Organic & Biomolecular Chemistry (v.14, #15)

Front cover (3657-3658).

Contents list (3659-3665).

Copper-catalyzed carboxylation reactions using carbon dioxide by Sheng Wang; Gaixia Du; Chanjuan Xi (3666-3676).
Carbon dioxide (CO2), as a waste of manufacture, is a cheap and abundant C1 source. Utilization of CO2 for synthesis of carboxylic acids has been developed. Transition-metal complexes play a key role in catalytic carboxylation reactions employing CO2. This review summarizes recent advances in copper-catalyzed carboxylation reactions using CO2. The contents are arranged based on various substrates: organometallic reagents, aryl iodides, sodium sulfinates, terminal alkynes, arenes, heteroarenes, and unsaturated substrates.

The complete tetracyclic core structure of plicamine, a novel Amaryllidaceae-type alkaloid, was expeditously prepared by a Ugi four-component condensation reaction, followed by a one-pot sequential phenolic oxidation and intramolecular coupling process. The employment of this strategy resulted in a rapid, formal synthesis of (±)-plicamine.

Fe-catalyzed synthesis of substituted N-aryl oxazolidines by Siva Murru; Charles Seth Lott; Brandon McGough; Dakota M. Bernard; Radhey S. Srivastava (3681-3685).
A novel iron-catalyzed synthesis of substituted N-aryl oxazolidines was developed via C–N bond formation and methylenation. The reaction of aryl hydroxylamines with allyl alcohols, in the presence of formaldehyde or its equivalents, afforded variety of oxazolidine heterocycles in very good yields. This catalytic method is most effective for para-substituted aryl hydroxylamines and 3-methyl allyl alcohols. Furthermore, acid catalyzed demethylenation of oxazolidines allowed access to N-aryl amino alcohols in good yields.

Two phenyls are better than one or three: synthesis and application of terminal olefin-oxazoline (TOlefOx) ligands by Yi-Shuang Zhao; Jian-Kang Liu; Zhi-Tao He; Jing-Chao Tao; Ping Tian; Guo-Qiang Lin (3686-3689).
A novel terminal olefin-oxazoline ligand was introduced into rhodium-catalyzed asymmetric conjugate addition of arylboronic acids to enones and gave excellent enantioselectivities. The two phenyls proved better than one or three in ligand evaluations.

Efficient visualization of H2S via a fluorescent probe with three electrophilic centres by Sharad Kumar Asthana; Ajit Kumar; Neeraj; Shweta; K. K. Upadhyay (3690-3694).
H2S is a reactive nucleophilic species with toxic effects towards human beings. Its efficient detection and marking is still a challenging job due to its similar nucleophilic character to a number of biothiols, like glutathione, cysteine, homocysteine etc. We report herein the first ever use of a chemosensor incorporating three electrophilic centres to achieve high sensitivity and very fast response time (40 s) towards H2S.

A surprising switch in absolute configuration of anti-inflammatory macrolactones by Johannes Tauber; Markus Rohr; Thorsten Walter; Dieter Schollmeyer; Karin Rahn-Hotze; Gerhard Erkel; Till Opatz (3695-3698).
Oxacyclododecindione-type macrolactones exhibit highly potent anti-inflammatory activities even at nanomolar concentration. After the determination of the relative configuration of the stereocenters at C14 and C15 by total synthesis of 4-dechloro-14-deoxyoxacyclododecindione and 14-deoxyoxacyclododecindione, the absolute configuration has now been assigned by X-ray crystallography. Surprisingly, the absolute configuration is (14S,15R) which differs for C15 from that of the well-known derivatives of (S)-curvularin. The biological activities of both enantiomers of 14-deoxyoxacyclododecindione, obtained by racemic synthesis and optical resolution, were investigated and the ring conformation of the natural product was compared to that of (S)-curvularin and (R)-dehydrocurvularin.

Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator by Tony M. Banks; Samuel F. Clay; Stephen A. Glover; Rhiannon R. Schumacher (3699-3714).
N-Acyloxy-N-alkoxyamides are direct-acting mutagens in S. typhimurium TA100 with a linear dependence upon log P that maximises at log P0 = 6.4. Eight N-acyloxy-N-alkoxyamides (2–9) bearing a naphthalene group on any of the three side-chains and with log P0 < 6.4 have been demonstrated to be significantly and uniformly more mutagenic towards S. typhimurium TA100 than 50 mutagens without naphthalene. The activity enhancement of 2–9 is likely due to intercalative binding of naphthalene to bacterial DNA as a number are also active in TA98, a frame-shift strain of S. typhimurium, which is modified by intercalators. DNA damage profiles for naphthalene-bearing mutagens confirm enhanced reactivity with DNA when naphthalene is incorporated and a different binding mode when compared to mutagens without naphthalene. The effect is independent of whether the naphthalene is attached to an electron-donating alkyl or electron-withdrawing acyl group, alkyl tether length or, in the case of 6 and 7, the point of attachment to naphthalene. A new quantitative structure activity relationship has been constructed for all 58 congeners incorporating log P and an indicator variable, I, for the presence (I = 1) or absence (I = 0) of naphthalene and from which the activity enhancing effect of a naphthalene has been quantified at between three and four log P units. Contrary to conventional views, simple naphthalene groups could target molecules to DNA through intercalation.

There is an ever-increasing need to design better methods to selectively connect two molecules under mild aqueous conditions on a small scale. The process of finding such methods significantly relies on the employment of an appropriate assay. We report here a modular FRET-based assay to monitor such reactions and illustrate how the assay is used to monitor two particular reactions: native chemical ligation (NCL) and oxime ligation. For both reactions we show that by employing appropriately designed probes FRET measurements could be used to monitor the reaction's progress. We additionally demonstrate the usefulness of the developed probe system to study the mechanisms of the ligation reactions, for example, in monitoring the formation of a trimeric intermediate in the NCL reaction. Finally, we demonstrate that FRET measurements conducted in our system allow the quantification of the reaction yield and we show the application of our FRET-based assay to catalyst screening for the oxime ligation.

The β-phosphorus hyperfine coupling constant in nitroxides: 6. Solvent effects in non-cyclic nitroxides by Gérard Audran; Lionel Bosco; Paulin Nkolo; Raphael Bikanga; Paul Brémond; Teddy Butscher; Sylvain R. A. Marque (3729-3743).
In two recent articles (Org. Biomol. Chem., 2015 and 2016), we showed that changes in the phosphorus hyperfine coupling constant aP at position β in β-phosphorylated nitroxides can be dramatic. Such changes were applied to the titration of water in organic solvents and conversely of organic solvents in water. One of the molecules tested was a non-cyclic nitroxide meaning that a thorough investigation of the solvent effect on the EPR hyperfine coupling constant is timely due. In this article, we show that the aP of persistent non-cyclic β-phosphorylated nitroxides decrease with the normalized polarity Reichardt's constant ENT. The Koppel–Palm and Kalmet–Abboud–Taft relationships were applied to gain deeper insight into the effects influencing aN and aP: polarity/polarizability, hydrogen bond donor properties, and the structuredness of the cybotactic region.

Evaluation of the transfection efficacies of quaternary ammonium salts prepared from sophorolipids by E. I. P. Delbeke; O. Lozach; T. Le Gall; M. Berchel; T. Montier; P.-A. Jaffrès; K. M. Van Geem; C. V. Stevens (3744-3751).
Five quaternary ammonium amphiphilic compounds were synthesized from sophorolipid 1. These compounds were formulated in aqueous media and some of them (5 and 6) produced well-defined supramolecular aggregates which were characterized by DLS and zeta measurements. Their capacity to transfect four different eukaryotic cell lines in vitro was assessed. To evaluate the influence of the carbohydrate head group from the sophorolipids on the transfection efficacies, their deglycosylated analogues were also synthesized and tested for gene delivery. For all the compounds, the use of DOPE as a helper lipid in a 1 : 1 molar ratio with the ammonium-based lipids was required to obtain homogeneous formulations. The transfection results indicate that quaternary ammonium-based sophorolipids proved to be more efficient pDNA carriers than their deglycosylated counterparts. Moreover, the presence of the carbohydrate head group clearly contributed to the good biocompatibility of these cationic lipids. These cationic sophorolipid derivatives thus offer good potential for the development of new vectors for gene delivery based on renewable resources.

