Organic & Biomolecular Chemistry (v.12, #22)

Front cover (3515-3515).

Inside front cover (3516-3516).

Contents list (3517-3525).

Phosphate esters and anhydrides – recent strategies targeting nature's favoured modifications by Henning J. Jessen; Nisar Ahmed; Alexandre Hofer (3526-3530).
Esters and anhydrides of phosphoric acid are essential in biology. It is very difficult to identify processes in life that do not involve these modifications and their transformation at some point. Consequently, phosphorylation chemistry is an essential methodology with significant impact on the biological sciences. This perspective gives an overview of some very recent achievements in synthetic phosphorylation chemistry and aims at identifying challenges that lie ahead.

Catalytic, enantioselective vinylogous Michael reactions by Christoph Schneider; Falko Abels (3531-3543).
Recent progress in the field of catalytic, enantioselective vinylogous Michael reactions of latent dienolates is described which furnish optically highly enriched chiral 1,7-dioxo compounds of great utility in one synthetic operation. Emphasis is given to new catalysis modes which realise this challenging transformation with high regio- as well as enantioselectivity.

Self-assembly of peptides to nanostructures by Dindyal Mandal; Amir Nasrolahi Shirazi; Keykavous Parang (3544-3561).
The formation of well-ordered nanostructures through self-assembly of diverse organic and inorganic building blocks has drawn much attention owing to their potential applications in biology and chemistry. Among all organic building blocks, peptides are one of the most promising platforms due to their biocompatibility, chemical diversity, and resemblance to proteins. Inspired by the protein assembly in biological systems, various self-assembled peptide structures have been constructed using several amino acids and sequences. This review focuses on this emerging area, the recent advances in peptide self-assembly, and formation of different nanostructures, such as tubular structures, fibers, vesicles, and spherical and rod–coil structures. While different peptide nanostructures have been discovered, potential applications are explored in drug delivery, tissue engineering, wound healing, and surfactants.

A novel synthetic approach to the bicyclo[5.3.1]undecan-11-one framework of vinigrol by Xian-Lei Wang; Yun-Yu Lu; Jie Wang; Xuan Wang; He-Quan Yao; Guo-Qiang Lin; Bing-Feng Sun (3562-3566).
The first synthetic attempt commencing from an eight-membered ring to approach the [5.3.1] bicyclic core of vinigrol has demonstrated the feasibility of using the conformational bias of the cyclooctane-ring system to realize highly diastereoselective reactions. The synthetic potential of the newly disclosed access to in/out isomerism may stimulate broader interests.

Efficient intramolecular N/O-nucleophilic cyclization of 2-aryl indoles has been developed to afford the corresponding 2-aza-3-oxaindolines and 3-indolinones in 80–95% yield. The methods provided convenient access to fused imidazo[1,2-c]oxazolidinone, oxazolidine, or tetrahydro-1,3-oxazine cores under mild conditions.

A domino addition–lactonization pathway has been applied to a dynamic covalent resolution protocol, leading to efficient oxathiazinanone formation as well as chiral discrimination. A new, double biocatalytic pathway has furthermore been proposed and evaluated where the initial product inhibition could be efficiently circumvented.

An easy arylation of 2-substituted 1,2,3-triazoles by Suping Shi; Wei Liu; Ping He; Chunxiang Kuang (3576-3580).
A selective, efficient and catalytic ligand-free method for the direct arylation of 2-aryl-1,2,3-triazoles via Pd-catalyzed C–H bond activation is described. The process smoothly proceeds in moderate to excellent yields.

Peptide-catalyzed consecutive 1,6- and 1,4-additions of thiols to α,β,γ,δ-unsaturated aldehydes by Kengo Akagawa; Nobuhiro Nishi; Jun Sen; Kazuaki Kudo (3581-3585).
Regio- and enantioselective addition of thiols to α,β,γ,δ-unsaturated aldehydes was performed with a resin-supported peptide catalyst. It was shown that a 1,4-adduct was generated mainly at the initial stage of the reaction, and this was eventually converted to a thermodynamically stable 1,6- and 1,4-diadduct through retro-addition/addition reactions.

The base discriminating potential of pyrrolidinyl PNA demonstrated by magnetic FexOy particles by Claudia Stubinitzky; Tirayut Vilaivan; Hans-Achim Wagenknecht (3586-3589).
Pyrrolidinyl PNA was immobilized on FexOy magnetic particles and was able to capture and thereby discriminate single base alterations in DNA counterstrands better than DNA. The selectivities of matched vs. mismatched oligonucleotides measured by the absorption differences were up to 10–12 which are remarkable values for linear probes.

