Organic & Biomolecular Chemistry (v.16, #31)

Front cover (5541-5542).

Contents list (5543-5550).

The trans-chelating bis(oxazoline) ligand (R,R)-4,6-dibenzofurandiyl-2,2′-bis(4-phenyloxazoline) [(R,R)-DBFOX/Ph] coordinates metal ions to give C2-symmetric complexes which effectively catalyze a variety of asymmetric reactions. (R,R)-DBFOX/Ph·Ni(ClO4)2·3H2O, whose crystal structure is octahedral with three aqua ligands, can be stored under air for several months without loss of catalytic activity and promotes highly enantioselective reactions even in the presence of excess amounts of water, alcohols, amines, and acids. The complex shows remarkable chiral amplification in asymmetric Diels–Alder (DA) reactions. This review focuses on enantioselective reactions catalyzed by (R,R)-DBFOX/Ph·metal complexes.

Two catalytic protocols for Achmatowicz rearrangement using cyclic diacyl peroxides as oxidants by Congyin Wei; Rong Zhao; Zhihong Shen; Denghu Chang; Lei Shi (5566-5569).
In situ generated bromonium-catalyzed and visible-light photocatalytic Achmatowicz rearrangements of furfuryl alcohols using cyclic diacyl peroxides as oxidants are described. Both protocols feature broad substrate scope, excellent functional group tolerance, and mild reaction conditions, affording the synthetically useful dihydropyranone derivatives in good yields.

A simple and efficient approach has been developed for the synthesis of imidazo[1,5-a]pyridines using the elemental sulfur mediated sequential dual oxidative Csp3–H amination of 2-pyridyl acetates and amines under metal- and peroxide-free conditions. Broad substrate scope, operational simplicity and gram-scale ability make this chemistry very practical.

Rhodol-based thallium sensors for cellular imaging of potassium channel activity by Brendan F. Dutter; Anna Ender; Gary A. Sulikowski; C. David Weaver (5575-5579).
Thallium (Tl+) flux assays enable imaging of potassium (K+) channel activity in cells and tissues by exploiting the permeability of K+ channels to Tl+ coupled with a fluorescent Tl+ sensitive dye. Common Tl+ sensing dyes utilize fluorescein as the fluorophore though fluorescein exhibits certain undesirable properties in these assays including short excitation wavelengths and pH sensitivity. To overcome these drawbacks, the replacement of fluorescein with rhodols was investigated. A library of 13 rhodol-based Tl+ sensors was synthesized and their properties and performance in Tl+ flux assays evaluated. The dimethyl rhodol Tl+ sensor emerged as the best of the series and performed comparably to fluorescein-based sensors while demonstrating greater pH tolerance in the physiological range and excitation and emission spectra 30 nm red-shifted from fluorescein.

A difficult challenge in synthetic enzymes is the creation of substrate-selective active sites with accurately positioned catalytic groups. Covalent molecular imprinting in cross-linked micelles afforded such active sites in protein-sized, water-soluble nanoparticle catalysts. Our method allowed a systematic tuning of the distance of the catalytic group to the bound substrate. The catalysts displayed enzyme-like kinetics and easily distinguished substrates with subtle structural differences.

Heteroaryl-linked norbornadiene dimers with redshifted absorptions by Mads Mansø; Behabitu Ergette Tebikachew; Kasper Moth-Poulsen; Mogens Brøndsted Nielsen (5585-5590).
Development of Molecular Solar Thermal (MOST) systems for harvesting and storing solar energy is based on molecular photoswitches that undergo photoisomerizations to metastable isomers. One challenge is to achieve low-molecular weight molecules that absorb at sufficiently long wavelengths to match the solar spectrum. Here we show that this can be achieved by linking two norbornadiene (NBD) photoswitches to a central heterocycle, thiophene or carbazole, via alkyne appendages. In this approach, the same heteroaryl is used to tune the properties of two photoswitches at the same time, thereby keeping the molecular weight as low as possible. A series of NBD dimers was prepared by Sonogashira coupling reactions, and these compounds showed remarkable redshifted absorptions, with onsets of absorption as high as 468 nm, and thermal half-lives ranging from 44 seconds to 16 hours.

