Organic & Biomolecular Chemistry (v.12, #48)

Front cover (9723-9723).

Inside front cover (9724-9724).

Contents list (9725-9732).

Radical reactions of borohydrides by Takuji Kawamoto; Ilhyong Ryu (9733-9742).
Borohydrides are an important class of reagents in both organic and inorganic chemistry. Though popular as hydride-transfer reagents for reduction, since earlier work from the 1970s, borohydride reagents have also been known to serve as hydrogen-transfer reagents. In pursuit of greener tin hydride substitutes, recent progress has been made to mediate radical C–C bond forming reactions, including Giese reactions, radical carbonylation and addition to HCHO reactions, with borohydride reagents. This review article focuses on state-of-the-art borohydride based radical reactions, also covering earlier work, kinetics and some DFT calculations with respect to the hydrogen transfer mechanism.

Sulfinate derivatives: dual and versatile partners in organic synthesis by Jessy Aziz; Samir Messaoudi; Mouad Alami; Abdallah Hamze (9743-9759).
Sulfinic acids and their salts have recently emerged as versatile coupling partners to efficiently access a wide variety of hetero- and carbocyclic compounds, under relatively mild conditions. Their growing importance is attributable to their dual capacity for acting as nucleophilic or electrophilic reagents. This report summarizes recent advances in the preparation and use of sulfinates in organic synthesis.

Regioselective S-acylation of coenzyme A (CoA) is achieved under aqueous conditions using various aliphatic and aromatic carboxylic acids activated as their methyl acyl phosphate monoesters. Unlike many hydrophobic activating groups, the anionic methyl acyl phosphate mixed anhydride is more compatible with aqueous solvents, making it useful for conducting acylation reactions in an aqueous medium.

A facile approach to tryptophan derivatives for the total synthesis of argyrin analogues by Chou-Hsiung Chen; Sivaneswary Genapathy; Peter M. Fischer; Weng C. Chan (9764-9768).
A facile route has been established for the synthesis of indole-substituted (S)-tryptophans from corresponding indoles, which utilizes a chiral auxiliary-facilitated Strecker amino acid synthesis strategy. The chiral auxiliary reagents evaluated were (S)-methylbenzylamine and related derivatives. To illustrate the robustness of the method, eight optically pure (S)-tryptophan analogues were synthesized, which were subsequently used for the convergent synthesis of a potent antibacterial agent, argyrin A and its analogues.

This paper describes azidation of indoles with NaN3 and ceric ammonium nitrate (CAN), giving a variety of spirocyclic 2-azido indolines in good yields and moderate diastereoselectivities.

An efficient synthetic route to 1,3-bis(arylethynyl)isobenzofuran using alkoxybenzocyclobutenone as a reactive platform by Kenta Asahina; Suguru Matsuoka; Ryosuke Nakayama; Toshiyuki Hamura (9773-9776).
An efficient synthetic method of 1,3-bis(arylethynyl)isobenzofurans is developed. Nucleophilic addition of alkynyllithium to benzocyclobutenone and subsequent oxidative ring cleavage of the four-membered ring gave a keto-aldehyde, which, in turn, accepted the second nucleophile to produce isobenzofurans after acid treatment.

Palladium catalyzed dual C–H functionalization of indoles with cyclic diaryliodoniums, an approach to ring fused carbazole derivatives by Yongcheng Wu; Xiaopeng Peng; Bingling Luo; Fuhai Wu; Bo Liu; Fenyun Song; Peng Huang; Shijun Wen (9777-9780).
Palladium(ii)-catalyzed dual C–H functionalization of indoles with cyclic diaryliodoniums was successfully achieved, providing a concise method to synthesize dibenzocarbazoles. In a single operation, two C–C bonds and one ring were formed. The reaction was ligand free and tolerated air and moisture conditions.

Strained olefin enables triflic anhydride mediated direct dehydrative glycosylation by Guohua Chen; Qiang Yin; Jian Yin; Xiangying Gu; Xiao Liu; Qidong You; Yue-Lei Chen; Bing Xiong; Jingkang Shen (9781-9785).
For the first time, we demonstrated that Tf2O mediated direct dehydrative glycosylation was possible simply with strained olefins, and other typical bases were inhibitors of this reaction. We optimized the glycosylation conditions and found that typical benzyl protected 1-OH pyranosyl donors and certain alcohol acceptors were suitable for our glycosylation system. Furthermore, we found that complete 1,2-trans selectivity and a wider acceptor scope could be achieved with 2-O-Bz 3,4,6-tri-O-Bn pyranosyl donors.