Palladium-catalyzed three-component reaction of N-tosylhydrazone, norbornene and aryl halide by Fangdong Hu; Ying Xia; Zhenxing Liu; Chen Ma; Yan Zhang; Jianbo Wang (3590-3593).
A palladium-catalyzed three-component reaction of N-tosylhydrazone, norbornene and aryl halide has been demonstrated. In this reaction, an intermolecular Heck-type reaction occurs, which is followed by the alkyl palladium carbene migratory insertion process. This transformation provides an efficient and convenient methodology for the double functionalization of norbornene with good to excellent yields.

Rh(iii)-catalyzed regioselective hydroarylation of alkynes via directed C–H functionalization of pyridines by Zhen-Chao Qian; Jun Zhou; Bo Li; Fang Hu; Bing-Feng Shi (3594-3597).
Rh(iii)-catalyzed C-3 selective alkenylation of pyridine derivatives via hydroarylation of alkynes has been developed. The reaction shows high regioselectivity, high yield and good functional group tolerance, providing a convenient strategy for the synthesis of trisubstituted (pyridin-3-yl)alkenes.

Practically convenient and industrially-aligned methods for iridium-catalysed hydrogen isotope exchange processes by A. R. Cochrane; C. Idziak; W. J. Kerr; B. Mondal; L. C. Paterson; T. Tuttle; S. Andersson; G. N. Nilsson (3598-3603).
The use of alternative solvents in the iridium-catalysed hydrogen isotope exchange reaction with developing phosphine/NHC Ir(i) complexes has identified reaction media which are more widely applicable and industrially acceptable than the commonly employed chlorinated solvent, dichloromethane. Deuterium incorporation into a variety of substrates has proceeded to deliver high levels of labelling (and regioselectivity) in the presence of low catalyst loadings and over short reaction times. The preparative outputs have been complemented by DFT studies to explore ligand orientation, as well as solvent and substrate binding energies within the catalyst system.

Gorlos-Phos for palladium-catalyzed borylation of aryl chlorides by Pengbin Li; Chunling Fu; Shengming Ma (3604-3610).
Using a readily available form of the mono-phosphine ligand, Gorlos-Phos·HBF4, Pd-catalyzed borylation of aryl chlorides afforded aryl boronates in high yields. A variety of functional groups are well compatible with this palladium catalyzed borylation reaction.

Continuous flow chemistry: a discovery tool for new chemical reactivity patterns by Jan Hartwig; Jan B. Metternich; Nikzad Nikbin; Andreas Kirschning; Steven V. Ley (3611-3615).
Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.

A new asymmetric total synthesis of a phenanthroindolizidine alkaloid (S)-tylophorine is reported, which features a catalytic asymmetric allylation of aldehydes and an unexpected one-pot DMAP promoted isocyanate formation and Lewis acid catalyzed intramolecular cyclization reaction. In addition, White's direct C–H oxidation catalyst system converting monosubstituted olefins to linear allylic acetates was also employed for late-stage transformation.

Cyclodextrin ion channels by Jonathan K. W. Chui; T. M. Fyles (3622-3634).
Seventeen derivatives of α- and β-cyclodextrins were prepared from the cyclodextrin per-6-azide by “click” cyclization with terminal alkynes. Sixteen of these “half-channel” compounds showed significant activity as ion channels in planar bilayer members as assessed by the voltage-clamp technique. Activity ranged from persistent square-top openings to highly erratic conductance; mixed behaviours were evident in virtually all data recorded. Some of the erratic behaviours were shown to follow an apparent power-law distribution of open duration times. The activities observed for the suite were summarized using a model-free activity grid method which displays conductance, duration, and opening behaviour. The overall activity shows the clustering of conductance–duration indicating that activity arises from system properties rather that solely as a property of the compound. The activity grids also support an analysis of structure–activity relationships as they apply to the global behaviour of the compounds and reveal the complexity of a single structure change in controlling the distribution of concurrent conductance behaviours. Transient blockage of channel activity by the hydrophobic guest of the cyclodextrin (1-adamantyl carboxylate) is consistent with the formation of an end-to-end dimer channel among several other competing and interconverting structures.