A diisopropylethylamine (DIPEA)-triggered, self-catalyzed, regioselective acylation of carbohydrates and diols is presented. The hydroxyl groups can be acylated by the corresponding anhydride in MeCN in the presence of a catalytic amount of DIPEA. This method is comparatively green and mild as it uses less organic base compared with other selective acylation methods. Mechanistic studies indicate that DIPEA reacts with the anhydride to form a carboxylate ion, and then the carboxylate ion could catalyze the selective acylation through a dual H-bonding interaction.

A bodipy–C70 dyad was synthesized and applied in triplet–triplet annihilation (TTA) upconversion of perylene as a novel metal-free organic photosensitizer. The photophysical processes were investigated by the methods of steady-state UV-Vis absorption and fluorescence spectroscopy, nanosecond time-resolved transient absorption spectroscopy, cyclic voltammetry, and density functional theory calculations. The bodipy–C70 dyad showed an increased molar extinction coefficient up to 82 300 mol−1 cm−1 at 518 nm compared with the C70 monomer. With photo-excitation of the bodipy moiety at 532 nm, the intramolecular singlet–singlet energy transfer between bodipy and C70 units was efficient with a quantum yield of nearly 100%, and the lowest triplet state of the dyad was subsequently populated via ISC of the C70 moiety, with a lifetime of ca. 80 μs in toluene. Electrochemical investigation suggested that the intramolecular electron transfer of the excited dyad was thermodynamically prohibited in toluene due to the positive ΔGCS for charge-separation. With the presence of perylene in solution as the triplet energy acceptor and emitter, the TTA upconverted fluorescence was observed with a maximum quantum yield of 10.3%. The overall upconversion capability of 4417 M−1 cm−1 exceeded that of C70 approximately two-fold. Moreover, the bodipy–C70 dyad also exhibited an enhanced optical stability under intense irradiation. All data indicated that the dyad was another ideal photosensitizer for TTA upconversion of perylene in the fullerene derivative family.

Thermoresponsive luminescence properties of polyfluorinated bistolane-type light-emitting liquid crystals by Shigeyuki Yamada; Masato Morita; Tomohiro Agou; Toshio Kubota; Takahiro Ichikawa; Tsutomu Konno (5609-5617).
We developed and characterized four polyfluorinated bistolane derivatives. These compounds, which possess either two alkoxy substituents or an alkoxy group and a bromine atom in their two molecular terminals, were synthesized from readily available 4-alkoxy-1-ethynylbenzene with a facile three-step procedure. Their thermodynamic and photophysical properties were evaluated in detail, and they were found to display both liquid-crystalline (LC) and photoluminescence properties. Remarkably, the photoluminescence behaviors dramatically changed during the thermal phase transition between the crystal and LC phases. Thus, these polyfluorinated bistolanes may be promising candidates for thermoresponsive luminous molecules.

A novel and efficient methodology concerning the Pd(ii)-catalyzed intermolecular difunctionalization of conjugated dienes is reported to synthesize a series of functionalized morpholines and 2-morpholones. Widely distributed and easily obtained β-amino alcohols and α-amino acids, as starting nitrogen and oxygen sources, are successfully applied in the difunctionalization of conjugated dienes respectively. The majority of the desired products were obtained in moderate to excellent yields. Oxygen was successfully employed as a terminal oxidant. Further transformation of the generated products allowed for the expansion of structural diversity.

