Organic & Biomolecular Chemistry (v.14, #8)

Front cover (2363-2363).

Inside front cover (2364-2364).

Contents list (2365-2372).

The application of design of experiments (DoE) reaction optimisation and solvent selection in the development of new synthetic chemistry by Paul M. Murray; Fiona Bellany; Laure Benhamou; Dejan-Krešimir Bučar; Alethea B. Tabor; Tom D. Sheppard (2373-2384).
This article outlines the benefits of using ‘Design of Experiments’ (DoE) optimisation during the development of new synthetic methodology. A particularly important factor in the development of new chemical reactions is the choice of solvent which can often drastically alter the efficiency and selectivity of a process. Whilst solvent optimisation is usually done in a non-systematic way based upon a chemist's intuition and previous laboratory experience, we illustrate how optimisation of the solvent for a reaction can be carried out by using a ‘map of solvent space’ in a DoE optimisation. A new solvent map has been developed specifically for optimisation of new chemical reactions using principle component analysis (PCA) incorporating 136 solvents with a wide range of properties. The new solvent map has been used to identify safer alternatives to toxic/hazardous solvents, and also in the optimisation of an SNAr reaction.

Insights into structure and redox potential of lignin peroxidase from QM/MM calculations by Ludovic Castro; Luke Crawford; Archford Mutengwa; Jan P. Götze; Michael Bühl (2385-2389).
Redox potentials are computed for the active form (compound I) of lignin peroxidase (LiP) using a suitable QM/MM methodology (B3LYP/SDD/6-311G**//BP86/SVP:CHARMM). Allowing for dynamic conformational averaging, a potential of 0.67(33) V relative to ferrocenium/ferrocene is obtained for the active form with its oxoiron(iv) core. The computed redox potential is very sensitive to the charge distribution around the active site: protonation of titratable residues close to the metal center increases the redox potential, thereby rationalising the known pH dependence of LiP activity. A simple MM-charge deletion scheme is used to identify residues that are critical for the redox potential. Two mutant proteins are studied through homology modelling, E40Q and D183N, which are predicted to have an increased redox potential by 140 mV and 190 mV, respectively, relative to the wild type. These mutant proteins are thus promising targets for synthesis and further exploration toward a rational design of biocatalytic systems for oxidative degradation of lignin.

A K2CO3-catalyzed one-pot protocol involving sequential C–C bond formation and cleavage of aromatic β-diketones with α,β-unsaturated esters is developed to obtain 1,5-ketoesters. The sequential reaction via Michael addition and retro-Claisen condensation proceeds smoothly under mild conditions in up to 98% isolated yield. The mechanism study disclosed that the cascade process involved C–C bond cleavage of aromatic β-diketone as a phenacyl donor under alcoholic alkalescent conditions.

The copper(i)-promoted cross-coupling of 1,2-di(pyrimidin-2-yl) disulfides with aromatic amines and aliphatic amines to deliver C–N coupling products in moderate to good yields is reported in this paper. Central to this strategy is the conversion of disulfides into aryl- and alkyl amines by a copper-promoted chemoselective C–S bond cleavage.

A novel and convenient method for the synthesis of β,γ-unsaturated nitriles using ACCN (1,1′-azobis(cyclohexane-1-carbonitrile)) as a cyano source was described. This reaction was amenable to a broad range of substrates and provided the desired β,γ-unsaturated nitriles containing an all-carbon quaternary carbon center in moderate yields with high selectivity via single electron transfer and decarboxylation.

Azulenium chemistry: towards new derivatives of photochromic dihydroazulenes by Anne Ugleholdt Petersen; Martyn Jevric; Jonas Elm; Stine T. Olsen; Christian G. Tortzen; Anders Kadziola; Kurt V. Mikkelsen; Mogens Brøndsted Nielsen (2403-2412).
Here we present the preparation of a selection of azulenium ions by hydride abstraction from photochromic 1,8a-dihydroazulenes (1,8a-DHAs) incorporating two cyano groups at C-1. The reactivity of the electrophilic tropylium ring of these molecules towards lithium triisopropylsilylacetylide was investigated. The position of attack by the nucleophile depended on the substitution pattern of the azulenium cation but was in general found to occur preferentially at positions C-4, C-5, and C-6, and to a minor extent at positions C-7 and C-8. The outcome was a mixture of non-photochromic, regioisomeric DHAs. One of these compounds containing the ethynyl substituent at position C-4 was partly tautomerized to the photochromic 1,8a-dihydroazulene, which was isolated and its switching properties were investigated by UV-Vis absorption spectroscopy. Upon irradiation, it undergoes a ring-opening reaction to form a vinylheptafulvene (VHF), which in turn returns to the original DHA. The half-life of this reaction was significantly smaller than for a derivative with the alkynyl substituent placed at C-7. This fast switching behavior was according to the calculations explained by an enhancement in the stability of the reactive s-cis conformer of the VHF relative to the, still more stable, s-trans conformer, and by a smaller activation energy for this s-cis conformer to undergo ring-closure.

