Organic & Biomolecular Chemistry (v.15, #33)

Front cover (6857-6858).

Contents list (6859-6866).

The intermolecular cross-benzoin and acyloin condensation reactions are powerful approaches to α-hydroxy carbonyls in a single step. However, their potentiality suffers from the occurrence of side reactions including self-condensation and the formation of the undesired cross-acyloin. The broad range of azolium salt precatalysts available confers high tunability to NHC mediated benzoin condensation, assuring a good level of selectivity to the direct coupling between two non-equivalent aldehydes. Many efforts have also been devoted to the design of strategies that expand the range of suitable reaction partners beyond the traditional aldehydes and to the discovery of novel umpolung catalytic systems. The synthesis of both racemic and enantiomerically enriched acyloins is reviewed.

The direct C–H activation of electron-deficient aza-BODIPYs has been effectively achieved via a concise and inexpensive Cu(ii)-promoted oxidative C–H/C–H coupling approach. The resulting indole-aza-BODIPY 6b covers a broad spectrum of 429–900 nm with a FWHM of 294 nm in solution and covers a UV-vis-NIR region up to 1100 nm in film.

Enzyme-instructed self-assembly with photo-responses for the photo-regulation of cancer cells by Zhengquan Zhou; Xian Xie; Qikun Yi; Wencui Yin; Adnan A. Kadi; Jinbo Li; Yan Zhang (6892-6895).
Using a short peptide precursor modified by the biaryltetrazole with intramolecular photo-click reactivity, we realized the photo-regulation of the pericellular nanofibers formed by the enzyme-instructed self-assembly on the cell membrane. Upon light irradiation, the fluorescence of nanofibers could be turned on to monitor both enzyme-instructed self-assembly and photo-induced disassembly processes. Moreover, the cell fate could be controlled through the photo-regulation.

Nickel-catalyzed N-vinylation of heteroaromatic amines via C–H bond activation by Vinod G. Landge; Jagannath Rana; Murugan Subaramanian; Ekambaram Balaraman (6896-6900).
Here, we report a ligand- and reductant-free nickel-catalyzed N-vinylation of heteroaromatic amines using biorenewable p-cymene as a solvent. This unprecedented cross-coupling strategy has high functional group tolerance (halides, alkoxy, cyano, chiral motif, etc.) and proceeded via C–H bond activation.

Solvent controlled radical cyclization of propargylamines for multi-iodinated quinoline formation by Yu Zhang; Xue-Ke Liu; Zheng-Guang Wu; Yi Wang; Yi Pan (6901-6904).
A solvent controlled regioselective metal-free synthesis of iodo-substituted N-heterocycles has been developed. This protocol undergoes a cascade iodination/cyclization/oxidation/aromatization pathway to afford multi-halogenated quinolines from readily available propargylamines under mild conditions.

A general and convenient palladium-catalyzed carbonylative synthesis of 2-benzylideneindolin-3-ones from 2-iodoanilines and arylacetylenes has been developed. With formic acid as the CO source and Ac2O as the activator, a variety of 2-benzylideneindolin-3-ones were obtained in good to excellent yields with exceptional functional group tolerance.

Intramolecular cyclopropylmethylation via non-classical carbocations by M. Skvorcova; A. Jirgensons (6909-6912).
Cyclopropyl–cyclopropyl rearrangement can be achieved selectively by intramolecular trapping of cyclopropylmethyl carbenium ions with an internal nucleophile. This can be exploited as a useful method for the introduction of a cyclopropyl group into complex molecules using readily accessible disubstituted cyclopropane intermediates.

Synthesis of selectively 4-substituted 9,9′-spirobifluorenes and modulation of their photophysical properties by Reinhard P. Kaiser; Jiří Mosinger; Ivana Císařová; Martin Kotora (6913-6920).
Synthesis of selectively 4-substituted 9,9′-spirobifluorenes was accomplished by using catalytic [2 + 2 + 2]-cyclotrimerization of specifically substituted diynols with alkynes to the corresponding fluorenols. Further synthetic transformations provided the target molecules. The measurement of the photophysical properties of the prepared 4-substituted 9,9′-spirobifluorenes revealed that their emission maxima depended on the electronic properties of the substituents present in the para position: the presence of an electron accepting group strongly favored the maxima red shift toward the blue VIS region (CF3λmax = 361 nm vs. MeO λmax = 330 nm). Adding further substituents (aryl or arylethynyl moieties) on the phenyl ring in position 4 did not lead to a dramatic improvement in the emission maxima (CF3C6H4, λmax = 369 nm, CF3C6H4CC, λmax = 370 nm), but increased their quantum yields considerably. In addition, a series of 9,9′-spirobifluorenes possessing various extended π-systems (pyrene, anthracene, etc.) were synthesized. In general, the emission maxima pattern reflected that of the parent π-systems, but they were red shifted by 10–30 nm. Finally, also a 1-[4-(9,9′-spirobifluorene-4-yl)phenyl]-2-aryl-ortho-carborane was prepared. These data thus may provide guidelines for further design of 9,9′-spirobifluorenes with tailored properties.

