Organic & Biomolecular Chemistry (v.17, #34)

Front cover (7797-7798).

Contents list (7799-7806).

Recently, missing pieces of organophosphorus compounds, i.e., aromatic-fused diketophosphanyl compounds, have attracted much attention as promising scaffolds of building blocks for functional organic materials. In this review, the brief historical background, synthetic methods, structures, and optoelectronic aspects of aromatic-fused diketophosphanyls are overviewed.

Hypervalent iodine reactions utilized in carbon–carbon bond formations by I. F. Dempsey Hyatt; Loma Dave; Navindra David; Kirandeep Kaur; Marly Medard; Cyrus Mowdawalla (7822-7848).
Advances in hypervalent iodine chemistry have put the field on the precipice of a second golden age; the first being pioneered in the 1990s. During that period, C–C bond forming reactions would be published but rarely with the intended goal of developing a C–C bond forming methodology. More recently, the development of hypervalent iodine-guided electrophilic substitution, arylations using hypervalent iodine, and photoredox reactions with hypervalent iodine have shown great progress in the area of C–C bond formation.

The first organocatalytic asymmetric synthesis of spiro-dihydropyrano cyclohexanones has been developed via the cascade reaction between cyanoketones and cyclic 2,4-dienones. A cinchona alkaloid-derived bifunctional primary amine catalyst in combination with N-Boc-tleucine was found to be the most effective for this spirocyclization reaction and provided the desired products in moderate to good yields with high enantioselectivities.

Direct thiocarbamation of imidazoheterocycles via dual C–H sulfurization by Jian-Chao Deng; Jun-Rong Zhang; Ming-Hua Li; Jie-Cheng Huang; Zhi-Sheng Lai; Xin-Yu Tong; Zi-Ning Cui; Ri-Yuan Tang (7854-7857).
A copper-catalyzed DTBP oxidative dual C–H sulfurization has been developed for the direct thiocarbamation of imidazopyridines using a combination of elemental sulfur and formamides as carbamothioyl surrogates. NBS (bromo succinimide) was found to promote the thiocarbamation in good yields. This dual C–H sulfurization strategy enables access to a wide range of carbamothioyl imidazoheterocycles without the use of highly toxic phosgene.

A new natural product compound library, photohexapeptide library, was identified from entomopathogenic Photorhabdus asymbiotica PB68.1 after the NRPS-encoding gene phpS was activated via promoter exchange. Peptide structures, including the absolute configurations of amino acids, were determined by using a combination of bioinformatics analysis and isotopic labelling experiments followed by detailed HPLC-MS analysis. Additionally, their structures were confirmed by chemical synthesis and NMR after preparative isolation. The chemical diversity of the photohexapeptides results from promiscuous adenylation domain specificity being an excellent example of how to create libraries in nature.

Distortion of mannoimidazole supports a B2,5 boat transition state for the family GH125 α-1,6-mannosidase from Clostridium perfringens by Alexandra Males; Gaetano Speciale; Spencer J. Williams; Gideon J. Davies (7863-7869).
Enzyme transition-state mimics can act as powerful inhibitors and allow structural studies that report on the conformation of the transition-state. Here, mannoimidazole, a mimic of the transition state of mannosidase catalyzed hydrolysis of mannosides, is shown to bind in a B2,5 conformation on the Clostridium perfringens GH125 α-1,6-mannosidase, providing additional evidence of a OS2–B2,51S5 conformational itinerary for enzymes of this family.

Optimised approach to albumin–drug conjugates using monobromomaleimide-C-2 linkers by Archie Wall; Karl Nicholls; Mikael B. Caspersen; Stig Skrivergaard; Kenneth A. Howard; Kersti Karu; Vijay Chudasama; James R. Baker (7870-7873).
Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisation. This improved reagent design is applied to the construction of an HSA-paclitaxel conjugate, preventing drug loss during maleimide hydrolysis.

