Organic & Biomolecular Chemistry (v.12, #3)

Front cover (385-385).

Inside front cover (386-386).

Contents list (387-393).

Catalytic decarboxylative reactions are attractive as biomimetic reactions and environmentally friendly reaction processes. In this review, the origin and recent development of organocatalytic enantioselective decarboxylative reactions of malonic acid half oxy- or thioesters, or β-ketoacids are summarized.

Ylide mediated carbonyl homologations for the preparation of isatin derivatives by Christina T. Lollar; Katherine M. Krenek; Kevin J. Bruemmer; Alexander R. Lippert (406-409).
An exceptionally mild method for the preparation of isatin derivatives has been developed using a sulfur ylide mediated carbonyl homologation sequence starting from anthranilic acid precursors. This method proceeds at ambient temperature via a sulfur ylide intermediate without the need for protection of the amine or chromatographic isolation of the intermediate ylide. Gentle oxidation of the sulfur ylides provides isatin derivatives with N–H, N-alkyl, N-aryl substitution, electron-rich and electron-poor aromatic rings, and heterocyclic aromatic systems. We anticipate that this method will greatly expand the accessibility of complex isatin derivatives.

Two protocols for oxygenation of aromatic C–H bonds ortho-positioned to the phthalazine ring were developed. The transannulation of the phthalazine ring to a naphthalene moiety by an Inverse Electron Demand Diels–Alder (IEDDA) reaction led to the synthesis of naphtho[2,1-c]chromenes, 1-(ortho-hydroxyaryl)naphthalenes and 6,7-dihydrobenzo[b]naphtho[1,2-d]oxepine. This new strategy based on the utilization of transformable nitrogen heterocycles in C–H functionalization chemistry can be potentially applicable to the synthesis of a broad range of biaryl compounds.

Et4NI-catalyzed amidation of aldehydes and alcohols with ammonium salts by Gao Wang; Qing-Ying Yu; Shan-Yong Chen; Xiao-Qi Yu (414-417).
An efficient method for the oxidative amidation of benzylic aldehydes or alcohols with ammonium salts has been developed for the synthesis of primary amides using Et4NI as the catalyst and tert-butyl hydroperoxide as the oxidant. This amidation reaction is operationally straightforward and provides primary amides in moderate to good yields under mild conditions.

Napyradiomycins CNQ525.510B and A80915C target the Hsp90 paralogue Grp94 by Lauge Farnaes; James J. La Clair; William Fenical (418-423).
The intracellular localization and target of the napyradiomycin congeners CNQ525.510B and A80815C were explored using an immunoaffinity fluorescence (IAF) approach. Semi-synthetic methods were used to prepare probes from napyradiomycin CNQ525.510B and derivative A80815C. The results of confocal microscopy indicated that probes from both natural products localized predominantly within the endoplasmic reticulum (ER) of HCT-116 human colon carcinoma cells. Parallel immunoaffinity precipitation efforts using a monoclonal antibody designed against the IAF tag, resulted in the isolation of an Hsp90 family member. This protein was identified as human Grp94 (hGrp94), by its specific mass spectral signature. This observation was validated by Western blot analyses and by the result of an in vitro Grp94 binding assay. The fact that the napyradiomycins CNQ525.510B and A80815C bind to hGrp94, and their associated probes localize within the ER, suggest the use of these materials as molecular probes for monitoring ER-based chaperone function.

Gadolinium-binding cyclic hexapeptoids: synthesis and relaxometric properties by Chiara De Cola; Gaetano Fiorillo; Alessandra Meli; Silvio Aime; Eliana Gianolio; Irene Izzo; Francesco De Riccardis (424-431).
Two new cyclic hexapeptoids incorporating N-carboxyethylglycine and N-methoxyethylglycine residues are able to efficiently bind Gd3+. Their thermodynamic stabilities and relaxivities have been assessed by 1H-relaxometric investigations.

Stereoselective synthesis of protectin D1: a potent anti-inflammatory and proresolving lipid mediator by M. Aursnes; J. E. Tungen; A. Vik; J. Dalli; T. V. Hansen (432-437).
A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao's chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS–MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material.