“On water” catalytic enantioselective sulfenylation of deconjugated butyrolactams by Soumya Jyoti Singha Roy; Santanu Mukherjee (6921-6925).
The first catalytic enantioselective α-sulfenylation of deconjugated butyrolactams has been developed using dimeric cinchona alkaloids as catalysts in a water-enriched reaction medium. Highly substituted and densely functionalized γ-lactams, bearing a quaternary stereogenic center, are produced with up to 99.5 : 0.5 er. The applicability of the same catalyst system for the enantioselective α-selenylation and formal vinylogous γ-hydroxylation of deconjugated butyrolactam has also been described.

A bis(pyridyl)-N-alkylamine/Cu(i) catalyst system for aerobic alcohol oxidation by Lindie Marais; Jordi Burés; Johan H. L. Jordaan; Selwyn Mapolie; Andrew J. Swarts (6926-6933).
Herein a bis(pyridyl)-N-alkylamine/CuI/TEMPO/NMI catalyst system is reported for aerobic oxidation of a variety of primary alcohols to the corresponding aldehydes using readily available reagents, at room temperature and ambient air as the oxidant. ESI-MS analysis of the reaction showed the formation of a [(L1)(NMI)CuII-OOH]+ species, which is a key intermediate in the alcohol oxidation reaction. Evaluation of the effect of reaction parameters on the initial rate of the reaction allowed us to obtain the optimum conditions for catalytic activity. The careful choice of reaction solvent allowed for the oxidation of 4-hydroxybenzyl alcohol, a substrate which proved problematic in previous studies. In the case of 2-pyridinemethanol as substrate, experimental evidence shows that catalytic activity is diminished due to competitive inhibition of the catalyst by the alcohol substrate.

Ag(i)-Catalyzed cycloisomerization reactions: synthesis of substituted phenanthrenes and naphthothiophenes by Rakesh K. Saunthwal; Abhinandan K. Danodia; Kapil Mohan Saini; Akhilesh K. Verma (6934-6942).
This paper describes silver catalyzed synthesis of substituted phenanthrenes and naphthothiophenes from ortho-alkylated biaryl derivatives via 6-endo-dig intramolecular alkyne–arene coupling. The mechanistic study reveals that 6-endo-dig cyclization proceeds through initial π-coordination of the alkyne unit followed by a Friedel–Crafts-type electrophilic aromatic cyclization at the adjacent arene ring. X-ray crystallographic studies further supported the formation of carbocycles.

Chiral BINOL-derived phosphoric acids catalyse the transfer hydrogenation of ketimines using Hantszch esters. In many cases the nitrogen on the imine binds to the catalyst through the catalyst hydroxyl group and the nucleophile forms a second hydrogen bond to the phosphoryl oxygen. DFT and ONIOM calculations show that the introduction of an ortho-hydroxyaryl group on the carbon atom of the ketimine leads the reaction to proceed through a 14-membered bifunctional mechanism. The transition states of these reactions involve both hydrogen bonding from the hydroxyl group on the imine and the nucleophile's proton to the phosphate catalyst. This mechanistic pathway is lower in energy than the conventional route, consistent with the experimentally observed increased rates of reaction relative to imines that are not derived from ortho-hydroxybenzophenone. To complement the high-level calculations, an accessible qualitative model has been developed that predicts the correct sense of stereoinduction for all examples.

A hybrid molecule of a GFP chromophore analogue and cholestene as a viscosity-dependent and cholesterol-responsive fluorescent sensor by Masahiro Ikejiri; Kenta Mori; Rina Miyagi; Rino Konishi; Yoshiko Chihara; Kazuyuki Miyashita (6948-6958).
Diarylmethylenated and cholestene (or -tane)-hybrid analogues of the GFP chromophore, namely, Ch-DAINs were successfully synthesised by a condensation reaction between methyl imidates and N-(diarylmethylene)glycinates. Among the Ch-DAINs synthesised, a diphenyl-type analogue showed viscosity-dependent and cholesterol-responsive fluorescent properties. It showed a nearly linear increase of the fluorescence emission in triglycerides and vesicles as the amount of cholesterol was increased.