Silyl alkynylphosphine-boranes: key precursors of triazolylphosphines via tandem desilylation-Click chemistry by Romain Veillard; Elise Bernoud; Ibrahim Abdellah; Jean-François Lohier; Carole Alayrac; Annie-Claude Gaumont (3635-3640).
A versatile synthesis of 1,2,3-triazolyl-4-phosphines from the borane complexes of phosphino-alkynes is reported. The efficiency of the procedure relies on the use of readily available silyl-protected alkynylphosphine-boranes, which were subjected to desilylation with TBAF followed by copper-catalyzed azide–alkyne-cycloaddition in one pot. Subsequent treatment with DABCO afforded the targeted triazolylphosphines in high yields. The reported method was applied to the synthesis of the first example of an enantioenriched P-stereogenic triazolylphosphine (98.8% ee).

Fluorescent push–pull pH-responsive probes for ratiometric detection of intracellular pH by Martin Ipuy; Cyrielle Billon; Guillaume Micouin; Jacques Samarut; Chantal Andraud; Yann Bretonnière (3641-3648).
A family of fluorescent push–pull pH-responsive probes based on 2-dicyanomethylidene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran as a strong electron acceptor group is described. Small structural variations allow obtaining pKa ranging from 4.8 to 8.6, underlining the role of the substituent in modulating the acidic properties. Remarkable changes in the optical properties (in particular the fluorescence intensity ratios) were observed as a function of pH. The most interesting probes with pKa close to neutrality were used for ratiometric imaging of intracellular pH.

Three novel diglycerol tetraether lipids with one membrane-spanning chain have been synthesized. These lipids contain only two or four racemic methyl branches at selected positions of the hydrophobic chains in contrast to natural lipids from archaebacterial membranes with an isoprenoid substitution pattern. The insertion of the methyl moieties was realized starting from either (RS)-citronellyl bromide or the inexpensive methyl malonic acid ethyl ester. For chain elongation the Cu-catalysed Grignard coupling reaction was used. The preparation of diglycerol tetraethers was either performed by condensing suitable blocked monoglycerol diethers by Grubbs metathesis or by reaction of the transmembrane C32-chain with blocked glycerols followed by further alkylation steps. Finally, we could show that the resulting lipids can form closed lipid vesicles comparable to the optically pure counterparts. Therefore, these much simpler lipids compared to the natural lipids from archaebacterial membranes are also suitable for preparation of stable tailored liposomes.

In this study, 5,10,15-tri[p(9-methoxy-triethyleneoxy)phenyl]-20-[p-phenylisophthalate-β-cyclodextrin]porphyrin, a compound containing a porphyrin and a β-cyclodextrin unit covalently linked by means of an isophthalic bridge, was synthesized and characterized by NMR, MALDI-TOF mass spectrometry and UV-vis and circular dichroism spectroscopies. This porphyrin/β-cyclodextrin system, with the porphyrin unit connected to the lower rim (OH-2) of the cyclodextrin structure, is water-soluble and no evidence of a self-assembly arrangement between the porphyrin and cyclodextrin units appears. In this way, the β-cyclodextrin cavities remain free, retaining their potential ability of drug-delivery, with the spectroscopic advantage induced by the high absorbance of the porphyrin unit. Furthermore, the porphyrin unit, interacting with the guest and acting as a lid, could have a role in the controlled release process of the drug.

Microwave-assisted one-pot synthesis and anti-biofilm activity of 2-amino-1H-imidazole/triazole conjugates by Hans Steenackers; Denis Ermolat'ev; Tran Thi Thu Trang; Bharat Savalia; Upendra K. Sharma; Ami De Weerdt; Anamik Shah; Jozef Vanderleyden; Erik V. Van der Eycken (3671-3678).
A microwave-assisted protocol was developed for the construction of 2-amino-1H-imidazole/triazole conjugates starting from the previously described 2-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium salts. The process involves a one-pot hydrazinolysis/Dimroth-rearrangement of these salts followed by a ligand-free copper nanoparticle-catalyzed azide–alkyne Huisgen cycloaddition. The 2-amino-1H-imidazole/triazole conjugates showed moderate to high preventive activity against biofilms of S. Typhimurium, E. coli, P. aeruginosa and S. aureus. The most active compounds had BIC50 values between 1.3 and 8 μM. A remarkable finding was that introduction of the triazole moiety into the side chain of 2-aminoimidazoles with a long (C8–C13) 2N-alkyl chain did drastically improve their activity. Conclusively, the 2-amino-1H-imidazole/triazole scaffold provides a lead structure for further design and development of novel biofilm inhibitors.