The absorbance and fluorescence spectra of carboxylated spiropyrans containing methyl-1-aza-12-crown-4, methyl-1-aza-15-crown-5, methyl-1-aza-18-crown-6 moieties are compared. Characteristic changes in spectra after addition of the alkali metal salts of Li+, Na+, K+ and Cs+ were observed. Chromism induced by the binding of the metal cations was observed as an increase in absorbance and fluorescence. Of these metal cations, the Li+ ion produced the largest change in all three spiropyran systems. Reversible photoswitching of the spiropyran-metal complexes was observed on irradiation with alternating 352 nm UV and white light. This results in reversible fluorescence based sensing of lithium ions with potential for use in a biological sensor device.

A novel fast, convenient and inexpensive synthesis of 1′,3′-dioxo-1′,3′-dihydrospiro[cyclopropane-1,2′-indene]-2,2,3,3-tetracarbonitrile and dimethyl 2,3-dicyano-1′,3′-dioxo-1′,3′-dihydrospiro[cyclopropane-1,2′-indene]-2,3-dicarboxylate is reported. These compounds undergo double carbanion cleavage under the action of alcohols resulting in the formation of stable salts, containing new allylic-type anions with potential application in organic electronics and as ionic liquid components.

The synthesis of a series of adenosine A3 receptor agonists by Kenneth J. Broadley; Erica Burnell; Robin H. Davies; Alan T. L. Lee; Stephen Snee; Eric J. Thomas (3765-3781).
A series of 1′-(6-aminopurin-9-yl)-1′-deoxy-N-methyl-β-d-ribofuranuronamides that were characterised by 2-dialkylamino-7-methyloxazolo[4,5-b]pyridin-5-ylmethyl substituents on N6 of interest for screening as selective adenosine A3 receptor agonists, have been synthesised. This work involved the synthesis of 2-dialkylamino-5-aminomethyl-7-methyloxazolo[4,5-b]pyridines and analogues that were coupled with the known 1′-(6-chloropurin-9-yl)-1′-deoxy-N-methyl-β-d-ribofuranuronamide. The oxazolo[4,5-b]pyridines were synthesized by regioselective functionalisation of 2,4-dimethylpyridine N-oxides. The regioselectivities of these reactions were found to depend upon the nature of the heterocycle with 2-dimethylamino-5,7-dimethyloxazolo[4,5-b]pyridine-N-oxide undergoing regioselective functionalisation at the 7-methyl group on reaction with trifluoroacetic anhydride in contrast to the reaction of 4,6-dimethyl-3-hydroxypyridine-N-oxide with acetic anhydride that resulted in functionalisation of the 6-methyl group. To optimise selectivity for the A3 receptor, 5-aminomethyl-7-bromo-2-dimethylamino-4-[(3-methylisoxazol-5-yl)methoxy]benzo[d]oxazole was synthesised and coupled with the 1′-(6-chloropurin-9-yl)-1′-deoxy-N-methyl-β-d-ribofuranuronamide. The products were active as selective adenosine A3 agonists.

Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups by George M. Burslem; Hannah F. Kyle; Panchami Prabhakaran; Alexander L. Breeze; Thomas A. Edwards; Stuart L. Warriner; Adam Nelson; Andrew J. Wilson (3782-3786).
α-Helix proteomimetics represent an emerging class of ligands that can be used to inhibit an array of helix mediated protein–protein interactions. Within this class of inhibitor, aromatic oligobenzamide foldamers have been widely and successfully used. This manuscript describes alternative syntheses of these compounds that can be used to access mimetics that are challenging to synthesize using previously described methodologies, permitting access to compounds functionalized with multiple sensitive side chains and accelerated library assembly through late stage derivatisation.