Splitting a DNAzyme enables a Na+-dependent FRET signal from the embedded aptamer by Wenhu Zhou; Jinsong Ding; Juewen Liu (6959-6966).
Recently, a few Na+-specific RNA-cleaving DNAzymes have been reported, and a Na+ aptamer was identified from the NaA43 and Ce13d DNAzymes. These DNAzymes and the embedded aptamer have been used for Na+ detection. In this work, we studied the Na+-dependent folding of the Ce13d DNAzyme using fluorescence resonance energy transfer (FRET). When a FRET donor and an acceptor were respectively labeled at the ends of the DNAzyme, Na+ failed to induce an obvious end-to-end distance change, suggesting a rigid global structure. To relax this rigidity, the Ce13d DNAzyme was systematically split at various sites on both the enzyme and the substrate strands. The Na+ binding activity of the split structures was characterized by 2-aminopurine fluorescence, enzymatic activity, Tb3+-sensitized luminescence, and DMS footprinting. Among the various constructs, the only one that retained Na+ binding was the split at the cleavage site, and this construct was further labeled with two dyes near the split site. This FRET result showed Na+-dependent folding with a Kd of 26 mM Na+. This study provides important structural information related to Na+ binding to this new aptamer, which might also be useful for future work in biosensor design.

Aliphatic macrolides are used by various organisms as semiochemicals or pheromones, e.g. by the endemic Madagascan frog family Mantellinae. Volatile, methyl-branched aliphatic macrolides occur in various species, but their identification by MS is difficult, while isolation is not possible due to the low amounts produced. Therefore, we synthesized a library of methyl-branched 11-dodecanolides to identify unknown macrolides secreted by Gephyromantis moseri, a mantelline frog restricted to the rainforest and characterized by largely terrestrial habitats. The syntheses used metal-organic epoxide opening and ring-closing-metathesis as key steps. All library members 2-, 4-, 6-, 8-, and 10-methyl-11-dodecanolide were thus identified as part of the secretion by comparison of their mass spectra and their gas chromatographic retention indices. These compounds comprise new natural products.

Asymmetric synthesis of α-deuterated α-amino acids by Ryosuke Takeda; Hidenori Abe; Norio Shibata; Hiroki Moriwaki; Kunisuke Izawa; Vadim A. Soloshonok (6978-6983).
α-Deuterated-α-amino acids represent a very special class of stable isotopically labeled compounds, used in advanced biomedical research. Herein, we disclose a generalized approach for the preparation of α-2H-α-amino acids in enantiomerically pure form and with up to 99% deuteration. The reaction chemistry involved in this process is based on the dynamic kinetic resolution of racemates or (S)–(R) interconversion via the formation of intermediate Ni(ii) complexes derived from unprotected amino acids and recyclable tridentate ligands. Operationally convenient conditions, excellent chemical yields, diastereoselectivity and the degree of the deuteration bode well for the wide application of this methodology for the preparation of tailor-made α-2H-α-amino acids.

Phenothiazine-linked nucleosides and nucleotides for redox labelling of DNA by Anna Simonova; Luděk Havran; Radek Pohl; Miroslav Fojta; Michal Hocek (6984-6996).
Nucleosides and 2′-deoxyribonucleoside triphosphates (dNTPs) bearing phenothiazine (PT) attached to a nucleobase (cytosine or 7-deazaadenine) either directly or through an acetylene linker were prepared through Suzuki or Sonogashira cross-coupling and triphosphorylation, and were studied as building blocks for polymerase construction of modified DNA. The directly PT-substituted dNTPs were better substrates for polymerases than the alkyne-linked dNTPs but all of them were used in enzymatic synthesis of DNA using primer extension, nicking enzyme amplification, PCR or 3′-tail labelling by terminal deoxynucleotidyl transferase. The phenothiazine served as an oxidizable redox label (giving two analytically useful signals of oxidation on electrode) for nucleosides and DNA and was also used in orthogonal combination with previously developed benzofurazane or nitrophenyl labels for redox coding of DNA bases. Therefore, the title PT-linked dNTPs are useful additions to the portfolio of nucleotides for enzymatic synthesis of redox-labelled DNA for electrochemical analysis.

