Organic & Biomolecular Chemistry (v.10, #16)

Front cover (3133-3133).

Inside front cover (3134-3134).

Contents list (3135-3146).

Recent advances and applications of iridium-catalysed asymmetric allylic substitution by Paolo Tosatti; Adam Nelson; Stephen P. Marsden (3147-3163).
Since their discovery in 1997, iridium-catalysed asymmetric allylic substitutions have been developed into a broadly applicable tool for the synthesis of chiral building blocks via C–C and C–heteroatom bond formation. The remarkable generality of these reactions and the high levels of regio- and enantioselectivity that are usually obtained in favour of the branched products have been made possible by a thorough investigation of the catalyst system and its mode of action. Therefore, today the Ir-catalysed asymmetric allylic substitution is a powerful reaction in the organic chemist's repertoire and has been used extensively for several applications. This article aims to provide an overview of the development of iridium catalysts derived from an Ir salt and a chiral phosphoramidite and their application to the enantioselective synthesis of natural products and biologically relevant compounds.

Expedient synthesis of α-substituted fluoroethenes by Samir K. Mandal; Arun K. Ghosh; Rakesh Kumar; Barbara Zajc (3164-3167).
A mild and efficient synthesis of 1-aryl-1-fluoroethenes from benzothiazolyl (aryl)fluoromethyl sulfones and paraformaldehyde, under DBU- or Cs2CO3-mediated conditions at room temperature, is described. A comparable diethyl fluoro(naphthalen-2-yl)methylphosphonate reagent does not react with paraformaldehyde under these mild conditions. The utility of the methodology for synthesis of terminal α-fluoroalkenes bearing electron-withdrawing functionalities is also shown.

α-Oxo gold carbenes generated via intermolecular oxidation of terminal alkynes are shown to be highly electrophilic and can effectively abstract halogen from halogenated solvents such as 1,2-dichloroethane or 1,2-dibromoethane. Chloro/bromomethyl ketones are prepared in moderate efficiencies in one step using Ph3PAuNTf2 as the catalyst and 8-methylquinoline N-oxide as the oxidant.

Selective deuteration of (hetero)aromatic compounds via deutero-decarboxylation of carboxylic acids by Rachel Grainger; Arif Nikmal; Josep Cornella; Igor Larrosa (3172-3174).
A practical, mild and highly selective protocol for the monodeuteration of a variety of arenes and heteroarenes is presented. Catalytic amounts of Ag(i) salts in DMSO/D2O are shown to facilitate the deutero-decarboxylation of ortho-substituted benzoic and heteroaromatic α-carboxylic acids in high yields with excellent levels of deuterium incorporation.

Intramolecular addition of a Si–Si bond across a C–C triple bond occurs in a trans fashion in the presence of rhodium(i) catalysts. The trans-bis-silylation reaction of (2-alkynylphenyl)disilanes affords 3-silyl-1-benzosiloles.

A catalytic metal-free Ritter reaction to 3-substituted 3-aminooxindoles by Feng Zhou; Miao Ding; Jian Zhou (3178-3181).
The first Ritter reaction of 3-substituted 3-hydroxyoxindoles with nitriles, catalyzed by HClO4, is developed, which enables the synthesis of 3-substituted 3-aminooxindoles in good to excellent yield with rich diversity.

A simple, efficient, and non-metal-catalyzed synthetic method for allyl-epoxides and diallyl-epoxides by allylation of α-haloketones and esters with allylmagnesium bromide in mild conditions is reported in this article. It inherited some advantages of the organomagnesium reagents such as availability, operational simplicity and low toxicity.

Design of switchable wettability sensor for paraquat based on clicking calix[4]arene by Guifen Zhang; Xiaolei Zhu; Fajun Miao; Demei Tian; Haibing Li (3185-3188).
A calix[4]arene acetylene (C4AE)-modified gold surface is successfully constructed in situ via click chemistry. The functionalized surface is used for selective recognition of paraquat by a wettability switch. Impedance measurements showed that the surface also expresses recognition for paraquat with a high sensitivity of 10 pM. The recognition mode, based on host–guest inclusion, is studied by computational calculations and the possible mechanism is analyzed.