Highly efficient modular metal-free synthesis of 3-substituted 2-quinolones by Alexander V. Aksenov; Alexander N. Smirnov; Nicolai A. Aksenov; Inna V. Aksenova; Asiyat S. Bijieva; Michael Rubin (9786-9788).
A modular approach to 3-substituted 2-quinolones via a cascade annulation reaction between 4-nitroketones and hydrazines has been developed.

Primary amino acids are found to be good enantioselective catalysts for the direct asymmetric Mannich reaction between 2-amino acetophenone and aldehydes. The 2-aryl-2,3-dihydro-4-quinoline products are obtained in moderate to good yields and good to high enantioselectivities with 10 mol% of the primary amino acid catalyst under mild reaction conditions.

Design and synthesis of a mitochondria-targeting carrier for small molecule drugs by Junyan Han; Tae Hoon Lee; Ching-Hsuan Tung; Daniel Y. Lee (9793-9796).
A novel mitochondria-targeting carrier QCy7HA was developed. QCy7HA transported the covalently attached doxorubicin (DOX) to mitochondria specifically. The conjugate limited the effects of P-glycoprotein (Pgp) efflux pumps of multidrug-resistant cells on DOX, indicating that diverting drugs to mitochondria is a potential promising method for treatment of drug-resistant cancers.

Thermodynamic epimeric equilibration and crystallisation-induced dynamic resolution of lobelanine, norlobelanine and related analogues by Z. Amara; G. Bernadat; P.-E. Venot; P. Retailleau; C. Troufflard; E. Drège; F. Le Bideau; D. Joseph (9797-9810).
The step-economical synthesis of lobelanine involving a ring closing double aza-Michael (RCDAM) reaction is revisited and successfully extended to the synthesis of various configurationally more stable analogues. Owing to the presence of a configurationally labile β-aminoketone subunit, lobelanine is prone to self-catalyze mutarotation in solution. Through the synthesis of original lobelanine analogues, we studied the influence of (i) the size of the central heterocycle, (ii) the bulkiness of the nitrogen protecting group, and (iii) the phenacyl arm substituent on the thermodynamic equilibrium and its displacement by crystallisation-induced dynamic resolution (CIDR). We demonstrated that fine structural tuning combined with optimized CIDR conditions favours the first efficient diastereoselective synthesis of lobelanine's analogues.

Anion carrier formation by calix[4]arene-bis-hydroxymethylphosphonic acid in bilayer membranes by Oleg Ya. Shatursky; Ludmila A. Kasatkina; Roman V. Rodik; Sergiy O. Cherenok; Alexander A. Shkrabak; Tatiana O. Veklich; Tatiana A. Borisova; Sergyi O. Kosterin; Vitaly I. Kalchenko (9811-9821).
The action of calix[4]arenes C-91, C-97, C-99, C-107 and C-160 on solvent-containing planar bilayer membranes made of cholesterol and egg phosphatidylcholine (egg PC) or synthetic 18-carbon-tail phospholipid DOPC has been investigated in a voltage-clamp mode. Within the range of calix[4]arenes tested, a steady-state voltage-dependent transmembrane current was achieved only after addition of calix[4]arene C-99 (calix[4]arene-bis-hydroxymethylphosphonic acid) from the side of the membrane the positive potential was applied to. This current exhibited anion selectivity passing more chloride at negative potentials applied from the side of the membrane to which calix[4]arene C-99 was introduced. The kinetics and temperature-dependence determined for calix[4]arene C-99-mediated ionic transport suggest a carrier mode of facilitated diffusion.

Base-switched annuloselectivity in the reactions of ethyl malonyl chloride and imines by Zhanhui Yang; Siqi Li; Zhong Zhang; Jiaxi Xu (9822-9830).
The base-switched annuloselectivity, namely [2 + 2] and [2 + 2 + 2] selectivity, in the reactions of ethyl malonyl chloride and imines is successfully realized. In the presence of the weak nucleophilic base 2-chloropyridine, the reactions deliver ethyl trans-β-lactam-3-carboxylates as the exclusive [2 + 2] products in up to 93% yields, while with the strong nucleophilic N-methylimidazole as the base, the reactions give rise to 2,3-dihydro-1,3-oxazin-4-one derivatives as the sole products in up to 99% yields via the formal [2 + 2 + 2] cycloaddition involving one molecule of the imine and two molecules of the ketene generated from malonyl chloride. Notably, ethyl trans-β-lactam-3-carboxylates are synthesized for the first time directly from the reactions of ethyl malonyl chloride and imines. Mechanistic discussions reveal that the annuloselectivity is controlled by the nucleophilicity of organic bases.