Modelling flavoenzymatic charge transfer events: development of catalytic indole deuteration strategies by Alexander T. Murray; Jonathan D. Challinor; Christina E. Gulácsy; Cristina Lujan; Lauren E. Hatcher; Christopher R. Pudney; Paul R. Raithby; Matthew P. John; David R. Carbery (3787-3792).
The formation and chemistry of flavin–indole charge transfer (CT) complexes has been studied using a model cationic flavin. The ability to form a CT complex is sensitive to indole structure as gauged by spectroscopic, kinetics and crystallographic studies. Single crystals of sufficient quality of a flavin–indole CT complex, suitable for X-ray diffraction, have been grown, allowing solid-state structural analysis. When CT complex formation is conducted in d4-methanol, an efficient and synthetically useful C-3 indole deuteration is observed.

Tuning the photophysical properties of 4′-substituted terpyridines – an experimental and theoretical study by Anna Maroń; Agata Szlapa; Tomasz Klemens; Slawomir Kula; Barbara Machura; Stanisław Krompiec; Jan Grzegorz Małecki; Anna Świtlicka-Olszewska; Karol Erfurt; Anna Chrobok (3793-3808).
Several 2,2′:6′,2′′-terpyridines substituted in the 4′-position were synthesized and their photophysical properties were investigated by absorption and photoluminescence spectroscopy in dilute solutions and solid state. The studies confirmed that the absorption and emission wavelengths, fluorescence quantum yields and lifetimes of 1-R1–16 are strongly structure-related, demonstrating a decisive role of the nature of the substituent in determining the photophysical properties of 4′-functionalized terpyridines. Additionally, the density functional theory (DFT) calculations were performed for 1-R1–16 to get insight into their electronic structure and spectroscopic properties.

Pd(0)-catalyzed cross-coupling of allyl halides with α-diazocarbonyl compounds or N-mesylhydrazones: synthesis of 1,3-diene compounds by Kang Wang; Shufeng Chen; Hang Zhang; Shuai Xu; Fei Ye; Yan Zhang; Jianbo Wang (3809-3820).
With palladium catalysis, allyl bromides or chlorides react with α-diazocarbonyl compounds or N-mesylhydrazones to afford 1,3-diene derivatives. The reaction represents a novel and efficient method for the synthesis of 1,3-butadiene derivatives. Mechanistically, the reaction is proposed to follow a pathway involving the formation of a π-allylic palladium carbene complex and subsequent migratory insertion.

A major reason for the low success rate in current drug development through chemical synthesis has been ascribed to the large fraction of quasi planar candidate molecules. Therefore, an “escape from flatland” strategy has been recommended for the generation of bioactive chemical entities. In a first attempt to test this recommendation, we synthesized a small collection of bridged bicyclic compounds possessing a rigid spherical core structure by combining a group of cyclic dienes with a collection of dienophiles. We started from planar biphenyl analogues and, by enzymatic dioxygenation, transformed them into hydroxylated diene structures. Using a small library of newly synthesized dienophiles, the dienes were converted into bridged bicycles via the Diels–Alder reaction. The resulting collection of 78 structures was first tested for bioactivity in a generic assay based on interference with the proliferation of mammalian cells. A more mechanism-targeted bioactivity profiling method, exploiting cellular impedance monitoring, was subsequently used to obtain suggestions for the mode of action exerted by those compounds that were the most active in the proliferation assay. Proteasome inhibition could be confirmed for 8 of a series of 9 respective candidates. Whilst 7 of these molecules showed relatively weak interference with proteasome activity, one candidate exerted a moderate but distinct inhibition. This result appears remarkable in view of the small size of the compound library, which was synthesized following a few basic considerations. It encourages the application of diverse synthetic approaches to further investigate the role of spherical shape for the success of compound libraries.

Correction: New synthesis of phenyl-isothiocyanate C-functionalised cyclams. Bioconjugation and 64Cu phenotypic PET imaging studies of multiple myeloma with the te2a derivative by Zakaria Halime; Mathieu Frindel; Nathalie Camus; Pierre-Yves Orain; Marie Lacombe; Karine Bernardeau; Michel Chérel; Jean-François Gestin; Alain Faivre-Chauvet; Raphaël Tripier (3838-3838).
Correction for ‘New synthesis of phenyl-isothiocyanate C-functionalised cyclams. Bioconjugation and 64Cu phenotypic PET imaging studies of multiple myeloma with the te2a derivative’ by Zakaria Halime et al., Org. Biomol. Chem., 2015, 13, 11302–11314.

Back cover (3839-3840).