A mechanism-based fluorescent probe for labeling O6-methylguanine-DNA methyltransferase in live cells by Xin Li; Shijing Qian; Lin Zheng; Bo Yang; Qiaojun He; Yongzhou Hu (3189-3191).
A mechanism-based small molecular fluorescent probe has been developed to label active O6-methylguanine-DNA methyltransferase in live cells.

Cyclization–carbonylation–cyclization coupling reaction of γ-propynyl-1,3-diketones with palladium(ii)-bisoxazoline catalyst by Taichi Kusakabe; Yasuko Kawai; Rong Shen; Tomoyuki Mochida; Keisuke Kato (3192-3194).
Cyclization–carbonylation–cyclization coupling reaction (CCC-coupling reaction) of γ-propynyl-1,3-diketones catalyzed by (box)PdII complexes afforded symmetrical ketones bearing two oxabicyclic groups in moderate to excellent yields.

Highly enantioselective [4 + 2] cycloadditions of allenoates and dual activated olefins catalyzed by N-acyl aminophosphines by Hua Xiao; Zhuo Chai; Dongdong Cao; Hongyu Wang; Jinghao Chen; Gang Zhao (3195-3201).
An asymmetric organocatalytic [4 + 2] cycloaddition between α-substituted allenoates and dual activated olefins using bifunctional N-acyl aminophosphine catalysts is described. The use of 2-cyano acrylate derived olefins led to the first successful incorporation of an electrophile derived from an aliphatic aldehyde into this reaction.

A highly efficient tandem double Friedel–Crafts reaction between indoles and 2-formylbiphenyl derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl) fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products with opposite absolute configuration.

The aza-Morita–Baylis–Hillman reaction of electronically and sterically deactivated substrates by Christoph Lindner; Raman Tandon; Yinghao Liu; Boris Maryasin; Hendrik Zipse (3210-3218).
The aza-Morita–Baylis–Hillman (azaMBH) reaction has been studied for electronically and sterically deactivated Michael acceptors. It is found that electronically deactivated systems can be converted with electron-rich phosphanes and pyridines as catalysts equally well. For sterically deactivated systems clearly better catalytic turnover can be achieved with pyridine catalysts. This is in accordance with the calculated affinities of the catalysts towards different Michael-acceptors.

Hydrogen atom isomerisations within five radical systems (i.e., CH3˙NH/˙CH2NH; CH3O˙/˙CH2OH; ˙CH2SH/CH3S˙; CH3CO2˙/˙CH2CO2H; and HOCH2CH2O˙/HO˙CHCH2OH) have been studied via quantum-mechanical hydrogen tunnelling through reaction barriers. The reaction rates including hydrogen tunnelling effects have been calculated for these gas phase reactions at temperatures from 300 K to 0 K using Wenzel–Kramers–Brillouin (WKB) and Eckart methods. The Eckart method has been found to be unsatisfactory for the last two systems listed above, because it significantly underestimates the width of the reaction barriers for the interconversions. The calculations at all-electron CCSD(T)/CBS level of theory indicate that the barriers for all reactions (forward and reverse) are greater than 100 kJ mol−1, meaning that the chemical reactivity of the reactants is limited in the absence of hydrogen tunnelling. Hydrogen tunnelling, in some cases, enhance rates of reaction by more than 100 orders of magnitude at low temperature, and around 2 orders of magnitude at room temperature, compared to results obtained from canonical variational transition state theory. Tunnelling corrected reaction rates suggest that some of these isomerisation reactions may occur in interstellar media.

