling between the resulting anionic sulfide and the vinylic carbon.

Modular DNA-based hybrid catalysts as a toolbox for enantioselective hydration of α,β-unsaturated ketones by Ji Hye Yum; Soyoung Park; Ryota Hiraga; Izumi Okamura; Shunta Notsu; Hiroshi Sugiyama (2548-2553).
The direct addition of water to a carbon–carbon double bond remains a challenge, but such a reaction is essential for the development of efficient catalysts that enable direct access to chiral alcohols. We now report on the enantioselective hydration of α,β-unsaturated ketones, catalyzed by modular DNA-based hybrid catalysts, affording β-hydroxy ketones with up to 87% enantiomeric excess. Oligonucleotides containing an intrastrand bipyridine ligand were readily synthesized by a straightforward process using an automated solid-phase synthesis. A library of DNA-based hybrid catalysts could be systematically generated based on the composition of nucleobases, and the incorporation of a binding ligand and a nonbinding steric moiety. This study demonstrates the potential of modular DNA-based hybrid catalysts as a toolbox to accomplish the challenging enantioselective hydration reaction.

The first report on Ir(iii)-catalyzed C–H alkylation/cyclization of azobenzene with diazotized Meldrum's acid is described for the synthesis of cinnolin-3(2H)-one derivatives under mild conditions. Controlled experiments led to the isolation of intermediate ortho-alkylated product of azobenzene, which was converted to both cinnolin-3(2H)-one-4-carboxylic acid and its ester derivative. Additionally, the iridacyclic complex of azobenzene was isolated and found to be an active intermediate in the catalytic cycle.

Correction: Bioactive spiropyrrolizidine oxindole alkaloid enantiomers from Isatis indigotica fortune by Si-Fan Liu; Bin Lin; Yu-Fei Xi; Le Zhou; Li-Li Lou; Xiao-Xiao Huang; Xiao-Bo Wang; Shao-Jiang Song (2564-2564).
Correction for ‘Bioactive spiropyrrolizidine oxindole alkaloid enantiomers from Isatis indigotica fortune’ by Si-Fan Liu et al., Org. Biomol. Chem., 2018, 16, 9430–9439.

Back cover (2565-2566).