Influence of amino acid sequence in a peptidic Cu+-responsive luminescent probe inspired by the copper chaperone CusF by A. Roux; M. Isaac; V. Chabert; S. A. Denisov; N. D. McClenaghan; O. Sénèque (5626-5634).
Copper(i) is a soft metal ion that plays an essential role in living organisms and Cu+-responsive probes are required to detect Cu+ ions in physiological conditions and understand its homeostasis as well as the diseases associated with its misregulation. In this article, we describe a series of cyclic peptides, which are structurally related to the copper chaperone CusF, and that behave as Cu+-repsonsive probes. These peptide probes comprise the 16-amino acid loop of CusF cyclized by a β-turn inducer dipeptide and functionalized by a Tb3+ complex for its luminescence properties. The mechanism of luminescence enhancement relies on the modulation of the antenna effect between a tryptophan residue and the Tb3+ ion within the probe when Cu+ forms a cation–π interaction with the tryptophan. Here, we investigate the influence of the amino acid sequence of these cyclic peptides on the copper-induced modulation of Tb3+ emission and show that the rigid β-turn inducer Aib-d-Pro and insertion of the Tb3+ complex close to its tryptophan antenna are required to obtain turn-on Cu+ responsive probes. We also show that the amino acid sequence, especially the number and position of proline residues has a significant impact on metal-induced luminescence enhancement and metal-binding constant of the probes.

Stereoselective synthesis of enantiomerically pure bowl-shaped hydroxytribenzotriquinacenes by Philipp Rommelmann; Beate Nachtigall; Tim Guntelmann; Harald Gröger; Dietmar Kuck (5635-5642).
Enzyme-catalysed hydrolysis of the inherently chiral aryl acetate rac-11 bearing the bowl-shaped tribenzotriquinacene (TBTQ) core enables the stereoselective synthesis of the enantiomerically pure (M)-2-hydroxytribenzotriquinacene (M)-12. Starting from rac-11, for which two independent routes are described, the use of immobilised lipase CAL-A in buffered biphasic solution at pH 7 led to the TBTQ-phenol (M)-12 in 33% yield and with >99% ee on a preparative scale. Extended enzyme screening revealed that the use of CAL-B gives the same enantioselectivity. Furthermore, the chiroptical properties of the enantiomerically pure TBTQ-acetates (M)-11 and (P)-11, TBTQ-phenols (M)-12 and (P)-12 and the corresponding 2-hydroxy-3-iodotribenzotriquinacenes (M)-13 and (P)-13 are reported.

The origin of enantioselectivity in asymmetric catalysis is attributed to the energy difference between lower and higher energy diastereomeric transition states, which are respectively responsible for the formation of major and minor enantiomers. Although the increase in the number of transition state models emphasizes the role of weak non-covalent interactions in asymmetric induction, the strength of such interactions is seldom quantified. Through this article, we propose a simple and effective method of quantifying the total non-covalent interaction in stereocontrolling transition states belonging to a group of three representative asymmetric catalytic reactions involving chiral phosphoric acids. Our method relies on rational partitioning of a given transition state into two (or three) sub-units, such that the complex network of intramolecular interactions can be ameliorated to a set of intermolecular interactions between two sub-units. The computed strength of interaction obtained using the counterpoise (CP) method on suitably partitioned transition states provides improved estimates of non-covalent interactions, which are also devoid of basis set superposition error (BSSE). It has been noted that catalysts decorated with larger aromatic arms provide cumulative non-covalent interactions (C–H⋯π, N–H⋯π and π⋯π) to the tune of 10 to 15 kcal mol−1. Fine-tuning of the magnitude and nature of these interactions can provide valuable avenues in the design of asymmetric catalysts.

Synthesis of imidazo[1,5-a]pyridines via I2-mediated sp3 C–H amination by Zhiyuan Hu; Jiao Hou; Jie Liu; Wenquan Yu; Junbiao Chang (5653-5660).
A transition-metal-free sp3 C–H amination reaction has been established for imidazo[1,5-a]pyridine synthesis employing molecular iodine from 2-pyridyl ketones and alkylamines. In the presence of sodium acetate (NaOAc), the I2-mediated oxidative annulations of readily available substrates produced a variety of imidazo[1,5-a]pyridine derivatives efficiently in a one-pot manner. The present synthetic approach is operationally simple and can be conveniently carried out on a gram scale. Moreover, under the optimal reaction conditions a series of 1-(2-pyridyl)imidazo[1,5-a]pyridine cysteine protease inhibitors were easily prepared from the corresponding di-2-pyridyl ketones and substituted benzylamines in satisfactory yields.