(S)-Proline-catalyzed nitro-Michael additions of aldehydes and ketones to β-nitrostyrene were investigated computationally (MP2/6-311+G**//M06-2X/6-31G**). Contrary to what is usually assumed in organocatalysis, the lowest-energy transition states of proline-catalyzed nitro-Michael reactions do not necessarily involve the carboxylic acid group of the proline moiety directing the incoming nitroalkene to the same face through hydrogen bonding. For the aldehyde substrates examined, the TS leading to the major (R,S) product was found to involve the anti-enamine and nitroalkene approaching from the opposite face of the carboxyl group. In the case of ketone substrates, the lowest-energy TSs leading to both enantiomeric products are characterized by the absence of hydrogen bonds and s-cis conformation of the carboxyl group, which functions as an electron donor to stablize the developing iminium. When both hydrogen bonded and non-hydrogen bonded types of TSs are considered, the calculated enantioselectivities for Michael additions of aldehyde and ketone substrates are in good agreement with experimental findings.

A rhodamine appended tripodal receptor as a ratiometric probe for Hg2+ ions by Kumaresh Ghosh; Tanmay Sarkar; Asmita Samadder (3236-3243).
A new rhodamine appended tripodal receptor 1 has been designed and synthesized. The receptor selectively recognizes Hg2+ ions in CH3CN–water (4 : 1, v/v; 10 μM tris HCl buffer, pH 7.0) by displaying a ratiometric change in emission. Additionally, the visual detection is possible by a sharp change in color. The receptor shows in vitro detection of Hg2+ ions in human cervical cancer (HeLa) cells.

The acid-mediated ring opening reactions of α-aryl-lactams by Frank D. King; Stephen Caddick (3244-3252).
4-Aryl-azetidin-2-ones (β-lactams) undergo ring opening with triflic acid to give cinnamamides which, in benzene, react further to give 3-aryl-3-phenyl-propionamides. Prolonged reaction times in benzene give 3,3-diphenyl-propionamide via an aryl/phenyl exchange. Lactams of ring size 7 and higher also ring open, but only 7- and 8-membered rings give pure diphenylalkylamides. AlCl3 only ring opens the 4-aryl-azetidinones.

Intramolecular reductive ketone–alkynoate coupling reaction promoted by (η2-propene)titanium by Christian Schäfer; Michel Miesch; Laurence Miesch (3253-3257).
Intramolecular reductive coupling of cycloalkanones tethered to alkynoates in the presence of (η2-propene)titanium was successfully performed to provide hydroxy-esters in a diastereoselective manner. Subsequent lactonization afforded angularly fused unsaturated tricyclic lactones which represent relevant substructures of numerous bioactive compounds.

Solid-phase-assisted synthesis of targeting peptide–PEG–oligo(ethane amino)amides for receptor-mediated gene delivery by Irene Martin; Christian Dohmen; Carlos Mas-Moruno; Christina Troiber; Petra Kos; David Schaffert; Ulrich Lächelt; Meritxell Teixidó; Michael Günther; Horst Kessler; Ernest Giralt; Ernst Wagner (3258-3268).
In the forthcoming era of cancer gene therapy, efforts will be devoted to the development of new efficient and non-toxic gene delivery vectors. In this regard, the use of Fmoc/Boc-protected oligo(ethane amino)acids as building blocks for solid-phase-supported assembly represents a novel promising approach towards fully controlled syntheses of effective gene vectors. Here we report on the synthesis of defined polymers containing the following: (i) a plasmid DNA (pDNA) binding domain of eight succinoyl-tetraethylenpentamine (Stp) units and two terminal cysteine residues; (ii) a central polyethylene glycol (PEG) chain (with twenty-four oxyethylene units) for shielding; and (iii) specific peptides for targeting towards cancer cells. Peptides B6 and c(RGDfK), which bind transferrin receptor and αvβ3 integrin, respectively, were chosen because of the high expression of these receptors in many tumoral cells. This study shows the feasibility of designing these kinds of fully controlled vectors and their success for targeted pDNA-based gene transfer.