Synthesis of homochiral tris-indanyl molecular rods by Niels Due Kjeldsen; Erik Daa Funder; Kurt V. Gothelf (3679-3685).
Homochiral tris-indanyl molecular rods designed for supramolecular surface self-assembly were synthesized. The chiral indanol moiety was constructed via a Ti-mediated alkyne trimerization. Further manipulations resulted in a homochiral indanol monomer. This was employed as the precursor for successive Sonogashira and Ohira–Bestman reactions towards the homochiral tris-indanyl molecular rods. The molecular rods will be applied for scanning tunnelling microscopy studies of their surface self-assembly and chirality.

Asymmetric synthesis of 3,3,5,5-tetrasubstituted 1,2-dioxolanes: total synthesis of epiplakinic acid F by Xiang-Yin Tian; Jian-Wei Han; Qiong Zhao; Henry N. C. Wong (3686-3700).
The first enantioselective total synthesis of epiplakinic acid F (1) was achieved through a pivotal step involving a radical-mediated asymmetric peroxidation of vinylcyclopropanes with molecular oxygen to construct highly substituted 1,2-dioxolanes. Subsequent conversions of the chiral 1,2-dioxolanes led to total synthesis of epiplakinic acid F (1) and the confirmation of its absolute configuration. The enantiomer of epiplakinic acid F methyl ester (2) was also prepared.

Combining metal–anion coordination and π–π stacking interactions, a zinc complex of a novel anthracene-based cyclophane was designed to recognise adenine nucleoside polyphosphates. This complex was found to show selective fluorescence enhancement for ATP, ADP, AMP and PPi in neutral aqueous solution. Among them, ADP induced the largest fluorescence change to the complex, while ATP showed the strongest binding affinity to the complex. This property was used to sense ATP in the presence of excess amounts of other phosphates such as ADP, AMP, PPi and Pi.

Synthesis of novel 1,2,3-triazolyl derivatives of pregnane, androstane and d-homoandrostane. Tandem “click” reaction/Cu-catalyzed d-homo rearrangement by Yury N. Kotovshchikov; Gennadij V. Latyshev; Nikolay V. Lukashev; Irina P. Beletskaya (3707-3720).
Copper-catalyzed 1,3-dipolar cycloaddition has been employed in the reaction of steroidal azides with various terminal alkynes. A number of novel 1,2,3-triazolyl derivatives of pregnane, androstane and d-homoandrostane were obtained in high yield (70–98%). The developed synthetic protocols allowed us to attach the triazolyl moiety to both the side chain and the steroidal backbone directly, despite the steric hindrance exerted by the polycyclic system. The presence of Cu(ii) was shown to evoke d-homo rearrangement under mild conditions. A rational choice of the copper precatalyst permitted us to carry out the “click” reaction either along with tandem d-homo rearrangement or in the absence of this process. The tendency of 16-heterosubstituted steroids to undergo d-homo rearrangement under Cu(ii) catalysis was studied.

Design and synthesis of 3,3′-biscoumarin-based c-Met inhibitors by Jimin Xu; Jing Ai; Sheng Liu; Xia Peng; Linqian Yu; Meiyu Geng; Fajun Nan (3721-3734).
A library of biscoumarin-based c-Met inhibitors was synthesized, based on optimization of 3,3′-biscoumarin hit 3, which was identified as a non-ATP competitive inhibitor of c-Met from a diverse library of coumarin derivatives. Among these compounds, 38 and 40 not only showed potent enzyme activities with IC50 values of 107 nM and 30 nM, respectively, but also inhibited c-Met phosphorylation in BaF3/TPR-Met and EBC-1 cells.

An efficient one-pot synthetic approach towards β-methylstyrenes is reported. The transformation, based on sequential homobimetallic catalysis, involves a Stille cross-coupling reaction between aryl halides and allyltributylstannane, followed by an in situ palladium-catalyzed conjugative isomerization. The reaction was optimized, and the best results were obtained with 10 mol% Pd(PPh3)2Cl2, 8.0 equiv. LiCl, and 0.5 equiv. PPh3 in diglyme at 130 °C for 12 h. It was demonstrated that the reaction tolerates a wide variety of functional groups.

Aryl ethynyl anthraquinones: a useful platform for targeting telomeric G-quadruplex structures by Claudia Percivalle; Claudia Sissi; Maria Laura Greco; Caterina Musetti; Angelica Mariani; Anna Artese; Giosuè Costa; Maria Lucia Perrore; Stefano Alcaro; Mauro Freccero (3744-3754).
Aryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, by the FRET melting assay, circular dichroism, the DNA synthesis arrest assay and molecular docking. Both the binding properties and G-quadruplex vs. duplex selectivity are controlled by the structures of the aryl ethynyl moieties.

Back cover (3755-3756).