Formation of Nα-terminal 2-dialkyl amino oxazoles from guanidinated derivatives under mild conditions by Shimaa A. H. Abdel Monaim; Jessica T. Mhlongo; Ashish Kumar; Ayman El-Faham; Fernando Albericio; Beatriz G. de la Torre (5661-5666).
Oxazole-containing peptides are an important class of molecules in medicinal chemistry programs. Here we describe a convenient solid-phase synthesis of Nα-terminal oxazole peptides. The strategy took advantage of an intramolecular rearrangement side reaction that occurred during the guanidination of the Nα-amino function of a peptide still anchored on the solid-support. The substitution map of the N,N-dialkylamino oxazole obtained using this strategy differed completely from the one achieved through the heterocyclization of the Ser or Thr side chain with the preceding carbonyl group, which is a common approach for the preparation of these compounds. This unexpected reaction was observed with N-terminal aromatic and aliphatic amino acids that have a Gly as the last before residue in both short as well as long peptides; however, it does not form the oxazole ring if Gly was substituted with other amino acids.

Diverse applications of TMB-based sensing probes by Li Huang; Ying-Juan Cao; Xiang-Ying Sun; Bin Liu; Jiang-Shan Shen (5667-5676).
Extending the research on 3,3′,5,5′-tetramethylbenzidine (TMB) and its derivatives in analytical chemistry is important, considering that TMB is widely used as an enzyme catalytic substrate. In this work, two TMB derivatives, TMBS and TMBB, were synthesized via a facile and one-step condensation reaction between the –NH2 group of TMB and the –CHO group of salicylaldehyde or benzaldehyde. Because at low pH the two Schiff base compounds can release TMB which can emit strong fluorescence, the probes could show dual-modal signal responses, fluorescence and UV-vis absorption, towards the pH. Practical applications of pH sensing in Chinese rice vinegar and lemon juice samples were successfully demonstrated. On the basis of these findings, a catalytic chromogenic reaction was developed to monitor the pH with the naked eye, too. Furthermore, considering the chemical equilibrium reaction between CO2 and H2O and that glucose oxidase (GOD) can catalyse the dehydrogenation and oxidation reaction of β-d-glucose to produce gluconic acid, both of which can result in lowering the pH values of the two Schiff base systems, highly sensitive and selective dual-modal sensing systems for detecting CO2 and β-d-glucose have also been successfully established. Therefore, the two synthesized TMB derivatives can demonstrate their robust application potential.

Alternative formation of amides and β-enaminones from aroyl chlorides using the TiCl4-trialkylamine reagent system by Antonella Leggio; Alessandra Comandè; Emilia Lucia Belsito; Marianna Greco; Lucia Lo Feudo; Angelo Liguori (5677-5683).
The TiCl4/NR3 reagent system has been successfully employed for the synthesis of amides and β-enaminones. The reaction of variously substituted benzoyl chlorides with the TiCl4/NR3 reagent system, by using two different experimental procedures (Method A and Method B), afforded alternatively the corresponding amides and β-enaminones as unique or major products. The two developed protocols were investigated with a series of tertiary amines. The reactions, modulated by the presence of TiCl4, provided the corresponding amides or β-enaminones with satisfactory yields. This paper reports a new method for carbon–carbon bond formation via the reaction of aroyl chlorides with the TiCl4/NR3 reagent system.