Glycoside and peptide clustering around the octasilsesquioxane scaffold via photoinduced free-radical thiol–ene coupling. The observation of a striking glycoside cluster effect by Mauro Lo Conte; Samuele Staderini; Angela Chambery; Nathalie Berthet; Pascal Dumy; Olivier Renaudet; Alberto Marra; Alessandro Dondoni (3269-3277).
Two series of multivalent octasilsesquioxane glyco- and peptido-conjugates were synthesized using the photoinduced free-radical thiol–ene coupling (TEC). The first series was obtained by coupling C-glycosylpropyl thiols and cysteine containing peptides with the known octavinyl octasilsesquioxane while the second series was obtained by reacting glycosyl thiols with a new octasilsesquioxane derivative displaying eight PEGylated chains functionalized with terminal allyl groups. The evaluation of the binding properties of mannoside and glucoside clusters toward Concanavalin A by Enzyme-Linked Lectin Assay (ELLA) revealed a modest glycoside cluster effect. On the other hand, the PEGylated POSS-based glycocluster featuring eight N-acetyl-glucosamine residues showed high affinity toward Wheat Germ Agglutinin to give a measured IC50 at 3 nM. The calculated relative potency per number of sugar unit (rp/n) was superior to a value of 106, thus revealing the occurrence of a striking glycoside cluster effect.

A NMR and computational study of Smac mimics targeting both the BIR2 and BIR3 domains in XIAP protein by Donatella Potenza; Laura Belvisi; Francesca Vasile; Elisabetta Moroni; Federica Cossu; Pierfausto Seneci (3278-3287).
In this paper we report an extensive NMR analysis of small ligands (Smac mimics) complexed with different constructs of XIAP. The mimics-binding site of XIAP is known as the BIR3 domain – primary, and the linker BIR2 region – secondary site. Interactions between the BIR3 domain and Smac mimics have been extensively studied by X-ray but, as of today, there are scarce data about the interaction between BIR2, or the whole linker–BIR2–BIR3 construct, and Smac mimics. In order to characterize our Smac mimics, we performed a STD NMR study between our 4-substituted, 1-aza-2-oxobicyclo[5.3.0]decane scaffold-based molecules and three different XIAP fragments: single BIR2 and BIR3 domains, and bifunctional linker–BIR2–BIR3. The results were integrated with docking calculations and molecular dynamics simulations. NMR data, which are consistent with biological tests, indicated that the two BIR subunits interact differently with our Smac mimics and suggest that the ligands enter into more intimate contact with the linker–BIR2–BIR3. In conclusion, we observe that the SMAC mimics showed with the construct linker–BIR2–BIR3 a series of NOE contacts that were not observed in the mono-domain ligand:BIR2 or :BIR3 complexes. So, in agreement with the computational models we believe that the linker moieties of the binding site play a key role in the stability of the protein complex.

Synthesis and evaluation of novel aza-caged Garcinia xanthones by Xiaojin Zhang; Xiang Li; Haopeng Sun; Zhengyu Jiang; Lei Tao; Yuan Gao; Qinglong Guo; Qidong You (3288-3299).
Inspired by the therapeutic potential of the simplified caged xanthones, we have developed a chemical strategy for synthesizing novel aza-caged Garcinia analogues through a regioselective Claisen/Diels–Alder cascade reaction. The origin of regioselectivity has been explained using the DFT method. We have further evaluated the cell proliferation and IKKβ inhibitory activities of these compounds and studied their binding mode with IKKβ by molecular docking. The results suggested that the aza-caged scaffold provides a suitable modification site and the introduction of a hydrophobic moiety leads to improvement in the cytotoxicity and IKKβ inhibitory activity. The aza-caged compound 6c exhibited an IC50 value of 2.68, 2.10, 8.02 μM against the HepG2, A549 cells and IKKβ, respectively. Mechanism studies with 6c showed that the aza-caged compounds induce apoptosis and cell cycle S phase arrest in A549 cells.