In this paper, a visible light excitable ESIPT probe was developed, which was found to be a very promising colorimetric and fluorescent sensor for rapid and selective detection of hydrogen sulfide in aqueous solution. The sensing mechanism and the application of this probe for hydrogen sulfide detection in biological serum and in simulated wastewater samples were investigated.

Double-degradable responsive self-assembled multivalent arrays – temporary nanoscale recognition between dendrons and DNA by Anna Barnard; Paola Posocco; Maurizio Fermeglia; Ariane Tschiche; Marcelo Calderon; Sabrina Pricl; David K. Smith (446-455).
This article reports self-assembling dendrons which bind DNA in a multivalent manner. The molecular design directly impacts on self-assembly which subsequently controls the way these multivalent nanostructures bind DNA – this can be simulated by multiscale modelling. Incorporation of an S–S linkage between the multivalent hydrophilic dendron and the hydrophobic units responsible for self-assembly allows these structures to undergo triggered reductive cleavage, with dithiothreitol (DTT) inducing controlled breakdown, enabling the release of bound DNA. As such, the high-affinity self-assembled multivalent binding is temporary. Furthermore, because the multivalent dendrons are constructed from esters, a second slow degradation step causes further breakdown of these structures. This two-step double-degradation mechanism converts a large self-assembling unit with high affinity for DNA into small units with no measurable binding affinity – demonstrating the advantage of self-assembled multivalency (SAMul) in achieving highly responsive nanoscale binding of biological targets.

Effect of H-bonding and complexation with metal ions on the π-electron structure of adenine tautomers by Olga A. Stasyuk; Halina Szatyłowicz; Tadeusz M. Krygowski (456-466).
Influence of H-bonding and interactions with metals via complexation (probed by HF, F, Li+ and Na+) on structural and π-electronic changes in four of the most stable amino adenine tautomers has been studied in the gas phase using the B3LYP/6-311++G(2d,2p) computational level. It has been found that the presence of the amino group in adenine increases its energetic sensitivity to structural changes caused by tautomeric effects as compared to its analogue deprived of this group (purine). Furthermore, its shape depends not only on tautomerism but also on intermolecular interactions. The observed variability of its pyramidalizations caused by H-bonding indicates the dramatic changes of electron donating/accepting properties of –NH2 as a substituent, which results in a variation of aromaticity of particular rings in adenine tautomers. Bifurcated coordination of metal cations by two nitrogen atoms of adenine is also an important factor influencing aromaticity. The overall range of H-bond strengths is between −4.64 and −26.39 kcal mol−1, whereas energies for Li+ and Na+ complexes are in the ranges −41.45 to −67.50 and −25.04 to −51.39 kcal mol−1, respectively. However, the highest aromaticity changes, expressed by the HOMA index, have been found to be about 24% of the HOMA scale for all types of complexes depending on the location of the intermolecular interaction.

A series of tetrasubstituted fluoroalkene derivatives were synthesized by the reaction of α-fluoro-β-carbonyl benzothiazol-2-yl sulfones with various nucleophiles in good yields with high stereoselectivities. The predominant cis configuration of fluorine and alkynyl groups was observed. A single isomer was obtained when a ketone, acetate or amide was used as the substrate in the presence of a base.

Competitive binding for triggering a fluorescence response in a hydrazodicarboxamide-based [2]rotaxane by José Berná; Carlos Franco-Pujante; Mateo Alajarín (474-478).
The design and synthesis of an interlocked receptor based on a hydrogen bonded [2]rotaxane containing a hydrazodicarboxamide binding site are reported. An anion recognition process with tetrabutylammonium benzoate triggers the submolecular translational movement of its benzylic amide macrocycle developing a progressive increase of the fluorescence intensity, effectively quenched at the original state. The binding of the anion competes with the hydrogen-bond-connected cyclic component for the bis(urea)-based station pushing it towards a stoppered alkyl chain. Moreover, this interlocked system is able to work as a molecular switch restoring its initial state in two ways, either by an ion exchange reaction or by a high yielding oxidation/reduction sequence.