Synthesis and physicochemical characterization of (6S)-5-formiminotetrahydrofolate; a reference standard for metabolomics by A. H. Lewin; P. Silinski; D. Zhong; A. Gilbert; S. W. Mascarella; H. H. Seltzman (5684-5690).
The one-carbon carrier of the formate oxidation level derived from the interaction of tetrahydrofolate and formiminoglutamate, which has been tentatively identified as 5-formiminoltetrahydrofolate, has been prepared by chemical synthesis. Treatment of a solution of (6S)-tetrahydrofolate in aqueous base with excess ethyl formimidate in the presence of anti-oxidant under anaerobic conditions afforded a gummy solid which, based on mass spectral analysis, conformed to a monoformimino derivative of tetrahydrofolate. Further physicochemical characterization by validated methods strongly suggested that the product of chemical synthesis was identical to the enzymatically produced material and that it was, in fact, (6S)-5-formiminotetrahydrofolate. Conditions and handling methods toward maintaining the integrity of this highly sensitive compound were identified and are described, as is analytical methodology, useful for research studies using it.

An efficient Rh(iii)-catalyzed dehydrative C–H allylation of indoles with allyl alcohols viaβ-hydroxide elimination under oxidant-free conditions has been developed. This method features very mild reaction conditions, excellent regioselectivity and stereoselectivity, and compatibility with various functional groups. In addition, the directing group can be removed under mild reaction conditions, which further underscores the synthetic utility of this method.

CoCl2-promoted TEMPO oxidative homocoupling of indoles: access to tryptanthrin derivatives by Huiwu Liao; Xiangjun Peng; Dan Hu; Xianyun Xu; Panpan Huang; Qian Liu; Liangxian Liu (5699-5706).
A novel TEMPO/CoCl2-promoted aerobic oxidation of indoles was developed. The reaction provided one-step access to tryptanthrin derivatives in moderate to good yields and excellent regioselectivity via a cascade process. The reactions could be carried out under mild reaction conditions with varying functional group tolerance, especially halogen functional groups. Mechanistic studies disclosed that the oxygen atom in the desired product originated from molecular dioxygen.

Straightforward synthesis of quinolines from enones and 2-aminobenzyl alcohols using an iridium-catalyzed transfer hydrogenative strategy by Biao Xiong; Yingying Wang; Yuan Liu; Yandan Bao; Zhaoguo Liu; Yanan Zhang; Yong Ling (5707-5711).
A new protocol for the direct synthesis of quinolines from enones and 2-aminobenzyl alcohols via iridium-catalyzed transfer hydrogenative reactions has been demonstrated. This method employs easily available [IrCp*Cl2]2/t-BuOK as the efficient catalyst system, proceeding with the merits of high step- and atom efficiency, mild reaction conditions and operational simplicity. The experimental studies suggest that the reactions start with transfer hydrogenation, followed by the Friedländer reaction to give the final products.

Electro-active polychromophoric assemblies that undergo clam-like electromechanic actuation represent an important class of organic functional materials. Here, we show that the readily available cyclotetraveratrylene (CTTV) undergoes oxidation-induced folding, consistent with interconversion from a non-cofacial “sofa” conformation to a cofacial “boat” conformer. It is found that the non-cofacial “sofa” conformer of CTTV forms stable electron donor–acceptor complexes with chloranil and DDQ. Electron-transfer induced conformational transformation in CTTV provides a framework for the rational design of novel organic functional molecules.

Correction for ‘A facile and high-yield formation of dipyrrin-boronic acid dyads and triads: a light-harvesting system in the visible region based on the efficient energy transfer’ by Masaki Yamamura et al., Org. Biomol. Chem., 2015, 13, 2574–2581.

Correction: Directed nucleophilic addition of phenoxides to cyclopropenes by Pavel Yamanushkin; Michael Lu-Diaz; Andrew Edwards; Nicolai A. Aksenov; Marina Rubina; Michael Rubin (5719-5719).
Correction for ‘Directed nucleophilic addition of phenoxides to cyclopropenes’ by Pavel Yamanushkin et al., Org. Biomol. Chem., 2017, 15, 8153–8165.

Back cover (5721-5722).