The selectivity of nucleic acid hybridisation can be exploited to template chemical reactions, enabling materials discovery by chemical evolution. However, to date the range of reactions that can be used has been limited to those that are compatible with aqueous media, since the addition of organic co-solvents can have a large impact on the stability of nucleic acid duplexes. Peptide nucleic acids (PNAs) are promising in this regard because previous studies have suggested they may be stable as duplexes in high organic content solvent mixtures. Here, we use micro-differential scanning calorimetry (micro-DSC) to confirm for the first time that double-stranded PNA (dsPNA) is stable in N,N-dimethylformamide (DMF)/water mixtures up to 95 vol% DMF. Using fluorescence, we corroborate these results and show that the isothermal annealing of PNA in high DMF content solution is also rapid. These findings suggest that PNA could enable the use of a range of water-sensitive chemistries in nucleic acid templating applications.

A set of dendrons and dendrimers is synthesized divergently using an orthogonal combination of kinetically-driven thiol-maleimide “click” chemistry and thermodynamically reversible furan-maleimide cycloaddition/retrocycloaddition reactions. Growth is controlled by taking advantage of the selective thiol–ene addition of thiols to the electron withdrawn alkene of maleimide in the presence of electron rich alkene of oxanorbornene. Subsequent activation of growing dendrons/dendrimers requires only heat to induce the dynamic covalent liberation of peripheral furan protecting groups. The methodology introduced provides a new route to multifunctional dendrimers that could, in principle, be synthesized by introducing different branched monomers at any stage of dendrimer growth, allowing dendrimer architectures and properties to be better tailored to their intended applications.

Synthesis and electrochromic behavior of a multi-electron redox-active N-heteroheptacenequinone by Kyosuke Isoda; Mitsuru Matsuzaka; Tomoaki Sugaya; Takeshi Yasuda; Makoto Tadokoro (7884-7890).
We report a novel N-heteroheptacenequinone derivative (C6OAHCQ) as a large π-conjugated framework. C6OAHCQ shows good electron-accepting behaviour owing to eight electron-deficient imino-N atoms and two carbonyl moieties and excellent solubility in common organic solvents. When a potential between 0 and −2.20 V is applied, C6OAHCQ is able to accept four electrons, which is more than fullerene C60 (three electrons) could accept in this voltage range. Moreover, a solution of C6OAHCQ and nBu4NPF6 in CH2Cl2 exhibits a clearly reversible brown-to-green colour change, suggesting that C6OAHCQ has potential as an electrochromic material.

Reaction mechanism of nucleoside 2′-deoxyribosyltransferases: free-energy landscape supports an oxocarbenium ion as the reaction intermediate by Jon del Arco; Almudena Perona; Leticia González; Jesús Fernández-Lucas; Federico Gago; Pedro A. Sánchez-Murcia (7891-7899).
Insight into the catalytic mechanism of Lactobacillus leichmannii nucleoside 2′-deoxyribosyltransferase (LlNDT) has been gained by calculating a quantum mechanics–molecular mechanics (QM/MM) free-energy landscape of the reaction within the enzyme active site. Our results support an oxocarbenium species as the reaction intermediate and thus an SN1 reaction mechanism in this family of bacterial enzymes. Our mechanistic proposal is validated by comparing experimental kinetic data on the impact of the single amino acid replacements Tyr7, Glu98 and Met125 with Ala, Asp and Ala/norLeu, respectively, and accounts for the specificity shown by this enzyme on a non-natural substrate. This work broadens our understanding of enzymatic C–N bond cleavage and C–N bond formation.

First α-deuterium nitroxides; synthesis and EPR study by Hila Toledo; Boris Tumanskii; Denis Sh. Sabirov; Alexander Kaushansky; Natalia Fridman; Alex M. Szpilman (7900-7906).
Herein is reported the first preparation of stable α-deuterium nitroxides of the IAPNO family. The confirmation and characteristics of the α-deuterium nitroxides and their α-hydrogen analogues are compared and analyzed. Such α-deuterium nitroxides may find use in biology, medicine and physical chemistry.