A Pd(ii)–Ag(i) catalyzed highly efficient synthesis of diindolylmethane has been developed. This transformation consists of a one-pot sequential Sonogashira coupling (and desilylation) followed by cycloisomerization/C3-functionalization of 2-iodoanilines. Six new bonds (four C–C and two C–N) are formed in a one-pot fashion. A variety of diindolylmethanes were obtained in excellent yields (up to 94%) under mild reaction conditions and this strategy is amenable to gram scale synthesis also. The products were transformed into various synthetically useful compounds.

New bioluminescent coelenterazine derivatives with various C-6 substitutions by Tianyu Jiang; Xingye Yang; Yubin Zhou; Ilia Yampolsky; Lupei Du; Minyong Li (7008-7018).
A series of new coelenterazine analogs with varying substituents at the C-6 position of the imidazopyrazinone core have been designed and synthesized for the extension of bioluminescence substrates. Some of them display excellent bioluminescence properties compared to DeepBlueC™ or native coelenterazine with both in vitro and in vivo biological evaluations, thus placing these derivatives among the most ideal substrates for Renilla bioluminescence applications.

DFT studies on reactions of boroles with carbon monoxide by Zheng Wang; Yu Zhou; Todd B. Marder; Zhenyang Lin (7019-7027).
Boroles can react with CO to give Lewis acid–base adduct 1AD, tricyclic boracycle 1TB or ketene derivative 1KD depending on the substituents on the borole. DFT calculations at the M06-2X level of theory were performed to study systematically the influence of borole substituents on these reactions. It was found that the Lewis acid–base adduct 1AD is a kinetic product, which can further transform to the tricyclic boracycle 1TB or ketene derivative 1KD. The computational results show that strong electron-withdrawing perfluorophenyl substituents significantly stabilise the Lewis acid–base adduct 1AD, allowing its successful isolation. In most cases, the tricyclic boracycle 1TB is both kinetically and thermodynamically more favourable than the ketene derivative 1KD. However, a –B(C6F5)2 substituent at the 4-position and a silyl substituent at the 5-position together are able to lower the barrier leading to the formation of the ketene derivative 1KD.

A simple and efficient synthesis of enantiomerically pure (1S,2S)-1,2-di(pyridin-2-yl)- and (1R,2R)-1,2-di(pyridin-4-yl)-ethane-1,2-diamines from commercial picolinaldehyde or isonicotinaldehyde and 2,2′-((1S,2S)-1,2-diaminoethane-1,2-diyl)diphenol (HPEN) via a stereospecific diaza-Cope rearrangement has been developed. Diamine (R,R)-2b was readily converted to novel diastereomeric ionic group-supported bis-prolinamides (R,S)-1b and (R,R)-1b which appeared to be efficient organocatalysts of asymmetric cross-aldol reactions in aldehyde/aldehyde, ketone/ketone or ketone/aldehyde reagent systems under neat conditions to afford corresponding aldols in high yields and with up to 99% ee. Furthermore, catalyst (R,S)-1b could be reused over 15 times in the same or similar catalytic reactions exhibiting close to original activity and a high level of stereoinduction.

Forsythenethosides A and B: two new phenylethanoid glycosides with a 15-membered ring from Forsythia suspensa by Si-Yuan Shao; Zi-Ming Feng; Ya-Nan Yang; Jian-Shuang Jiang; Pei-Cheng Zhang (7034-7039).
Forsythenethosides A (1) and B (2), two new phenylethanoid glycosides with an unprecedented 15-membered carbon scaffold ring, were isolated from the fruits of Forsythia suspensa. Their structures, including their geometric configurations, were determined via extensive NMR spectroscopy techniques, especially using 2D NMR data combined with systematic conformational analysis. Forsythenethosides A and B showed strong neuroprotective activities against serum-deprivation-induced PC12 cell damage. Furthermore, they were active on rotenone-induced PC12 cell damage.

The concise and efficient total syntheses of the naturally-occurring coumarin derivatives gerberinol I, and the pterophyllins 2 and 4, from 5-methyl-4-hydroxycoumarin as a common precursor employing different Casnati–Skattebøl reaction conditions, are reported. The synthesis of the key intermediate coumarin was achieved by the organocatalytic condensation of acetylacetone and crotonaldehyde followed by a LiCl-assisted cyclization, CuCl2-promoted aromatization and a final Et2CO3-mediated cyclization. A Casnati–Skattebøl formylation under high-temperature conditions afforded gerberinol I, whereas milder conditions resulted in an unstable 3-formyl-4-hydroxycoumarin derivative, which was subjected to a basic alumina-mediated one pot O-alkylation with chloroacetone and intramolecular aldolization to furnish pterophyllin 4. Wittig methylenation of the latter conveniently afforded pterophyllin 2.

Back cover (7051-7052).