A one-pot synthesis of 1H-isochromenes and 1,2-dihydroisoquinolines by a I-MCR/Wittig sequence was developed. The reaction of phosphonium salt 5, an acid, an amine (or without), and an isocyanide gave the 1H-isochromenes 7 or 1,2-dihydroisoquinolines 9 in good yields by a sequential Passerini or Ugi condensation and an intramolecular Wittig reaction in the presence of K2CO3.

Palladium-catalyzed direct C–H arylation of pyridine N-oxides with potassium aryl- and heteroaryltrifluoroborates by Mengli Li; Xing Li; Honghong Chang; Wenchao Gao; Wenlong Wei (2421-2426).
An efficient ligand-free Pd(OAc)2-catalyzed selective arylation of pyridine N-oxides using potassium (hetero)aryltrifluoroborates as coupling partners via C–H bond activation was achieved in the presence of TBAI. This approach has a broad substrate scope and shows moderate to high yields.

Synthesis of hydrazinoheterocycles from Morita–Baylis–Hillman adducts of nitroalkenes with azodicarboxylates by Vaijinath Mane; Jyoti Pandey; Narasihmam Ayyagari; Chandan Dey; Raju Kale; Irishi N. N. Namboothiri (2427-2438).
Conjugated nitroalkenes and nitrodienes undergo smooth α-hydrazination with azodicarboxylates through an imidazole catalyzed carbon–heteroatom bond formation under Morita–Baylis–Hillman conditions. The resulting hydrazinonitroalkenes take part in 1,3-dipolar cycloaddition with azide under mild conditions to give hydrazinotriazoles. A [3 + 2] annulation with phenols and naphthols involving Michael addition and cyclization as the key steps lead to arenodihydrofurans bearing a key hydrazinodicarboxylate moiety. Both regioisomers of naphthodihydrofurans could be synthesized by our methodology by employing the appropriate naphthol.

Synthesis of 1,2-biphenylethane based single-molecule diodes by Elena Galán; Mickael L. Perrin; Martin Lutz; Herre S. J. van der Zant; Ferdinand C. Grozema; Rienk Eelkema (2439-2443).
We have described the synthesis of novel biphenylethane-based wires for molecular electronics. Exceptional single-molecule diode behavior was predicted for unsymmetrically substituted biphenylethane derivatives, synthesized here using the so far unexplored unsymmetrically substituted 1,2-bis(4-bromophenyl)ethanes as key intermediates, which were obtained from the corresponding tolane precursor by selective hydrogenation.

One-pot, highly efficient, asymmetric synthesis of ring-fused piperidine derivatives bearing N,O- or N,N-acetal moieties by Ji-Yao Li; Zhi-Long Li; Wei-Wei Zhao; Yan-Kai Liu; Zhi-Ping Tong; Rui Tan (2444-2453).
We successfully expand the application of lactols or cyclic hemiaminals as nucleophiles for the asymmetric synthesis of both N,O- and N,N-acetal moieties contained in the structure of ring-fused piperidine derivatives. This efficient one-pot protocol involves an organocatalyzed asymmetric aza-Diels–Alder reaction and iminium ion induced cyclization sequence to ultimately deliver heterocyclic compounds with excellent stereoselectivity in high yield, containing three continuous stereogenic centers.

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates by Nicholas D. Mullins; Nuala M. Maguire; Alan Ford; Kalyan Das; Eddy Arnold; Jan Balzarini; Anita R. Maguire (2454-2465).
As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

Polar solvent effects on tartaric acid binding by aromatic oligoamide foldamer capsules by Nagula Chandramouli; Mohammed Farrag El-Behairy; Guillaume Lautrette; Yann Ferrand; Ivan Huc (2466-2472).
Aromatic oligoamide sequences able to fold into single helical capsules were functionalized with two types of side chains to make them soluble in various solvents such as chloroform, methanol or water and their propensity to recognize tartaric acid was evaluated. The binding affinities to tartaric acid and binding thermodynamics in different media were investigated by variable temperature 1H NMR and ITC experiments, the two methods giving consistent results. We show that tartaric acid binding mainly rests on enthalpically favourable polar interactions that were found to be sufficiently strong to be effective in the presence of a polar aprotic solvent (DMSO) and even in pure methanol. Binding in water was very weak. The stronger binding interactions were found to be more susceptible to the effect of competitive solvents and compensated by unfavourable entropic effects. Thus, the best host in a less polar medium eventually was found to be the worst host in protic solvents. An interesting case of entropically driven binding was evidenced in methanol.