Facile synthesis of substituted quinolines by iron(iii)-catalyzed cascade reaction between anilines, aldehydes and nitroalkanes by Sachinta Mahato; Anindita Mukherjee; Sougata Santra; Grigory V. Zyryanov; Adinath Majee (7907-7917).
A library of substituted quinolines has been synthesized by the reaction of aldehydes, anilines and nitroalkanes using a catalytic amount of Fe(iii) chloride. The reaction is a simple, efficient, one-pot, three-component domino strategy in ambient air which afforded the products in high yields. A probable pathway of the reaction is a sequential aza-Henry reaction/cyclization/denitration. The use of commercially available chemicals as starting materials, an inexpensive metal catalyst, aerobic reaction conditions, tolerance of a wide range of functional groups, and operational simplicity are the notable advantages of this present protocol.

Visible-light-mediated difunctionalization of vinylcyclopropanes for the synthesis of 1-sulfonylmethyl-3,4-dihydronaphthalenes by Qiao-Lin Wang; Wen-Zheng Zhang; Quan Zhou; Cong-Shan Zhou; Bi-Quan Xiong; Ke-Wen Tang; Yu Liu (7918-7926).
An efficient method for visible-light-mediated sulfonylation/arylation of the C–C σ-bond in vinylcyclopropanes with sulfonyl chlorides to synthesize 1-sulfonylmethyl-substituted 3,4-dihydronaphalenes has been developed. A radical-type pathway has been proved in this transformation. This difunctionalization procedure shows a series of advantages, such as the use of commercially and easily available sulfonyl chlorides, mild conditions, and eco-friendly energy.

Solvent interception, heterocyclization and desilylation upon NBS-induced sulfamidation of trimethyl(vinyl)silane by Vera V. Astakhova; Mikhail Yu. Moskalik; Bagrat A. Shainyan (7927-7937).
The reaction of trimethyl(vinyl)silane with sulfonamides in the presence of N-bromosuccinimide was shown to proceed regioselectively in methylene chloride under mild conditions and led to the products of bromosulfamidation in up to 88% yield. The obtained adducts undergo base-promoted dehydrobromination to give 2-trimethylsilyl-N-sulfonyl aziridines in a close to quantitative yield. In the reaction with trifluoromethanesulfonamide in acetonitrile or tetrahydrofuran, the Ritter-type (solvent-interception) products were obtained and converted to 1-triflyl-2-methyl-5-(trimethylsilyl)-2-imidazoline or 4-triflyl-3-(trimethylsilyl)-1,4-oxazocane in almost quantitative yield.

Enantioselective photooxygenation of β-dicarbonyl compounds in batch and flow photomicroreactors by Xiao-Fei Tang; Jing-Nan Zhao; Yu-Feng Wu; Ze-Hao Zheng; Shi-Hao Feng; Zong-Yi Yu; Guang-Zhi Liu; Qing-Wei Meng (7938-7942).
A series of C-2′ modified cinchonine-derived phase-transfer catalysts were synthesized and used in the enantioselective photo-organocatalytic aerobic oxidation of β-dicarbonyl compounds with excellent yields (up to 97%) and high enantioselectivities (up to 90% ee). Furthermore, the reaction was carried out in a flow photomicroreactor, in which the heterogeneous gas–liquid–liquid asymmetric photocatalytic oxidation reaction was performed affording good yields (up to 97%) and enantioselectivities (up to 86% ee) within 0.89 min.

Copper-catalysed C–H functionalisation gives access to 2-aminobenzimidazoles by Peter R. Clark; Glynn D. Williams; Nicholas C. O. Tomkinson (7943-7955).
This paper describes the development, optimisation and exemplification of a copper-catalysed C–H functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines. High throughput screening was used as a tool to identify a catalytically active copper source, DoE was used for reaction optimisation and a range of aryl-guanidines were prepared and exposed to the optimum conditions to afford a range of 2-aminobenzimidazoles in moderate to good yields. The methodology has been applied to the synthesis of Emedastine, a marketed anti-histamine pharmaceutical compound, with the key cyclisation step performed on a gram-scale.