NBD-based colorimetric and fluorescent turn-on probes for hydrogen sulfide by Chao Wei; Qing Zhu; Weiwei Liu; Wenbin Chen; Zhen Xi; Long Yi (479-485).
Hydrogen sulfide (H2S) is an important endogenous signalling molecule and also an important environmental target for detection. New reaction-based colorimetric and fluorescent turn-on probes based on selective thiolyling of NBD (7-nitro-1,2,3-benzoxadiazole) ether were explored for sensing of H2S in aqueous buffer. The syntheses of both probes are simple and quite straightforward. The probes are highly sensitive and selective toward H2S over other biologically relevant species. Probe 1 can be used to directly visualize H2S by the naked eye and shows more than 1000-fold fluorescence increase upon reaction with H2S. Probe 2 is a near-infrared fluorescent sensor for H2S at physiological pH.

Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility by Martin Fisher; Ramkrishna Basak; Arnout P. Kalverda; Colin W. G. Fishwick; W. Bruce Turnbull; Adam Nelson (486-494).
An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.

In situ approach for testing the enantiopurity of chiral amines and amino alcohols by 1H NMR by Sandeep Kumar Mishra; Sachin R. Chaudhari; N. Suryaprakash (495-502).
An in situ approach involving a simple mix and shake method for testing the enantiopurity of primary, secondary and tertiary chiral amines and their derivatives, chiral amino alcohols, by 1H-NMR spectroscopy is developed. The protocol involves the in situ formation of chiral ammonium borate salt from a mixture of C2 symmetric chiral BINOL, trialkoxyborane and chiral amines. The proposed concept was demonstrated convincingly on a large number of chiral and pro-chiral amines and amino alcohols, and also aids the precise measurement of enantiomeric excess. The protocol can be completed in a couple of minutes directly in the NMR sample tube, without the need for any physical separation.

Self-recovering stimuli-responsive macrocycle-equipped supramolecular ionogels with unusual mechanical properties by Zhenhui Qi; Nora L. Traulsen; Paula Malo de Molina; Christoph Schlaich; Michael Gradzielski; Christoph A. Schalley (503-510).
A chiral, crown-ether-functionalized bisurea gelator forms supramolecular gels in ionic liquids. The resulting ionogels show a remarkably high thermal stability with gel–sol transition temperatures (Tgs) reaching more than 100 °C. The mechanical strength of these ionogels is surprisingly high and even comparable to that of cross-linked protein fibres. Furthermore, the ionogels exhibit rapid self-recovery properties after structural damage caused by deformation. Pseudorotaxanes form from the gelators’ benzo[21]crown-7 ethers as the wheels and secondary ammonium ions as the axles despite the competition between that cation and the imidazolium ions of the ionic liquid for crown ether binding. Pseudorotaxane formation as an external chemical stimulus triggers the gel–sol transition of the ionogels.

Protein-mediated dethreading of a biotin-functionalised pseudorotaxane by Stuart T. Caldwell; Catherine Maclean; Mathis Riehle; Alan Cooper; Margaret Nutley; Gouher Rabani; Brian Fitzpatrick; Vincent M. Rotello; Brian O. Smith; Belal Khaled; Patrice Woisel; Graeme Cooke (511-516).
In this article, we describe the synthesis of new biotin-functionalised naphthalene derivatives 3 and 4 and their complexation behaviour with avidin and neutravidin using a range of analytical techniques. We have shown using 2-(4′-hydroxyazobenzene)benzoic acid displacement and ITC experiments, that compounds 3 and 4 have the propensity to form reasonably high-affinity bioconjugates with avidin and neutravidin. We have also demonstrated using 1H NMR, UV-vis and fluorescence spectroscopy that the naphthalene moiety of 3 and 4 facilitates the formation of pseudorotaxane-like structures with 1 in water. We have then investigated the ability of avidin and neutravidin to modulate the complexation between 1 and 3 or 4. UV-vis and fluorescence spectroscopy has shown that in both cases the addition of the protein disrupts complexation between the naphthalene moieties of 3 and 4 with 1.