Selective synthesis of 1- and 3-substituted 2-methoxyindenes from the carboalkoxylations of 2-ethynylbenzyl ethers is described; the former is obtained efficiently with P(t-Bu)2(o-biphenyl)AuCl/NaBARF in DCM/MS 4 Å whereas the latter is produced preferably with P(t-Bu)2(o-biphenyl)AuCl/AgNTf2 in pre-dried DCM. Both 1- and 3-substituted 2-indenyl ethers are subjected to ozone oxidations to afford two distinct carbonyl products. Our new data indicate that 1-substituted 2-indenyl ethers are generated from gold catalysts whereas their 3-substituted analogues arise from Brønsted acids.

Conformational equilibria in selected A-type trimeric procyanidins by Marta K. Dudek (Jamróz); Sławomir Kaźmierski; Kamil Stefaniak; Vitold B. Gliński; Jan. A. Gliński (9837-9844).
A-type procyanidin trimers cinnamtannin B-1, cinnamtannin D-1, lindetannin, and aesculitannin B were studied in terms of their conformation and interaction with four solvents: methanol, acetone, DMSO and pyridine. The experiments demonstrated that for each trimer there are two principal conformers observable in the NMR. The ratio of the conformers (rotamers) depends on the structure of a given trimer as well as on the solvent used for NMR measurements. The DFT calculations (B3LYP/6-31G(d,p)) proved the presence of two main conformers to be the result of a steric hindrance that prevents free rotation along the B-type interflavan bond. An analysis of the solvent–procyanidin interactions showed that the strong electron donating solvents, pyridine and DMSO, favor different conformers from methanol and acetone, which prefer the lowest-energy gas phase conformer. These findings are in line with predictions of DFT/M06-2X calculations with the inclusion of the thermal corrections. The variations in the rotamer ratios in the studied solvents correlate with the solvent's capacity to induce local changes in the electron density of the particular procyanidin trimer.

The green fluorescent protein (GFP) variant S65T/H148D recovers the A-band fluorescence lost in the single mutant S65T, and it has been established that Asp148 is the alternate proton acceptor for the excited state proton transfer (ESPT). This mutant has been widely studied and presents unique spectroscopic properties, such as an ultrafast rise in the fluorescence (<50 fs). Also it exhibits a red-shift of the A absorption band of 20 nm with respect to wt-GFP's. The double mutant E222Q/H148D presents a very similar behaviour, at least within the experimental data available (which is scarcer than those of S65T/H148D). By means of dynamic theoretical studies we have been able to (1) reproduce and thoroughly analyse the red-shifted absorption spectra of both mutants and (2) predict the structure that the variant E222Q/H148D (for which there is no X-ray-resolved structure available) most probably adopts in water at room temperature. Our results deepen the understanding of the way GFP variants work and give some new insights into the rational design of fluorescent proteins and biological photosystems in general.

Enantioselective synthesis of α-benzylated lanthionines and related tripeptides for biological incorporation into E. coli peptidoglycan by Thibaut Denoël; Astrid Zervosen; Christian Lemaire; Bernard Joris; Mireille Hervé; Didier Blanot; Guillermo Zaragoza; André Luxen (9853-9863).
The synthesis of modified tripeptides (S)-Ala-γ-(R)-Glu-X, where X = (R,S) or (R,R) diastereomers of α-benzyl or α-(4-azidobenzyl)lanthionine, was carried out. The chemical strategy involved the enantioselective alkylation of a 4-MeO-phenyloxazoline. The reductive opening of the alkylated oxazolines, followed by cyclization and oxidation, led to four PMB-protected sulfamidates. Subsequent PMB removal, Boc protection and regioselective opening with cysteine methyl ester led to protected lanthionines. These compounds were further converted in a one pot process to the corresponding protected tripeptides. After ester and Boc deprotection, the four tripeptides were evaluated as potential analogues of the natural tripeptide (S)-Ala-γ-(R)-Glu-meso-A2pm. These compounds were evaluated for introduction, by means of the biosynthetic recycling pathway, into the peptidoglycan of Escherichia coli. A successful in vitro biosynthesis of UDP-MurNAc-tripeptides from the tripeptides containing α-benzyl lanthionine was achieved using purified murein peptide ligase (Mpl). Bioincorporation into E. coli W7 did not occur under different tested conditions probably due to the bulky benzyl group at the Cα carbon of the C-terminal amino acid.