An exploration of a tandem approach to the sustainable synthesis of N-heterocycles from readily available N-aryl benzylamines or imines and ortho-substituted anilines is described, which demonstrates, for the first time, an important synthetic application of dynamic imine chemistry. The key features to the successful development of this protocol include the utilisation of N-aryl benzylamines as imine precursors in transimination, the occurrence of transimination in acetonitrile in the absence of any catalysts, an intramolecular nucleophilic addition occurring in the newly formed imine causing irreversible transimination, and the tandem event occurring under green conditions.

Rhodium-catalyzed asymmetric ring opening reaction of oxabenzonorbornadienes with amines using ZnI2 as the activator by Xin Xu; Jingchao Chen; Zhenxiu He; Yongyun Zhou; Baomin Fan (2480-2486).
The complex of [Rh(COD)Cl]2 and (R,R)-BDPP was used as an effective catalyst for the asymmetric ring opening reaction of oxabenzonorbornadienes with various amines by employing ZnI2 as the activator. Under the optimized reaction conditions, high enantioselectivities with good yields could be obtained from a wide scope of oxabenzonorbornadienes and amines.

Synthesis of new dicinnamoyl 4-deoxy quinic acid and methyl ester derivatives and evaluation of the toxicity against the pea aphid Acyrthosiphon pisum by Xiubin Li; Lucie Grand; Thomas Pouleriguen; Yves Queneau; Pedro da Silva; Yvan Rahbé; Jean-Luc Poëssel; Sylvie Moebs-Sanchez (2487-2497).
New dicinnamoyl (caffeoyl, feruloyl, ortho and para-coumaroyl) 4-deoxyquinic acid and esters were synthesized by using a new 4-deoxy quinic acid triol intermediate. The optimisation of both coupling and deprotection steps allowed the preparation in good yields of the target products either as the carboxylic acid or the methyl ester form. Eight new compounds were evaluated for their ability to influence the feeding behaviour of the pea aphid Acyrthosiphon pisum. Artificial diet bioassays showed that two compounds are toxic (mortality and growth inhibition) at lower concentrations than the reference 3,5-dicaffeoyl quinic acid.

Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides by Yi Sing Gee; Neils J. M. Goertz; Michael G. Gardiner; Christopher J. T. Hyland (2498-2503).
The in situ reduction of ferrocenyl cyclopropylimines to the corresponding amines triggers a facile oxidative ring-opening to yield the formal four-electron oxidation products: N-ferrocenylmethyl β-hydroxyamides. This process is believed to proceed via generation of a ferrocinium ion in the presence of air, leading to facile formation of a distonic radical cation that is ultimately trapped by oxygen.

Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors by Vera Konieczny; John. G. Stefanakis; Efstratios D. Sitsanidis; Natalia-Anastasia T. Ioannidou; Nikolaos V. Papadopoulos; Konstantina C. Fylaktakidou; Colin W. Taylor; Alexandros E. Koumbis (2504-2514).
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are widely expressed in animal cells, where they mediate the release of Ca2+ from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure–activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca2+ release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP3R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca2+ release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP3Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.

An efficient, environmentally friendly and high-yielding route from inexpensive starting materials to 1,2-dihydroquinolines has been developed. This procedure proceeded via a cascade Friedel–Crafts-type reaction and 6-endo-trig hydroamination under the catalysis of FeCl3·6H2O, involving the formation of two new σ (C–C and C–N) bonds in a single operation for the construction of a 1,2-dihydroquinoline skeleton in good to excellent yields.