Label-free DNA nucleobase recognition by fluorescent small molecules has received much attention due to its simplicity in mutation identification and drug screening. However, sequence-dependent fluorescence light-up nucleobase recognition and multicolor emission with individual emission energy for individual nucleobases have been seldom realized. Herein, an abasic site (AP site) in a DNA duplex was employed as a binding field for berberine, one of isoquinoline alkaloids. Unlike weak binding of berberine to the fully matched DNAs without the AP site, strong binding of berberine to the AP site occurs and the berberine's fluorescence light-up behaviors are highly dependent on the target nucleobases opposite the AP site in which the targets thymine and cytosine produce dual emission bands, while the targets guanine and adenine only give a single emission band. Furthermore, more intense emissions are observed for the target pyrimidines than purines. The flanking bases of the AP site also produce some modifications of the berberine's emission behavior. The binding selectivity of berberine at the AP site is also confirmed by measurements of fluorescence resonance energy transfer, excited-state lifetime, DNA melting and fluorescence quenching by ferrocyanide and sodium chloride. It is expected that the target pyrimidines cause berberine to be stacked well within DNA base pairs near the AP site, which results in a strong resonance coupling of the electronic transitions to the particular vibration mode to produce the dual emissions. The fluorescent signal-on and emission energy-modulated sensing for nucleobases based on this fluorophore is substantially advantageous over the previously used fluorophores. We expect that this approach will be developed as a practical device for differentiating pyrimidines from purines by positioning an AP site toward a target that is available for readout by this alkaloid probe.

Non-activated 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines were used as building blocks for the stereoselective synthesis of novel cis-2-cyanomethyl-4-phenylpiperidines via a microwave-assisted aziridine to piperidine ring expansion followed by a radical-induced nitrile translocation through initial formation and subsequent cleavage of intermediate bicyclic iminyl radicals. Furthermore, these 2-(cyanomethyl)piperidines were shown to be eligible substrates for the preparation of methyl cis-(1-arylmethyl-4-piperidin-2-yl)acetates through a Pinner reaction using gaseous HCl in methanol.

Biotransformation of clovane derivatives. Whole cell fungi mediated domino synthesis of rumphellclovane A by Giovanni Gontijo de Souza; Thays Silva Oliveira; Jacqueline Aparecida Takahashi; Isidro González Collado; Antonio José Macías-Sánchez; Rosario Hernández-Galán (3315-3320).
Here we describe the biotransformation of clovane derivatives by filamentary fungi Pestalotiopsis palustris and Penicillium minioluteum, and the application of the latter to the synthesis and determination of the absolute configuration of rumphellclovane A (2). Methoxyclovanol (1), a growth inhibitor of the phytopathogen Botrytis cinerea, is metabolised by P. palustris to yield rumphellclovane A (2), a natural compound recently isolated from the gorgonian coral Rumphella antipathies, two new compounds, (1R,2S,5S,8R,9S,10R)-2-methoxyclovane-9,10-diol (5) and (1S,2S,5S,7R,8R,9R)-2-methoxyclovane-7,9-diol (6), hydroxylated in positions not easily accessed by classic synthetic chemistry, and clovanodiols 3 and 4. P. minioluteum is able to selectively transform methoxyclovanol (1) into clovanodiols 3 and 4 and, in turn, lactone 8, the putative intermediate in the above mentioned synthesis of rumphellclovane A (2), into compound 2via a domino process. The ability of P. minioluteum to carry out the cleavage of ethers on clovane derivatives is also evaluated.

The reversibly and repeatedly altered gliding motility of microtubules driven by kinesin on the photoresponsive monolayer surface is studied. It was confirmed that an azobenzene monolayer surface needs to have free amino terminal groups for the successful dynamic control of the motility of microtubule. The surface of the azobenzene monolayer with terminal amino groups can dynamically control the ATP hydrolysis activity of kinesin which resulted in the change in motility of the microtubules.

Enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones by Michal Fornalczyk; Kuldip Singh; Alison M. Stuart (3332-3342).
Two approaches have been developed for the enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones to form a quaternary carbon centre using (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol as the chiral ligand. Good yields and high enantioselectivities (80–91% ee) were achieved with a range of alkyl aryl ketones in a convenient one-pot protocol using ethyl iododifluoroacetate and diethylzinc to form the difluorinated Reformatsky reagent homogeneously. In the traditional two-step Reformatsky reaction using the preformed Reformatsky reagent generated from ethyl iododifluoroacetate and zinc dust, good yields and good enantioselectivities (75–84% ee) were also obtained.

Back cover (3343-3344).