Three-state switching in a double-pole change-over nanoswitch controlled by redox-dependent self-sorting by Sudhakar Gaikwad; Merve Sinem Özer; Susnata Pramanik; Michael Schmittel (7956-7963).
The four-arm nanomechanical switch 1 with four different terminals exhibits two switching arms (contacts A and D) and two distinct stations for binding (contacts B and C). In switching State I, the azaterpyridine arm is intramolecularly coordinated to a zinc(ii) porphyrin station (connection A ↔ B) while contact D (a ferrocenylbipyridine unit) and contact C (phenanthroline) remain disconnected. After addition of copper(i) ions (State II) both connections A ↔ B and C ↔ D are established. Upon one-electron oxidation, double-pole change-over switching cleaves both connections A ↔ B & C ↔ D and establishes the new connection A ↔ C (State III). Fully reversible three-state switching (State I → State II → State III → State II → State I) was achieved by adding appropriate chemical and redox stimuli.

Facile and versatile access to substituted hexabenzoovalene derivatives: characterization and optoelectronic properties by Lijiao Wang; Wei Hao; Yanbing Han; Yamei Shi; Shuzhou Li; Chunfang Zhang; Jinchong Xiao (7964-7972).
We describe the design and modular synthesis of a library of substituted hexabenzoovalene derivatives (SHBO), along with the key precursor dinaphthopyrenes (3), highlighting the influence of a wide array of substituent variation on the photophysical properties via UV-vis absorption, fluorescence spectra and electrochemical methods. The results show that the cyclized hexabenzoovalenes present a stronger spectroscopic red-shift than the corresponding dinaphthopyrenes. X-ray diffraction analysis suggests that intermediate 3hx containing two nitro groups forms a trans-configuration with twisted structures. Our systematic investigation might provide a realistic design strategy to construct large one-dimensional and two-dimensional materials via bottom-up approaches.

d-Amino acid oxidase (DAAO) is a flavoenzyme whose inhibition is expected to have therapeutic potential in schizophrenia. DAAO catalyses hydride transfer from the substrate to the flavin in the reductive half-reaction, and the flavin is reoxidized by O2 in the oxidative half-reaction. Quantum mechanical/molecular mechanical calculations were performed and their results together with available experimental information were used to elucidate the detailed mechanism of the oxidative half-reaction. The reaction starts with a single electron transfer from FAD to O2, followed by triplet–singlet transition. FAD oxidation is completed by a proton coupled electron transfer to the oxygen species and the reaction terminates with H2O2 formation by proton transfer from the oxidized substrate to the oxygen species via a chain of water molecules. The substrate plays a double role by facilitating the first electron transfer and by providing a proton in the last step. The mechanism differs from the oxidative half-reaction of other oxidases.

Curtachalasins, immunosuppressive agents from the endophytic fungus Xylaria cf. curta by Wen-Xuan Wang; Gui-Guang Cheng; Zheng-Hui Li; Hong-Lian Ai; Juan He; Jing Li; Tao Feng; Ji-Kai Liu (7985-7994).
Eleven new cytochalasins, curtachalasins F–P (1–11), were isolated from the rice fermentation of endophytic fungus Xylaria cf. curta. Their structures were identified by extensive spectroscopic methods, X-ray diffraction, and quantum chemistry calculations. Curtachalasin P possesses a unique 5/6/6/7 fused ring system. In the bioactivity screening for curtachalasins F–P, A–C, and E (1–15), compounds 1, 3–6, 8–13, and 15 did not show obvious cytotoxicity against primary mouse splenocytes. Furthermore, the immunosuppressive assay against concanavalin A (ConA) induced T lymphocyte cell proliferation and lipopolysaccharide (LPS) induced B lymphocyte cell proliferation showed that compound 1 results in significant selective inhibition on B-cell proliferation (IC50 value of 2.42 μM) and compound 10 has selective inhibition on T-cell proliferation (IC50 value of 12.15 μM). These interesting immunosuppressive properties of this class of compounds provide new clues to fulfill the urgent demand for new immunosuppressive drugs.