With the aid of DFT calculations, the FeBr3-catalyzed skeletal rearrangements of 2-cyclohexanal,2-p-C6H4OMe-propylaldehyde (1A) and 2-phenyl,2-p-C6H4OMe-propylaldehyde (1B) were investigated theoretically. As compared to mono-FeBr3 as a catalyst, the bis-FeBr3 serving as a catalyst is found to be not only enhancing the catalytic efficiency but also improving the product selectivity. For the reaction starting from 1A, the [1,2]-group shift (first step) is rate-determining, and why the Cy shift is the most favored is rationalized in comparison with the p-C6H4OMe and Me shifts. For the reaction starting from 1B, the [1,2]-H shift (second step) is rate-determining although the [1,2]-p-C6H4OMe shift is favored over the [1,2]-phenyl shift. In contrast to the experimental proposal, the newly established H2O/Br joint-assisted H-shift mechanism explains the partial α-H source of the [1,2]-Cy shift product. In addition, we discussed the inherent mechanism that explains why both the [1,2]-p-C6H4OMe and [1,2]-p-C6H4CF3 shifts are more facile than the [1,2]-phenyl shift although the substituents –OMe and –CF3 have opposite electronic behaviors.

Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors by Rob De Vreese; Yves Depetter; Tom Verhaeghe; Tom Desmet; Veronick Benoy; Wanda Haeck; Ludo Van Den Bosch; Matthias D′hooghe (2537-2549).
The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.

Enhancement of N-heterocyclic carbenes on rhodium catalyzed olefination of triazoles by Shixian Zhao; Feifei Wu; Yuyu Ma; Wanzhi Chen; Miaochang Liu; Huayue Wu (2550-2555).
A few rhodium complexes of N-heterocyclic carbenes were prepared through carbene transfer reactions and their structures were characterized by X-ray diffraction analysis. The rhodium complexes of NHCs are found to be efficient catalysts for vinylation of various triazoles via C–H activation. A number of double vinylated triazoles can be obtained in good yields.

Recognition of silver cations by a cucurbit[8]uril-induced supramolecular crown ether by Qing-Xia Geng; Fang Wang; Hang Cong; Zhu Tao; Gang Wei (2556-2562).
The host–guest interaction of cucurbit[8]uril (Q[8]) with a synthesized guest molecule, consisting of naphthalene and viologen moieties bridged by a carbon oxygen chain, was investigated by 1H NMR and UV-Vis spectroscopy. The results indicated the formation of an inclusion complex in a ratio of 1 : 1 with a moderate association constant of Ka = (1.1 ± 0.2) × 106 L mol−1. The formation of this special complex is driven by the markedly enhanced charge-transfer interaction between the electron-rich and electron-deficient guest molecule inside the hydrophobic cavity of Q[8], while the carbon oxygen chain stays outside of Q[8] to form a supramolecular crown ether. Screening of the metal cation substrate suggested that the inclusion complex recognizes Ag+ ions with high selectivity, as shown by UV-Vis spectroscopy.

A new type of N-heterocyclic carbene–PdCl2–(iso)quinoline complexes 3 were successfully achieved in acceptable to good yields from easily available starting materials under mild conditions, and their structures were unambiguously confirmed using X-ray single crystal diffraction. Furthermore, their catalytic activity toward Buchwald–Hartwig arylamination of aryl chlorides with primary and secondary amines was fully tested. Under the optimal reaction conditions, the expected arylated amines can be obtained in high to excellent yields at low catalyst loadings (0.005–0.05 mol%). It may be worth noting here that comparison of these complexes with other well-defined and easily available NHC–Pd(ii) complexes bearing different N-containing ancillary ligands was also carried out, showing their superior catalytic activity over all others.

The effects of an ionic liquid on unimolecular substitution processes: the importance of the extent of transition state solvation by Sinead T. Keaveney; Benjamin P. White; Ronald S. Haines; Jason B. Harper (2572-2580).
The reaction of bromodiphenylmethane and 3-chloropyridine, which proceeds concurrently through both unimolecular and bimolecular mechanisms, was examined in mixtures of acetonitrile and an ionic liquid. As predicted, the bimolecular rate constant (k2) gradually increased as the amount of ionic liquid in the reaction mixture increased, as a result of a minor enthalpic cost offset by a more significant entropic benefit. Addition of an ionic liquid had a substantial effect on the unimolecular rate constant (k1) of the reaction, with at least a 5-fold rate enhancement relative to acetonitrile, which was found to be due to a significant decrease in the enthalpy of activation, partially offset by the associated decrease in the entropy of activation. This is in contrast to the effects seen previously for aliphatic carbocation formation, where the entropic cost dominated reaction outcome. This change is attributed to a lessened ionic liquid–transition state interaction, as the incipient charges in the transition state were delocalized across the neighbouring π systems. By varying the mole fraction of ionic liquid in the reaction mixture the ratio between k1 and k2 could be altered, highlighting the potential to use ionic liquids to control which pathway a reaction proceeds through.

Back cover (2581-2582).