Synthesis and biological evaluation of imidazo[1,5-a]pyridine-benzimidazole hybrids as inhibitors of both tubulin polymerization and PI3K/Akt pathway by Ahmed Kamal; A. V. Subba Rao; V. Lakshma Nayak; N. V. Subba Reddy; Konderu Swapna; G. Ramakrishna; Mallika Alvala (9864-9880).
A series of imidazo[1,5-a]pyridine-benzimidazole hybrids (5a–aa) were prepared and evaluated for their cytotoxic activity against a panel of sixty human tumor cell lines. Among them compounds 5d and 5l showed significant cytotoxic activity with GI50 values ranging from 1.06 to 14.9 μM and 0.43 to 7.73 μM, respectively. Flow cytometric analysis revealed that these compounds arrest the cell cycle at G2/M phase and induced cell death by apoptosis. The tubulin polymerization assay (IC50 of 5d is 3.25 μM and 5l is 1.71 μM) and immunofluorescence analysis showed that these compounds effectively inhibited the microtubule assembly in human breast cancer cells (MCF-7). Further, the apoptotic effects of compounds were confirmed by Hoechst staining, mitochondrial membrane potential, cytochrome c release, ROS generation, caspase 9 activation and DNA fragmentation analysis. After treatment with these compounds for 48 h, p-PTEN and p-AKT levels were markedly decreased. Moreover, these compounds did not significantly inhibit the normal human embryonic kidney cells, HEK-293. The molecular docking simulations predicted the binding interactions of 5d and 5l with colchicine binding site of the tubulin, which is in compliance with the antiproliferative activity data.

Highly enantioselective reaction of 2-oxindoles with (3-indolyl)methanols by cooperative Catalysis of a Lewis acid and organocatalyst by Chuan-Li Ren; Tao Zhang; Xing-Yong Wang; Tao Wu; Jing Ma; Qing-Qing Xuan; Feng Wei; Hong-Yan Huang; Dong Wang; Li Liu (9881-9886).
An efficient cooperative biscinchona alkaloid and Lewis acid catalytic system was developed in the enantioselective α-alkylation of 2-oxindoles with (3-indolyl)(phenyl)methanols to provide (2-oxindole)-linker-indole derivatives in good yields (70–83%) with high enantioselectivities (81%–92%).

Synthesis and LC-MS/MS analysis of desmosine-CH2, a potential internal standard for the degraded elastin biomarker desmosine by Yuko Murakami; Rina Suzuki; Hiroto Yanuma; Jiangtao He; Shuren Ma; Gerard M. Turino; Yong Y. Lin; Toyonobu Usuki (9887-9894).
Desmosine-CH2, an analog of the elastic tissue degradation biomarker desmosine, can be regarded as a potential internal standard for precise quantification of desmosines by LC-MS/MS. In this study, the chemical synthesis of desmosine-CH2 was completed in 22% overall yield in five steps. The LC-MS/MS analysis of desmosine-CH2 was also achieved.

A simple and efficient approach to biologically important 1-trifluoromethylated isoquinolines starting with readily prepared β-aryl-α-isocyano-acrylates and the commercially available Togni reagent as the CF3 radical precursor is described. These transformations occur in the absence of any transition metals and the title compounds are obtained in moderate to excellent yields. This protocol comprises a trifluoromethylation with concomitant isoquinoline framework construction.

Quinoline-derived two-photon sensitive quadrupolar probes by Petra Dunkel; Christine Tran; Thibault Gallavardin; Hamid Dhimane; David Ogden; Peter I. Dalko (9899-9908).
The first quadrupolar 8-dimethylaminoquinoline-derived 6-(8-DMAQ-OAc)2 (1c) and 5-(8-DMAQ-OAc)2 (2c) photosensitive probes underwent photolysis under UV (365 nm) and NIR (730 nm two-photon (TP)) irradiation conditions, showing Qu = 9.3% and 6.6% quantum yields and δu = 0.07 GM and 0.40 GM uncaging cross-sections, respectively.

Selective oxygenation of alkynes: a direct approach to diketones and vinyl acetate by Xiao-Feng Xia; Zhen Gu; Wentao Liu; Ningning Wang; Haijun Wang; Yongmei Xia; Haiyan Gao; Xiang Liu (9909-9913).
Arylalkynes can be converted into α-diketones with the use of a copper catalyst, and also be transformed into vinyl acetates under metal-free conditions, both in the presence of PhI(OAc)2 as an oxidant at room temperature. A series of substituted α-diketones were prepared in moderate to good yields. A variety of vinyl halides could be regio- and stereo-selectively synthesized under mild conditions, and I, Br and Cl could be all easily embedded into the alkynes.

Complex oligosaccharide syntheses employ the use of more than one glycosyl donor and hence, methods for the interconversion of glycosyl donors are highly valuable for the overall synthesis plan. Herein, n-pentenyl glycosides are efficiently converted to glycosyl 1,2-O-orthoesters in the presence of both acid and base sensitive functional groups. The identified protocol was found to be suitable for the synthesis of trisaccharyl and tetrasaccharyl 1,2-O-orthoester as well. Furthermore, an iterative synthesis of pentaarabinofuranoside present on the Mycobacterium tuberculosis cell surface was accomplished using this method.

Back cover (9921-9922).