Triflic anhydride mediated synthesis of 3,4-dihydroquinazolines: a three-component one-pot tandem procedure by Christina L. Magyar; Tyler J. Wall; Steven B. Davies; Molly V. Campbell; Haven A. Barna; Sydney R. Smith; Christopher J. Savich; R. Adam Mosey (7995-8000).
A one-pot three-component tandem reaction involving a key Pictet–Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.

A novel photosensitizer BDPI-lyso has been developed for photodynamic therapy (PDT). The photosensitizer BDPI-lyso showed a high singlet oxygen quantum yield (ΦΔ = 0.95) and low fluorescence quantum yield (ΦF = 0.05) in EtOH. Different singlet oxygen quantum yields were found in acidic solution (pH = 5, ΦΔ = 0.51) and in neutral solution (pH = 7, ΦΔ = 0.38). DFT and TD-DFT calculations of BDPI-lyso and its protonated product BDPI-lysoH+ indicated that the S1/T3 transition was responsible for the intersystem crossing (ISC) enhancement which would promote the production of singlet oxygen. The negligible dark cytotoxicity toward the hepatoma cell line Bel-7402 was confirmed by MTT assay, AO/EB dual staining, and cell images. Upon exposure to a low dose of light illumination, the disruption of the cell plasma membrane and the calculated half-maximal inhibitory concentration (IC50) of 0.4 μM showed a high phototoxicity of the photosensitizer BDPI-lyso. The light-induced intracellular ROS generation was verified as the PDT mechanism of BDPI-lyso. Colocalization experiments of LysoTracker Green and BDPI-lyso in the dark indicated the good lysosome-targeting ability of BDPI-lyso. The images of cells costained with LysoTracker Green and BDPI-lyso, and the appearance of intracellular and extracellular blebs with green fluorescence after light illumination revealed the light-induced dysfunction of lysosomes and cell apoptosis.

The one-pot base-promoted cascade double [3 + 2] cycloaddition reaction of N-cyanomethylisoquinolinium chloride with (E)-3-arylideneindolin-2-ones and (E)-N-hydroxybenzimidoyl chloride afforded novel polycyclic spiro[indoline-3,8′-isoxazolo[5,4-c]pyrrolo[2,1-a]isoquinolines] in good yields and with high diastereoselectivity. When 4-arylidenepyrazol-3-ones, 2-arylidene-1,3-indanediones and arylidenemalononitriles were employed in the reaction, the corresponding spiro[isoxazolo[5,4-c]pyrrolo[2,1-a]isoquinoline-8,4′-pyrazole], spiro[indene-2,8′-isoxazolo[5,4-c]pyrrolo[2,1-a]isoquinoline], and isoxazolo[5,4-c]pyrrolo[2,1-a]isoquinoline derivatives were also prepared in good yields and with high diastereoselectivty. The relative configurations of the polycyclic spiro compounds were clearly elucidated by determination of fifteen single crystal structures.

Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry by Krishna Sharma; Alexander V. Strizhak; Elaine Fowler; Xuelu Wang; Wenshu Xu; Claus Hatt Jensen; Yuteng Wu; Hannah F. Sore; Yu Heng Lau; Marko Hyvönen; Laura S. Itzhaki; David R. Spring (8014-8018).
The Sondheimer dialkyne is extensively used in double strain-promoted azide–alkyne cycloadditions. This reagent suffers with poor water-solubility and rapidly decomposes in aqueous solutions. This intrinsically limits its application in biological systems, and no effective solutions are currently available. Herein, we report the development of novel highly water-soluble, stable, and azide-reactive strained dialkyne reagents. To demonstrate their extensive utility, we applied our novel dialkynes to a double strain-promoted macrocyclisation strategy to generate functionalised p53-based stapled peptides for inhibiting the oncogenic p53-MDM2 interaction. These functionalised stapled peptides bind MDM2 with low nanomolar affinity and show p53 activation in a cellular environment. Overall, our highly soluble, stable and azide-reactive dialkynes offer significant advantages over the currently used Sondheimer dialkyne, and could be utilised for numerous biological applications.

Back cover (8019-8020).