[2n2π + 2n2π] Cycloadditions: an alternative to forbidden [4π + 4π] processes. The case of nitrone dimerization by David Roca-López; Tomás Tejero; Pierluigi Caramella; Pedro Merino (517-525).
A theoretical study based on (U)M06-2X/cc-pVTZ calculations has been used to investigate the [3 + 3] thermal dimerization of nitrones to 1,4,2,5-dioxadiazinanes in both the gas phase and in dichloromethane solution. Calculations suggest that dimerization of nitrones takes place through a concerted mechanism involving a formal disallowed [4π + 4π] cycloaddition with a free energy barrier of 30.8 kcal mol−1. The corresponding diradical and zwitterionic stepwise mechanisms have also been studied, but the located transition structures are kinetically disfavoured. An alternative mechanism through a five-membered ring intermediate formed by a classical [3 + 2] dipolar cycloaddition can also be discarded. The five-membered ring intermediate is unstable to cycloreversion and its isomerization to the final dioxadiazinane involves a high free energy barrier (68.6 kcal mol−1). Calculations also show that the dimerization process is slower in dichloromethane than in the gas phase owing to the larger polarity of nitrones and that inclusion of diffuse functions at the studied level does not modify the observed results. The apparently disfavoured [3 + 3] dimerization of nitrones can actually be explained as a bispseudopericyclic [2n2π + 2n2π] process in which the favourable FO interactions between the nitrone oxygen and the CN π* bypass the WH-forbidden process.

Substituent effects on the turn-on kinetics of rhodamine-based fluorescent pH probes by William L. Czaplyski; Grace E. Purnell; Courtney A. Roberts; Rebecca M. Allred; Elizabeth J. Harbron (526-533).
Fluorescent turn-on probes based on a rhodamine spirolactam (RSL) structure have recently become a popular means of detecting pH, metal ions, and other analytes of interest. RSLs are colorless and non-fluorescent until the target analyte induces opening of the spirocyclic ring system, revealing the fully conjugated and highly fluorescent rhodamine dye. Among RSLs opened by acid, we have observed wide variation in the kinetics of the fluorescence turn-on process such that some probes would not be usable in situations where a rapid reading is desired or the pH fluctuates temporally. Herein we present a systematic investigation of the fluorescence turn-on kinetics of RSLs to probe the hypothesis that the reaction rates are influenced by the electronic properties of the spirolactam ring system. A series of 8 aniline-derived RSLs with para substituents ranging from electron-donating to electron-withdrawing was prepared from rhodamine B. The fluorescence turn-on rates are observed to increase by a factor of four as the substituent is tuned from methoxy to nitro. This effect is explained in terms of the destabilization of the reaction intermediate by the substituent. As the reaction rates increase across the series, a concomitant increase in fluorescence intensity is also observed. This result is attributed to an increase in the concentration of the fluorescent form of the dye and is consistent with the expected equilibrium properties of this system. These findings are applied to the design of a faster-reacting and more intensely fluorescent RSL pH probe.

More than one non-canonical phosphodiester bond in the G-tract: formation of unusual parallel G-quadruplex structures by Antonella Virgilio; Veronica Esposito; Luciano Mayol; Aldo Galeone (534-540).
In this article, we report an investigation, based on NMR and CD spectroscopic and electrophoretic techniques, of 5′TGGGGT3′ analogues containing two or three 3′-3′ or 5′-5′ inversion sites in the G-run, namely 5′TG3′-3′G5′-5′GGT3′ (Q350), 5′TG3′-3′GG5′-5′GT3′ (Q305), 5′TGG3′-3′G5′-5′GT3′ (Q035), 5′TG3′-3′G5′-5′G3′-3′GT5′ (Q353) and 3′TG5′-5′G3′-3′G5′-5′GT3′ (Q535). Although the sequences investigated contain either no or only one natural 3′-5′ linkage in the G-tract, all modified oligodeoxyribonucleotides (ODNs) have been shown to form stable tetramolecular quadruplex structures. The ability of the 3′-3′ or 5′-5′ inversion sites to affect the glycosidic conformation of guanosines and, consequently, base stacking, has also been investigated. The results of this study allow us to propose some generalizations concerning strand arrangements and the glycosidic conformational preference of residues adjacent to inverted polarity sites. These rules could be of general interest in the design of modified quadruplex structures, in view of their application as G-wires and modified aptamers.

Back cover (541-542).