Organic & Biomolecular Chemistry (v.11, #11)

Front cover (1745-1745).

Inside front cover (1746-1746).

Contents list (1747-1753).

Self-organizing surface-initiated polymerization, templated self-sorting and templated stack exchange: synthetic methods to build complex systems by Marco Lista; Edvinas Orentas; Jetsuda Areephong; Pierre Charbonnaz; Adam Wilson; Yingjie Zhao; Altan Bolag; Giuseppe Sforazzini; Raluca Turdean; Hironobu Hayashi; Yuya Domoto; Adam Sobczuk; Naomi Sakai; Stefan Matile (1754-1765).
In nature, spectacular function is achieved by highly sophisticated supramolecular architectures. Little is known what we would obtain if we could create complexity with similar precision, because the synthetic methods to do so are not available. This account summarizes recent approaches conceived to improve on this situation. With self-organizing surface-initiated polymerization (SOSIP), charge-transporting stacks can be grown directly on solid substrates with molecular-level precision. The extension to templated self-sorting (SOSIP-TSS) offers a supramolecular approach to multicomponent architectures. A solid theoretical framework for the transcription of information by templated self-sorting has been introduced, intrinsic templation efficiencies up to 97% have been achieved, and the existence of self-repair has been shown. The extension to templated stack exchange (SOSIP-TSE) offers the complementary covalent approach. Compatibility of this robust method with the creation of double-channel architectures with antiparallel two-component gradients has been demonstrated.

The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib by Benjamin J. Deadman; Mark D. Hopkin; Ian R. Baxendale; Steven V. Ley (1766-1800).
Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API's).

A novel ionic liquid-support organocatalyst, which contains the quaternary ammonium ion moiety, was recently developed and successfully applied to the asymmetric Michael reaction in the presence of a newly developed ionic liquid-supported (ILS) benzoic acid as co-catalyst. For the reactions studied, in which various aldehydes and nitroolefins were examined, excellent diastereo- and enantioselectivities were obtained with low catalyst loading. Also, the catalyst could be recycled for ten times without significant loss of enantioselectivity.

An acid catalyzed reversible ring-opening/ring-closure reaction involving a cyano-rhodamine spirolactam by Honglin Li; Hong Guan; Xinrui Duan; Jun Hu; Guiren Wang; Qian Wang (1805-1809).
Cyanamide was introduced into the rhodamine spirolactam framework to produce a colorless and non-fluorescent compound RBCN. It shows a reversible ring-opening/ring-closure process in response to the solution pH, which exhibits an “ON/OFF” switching in its fluorescence. Different from other rhodamine-type dyes, the ring-open form of RBCN is stable in protic solvents under neutral, near neutral and basic conditions, showing a pink color and very strong fluorescence. We also demonstrated the potential of RBCN in live cell imaging.

AlCl3 promoted Friedel–Crafts acylation between 4-tert-butylbenzoyl chloride and mesitylene was investigated. The donor–acceptor complex was observed as the major species. Kinetic investigation demonstrated that the reaction was first-order on the donor–acceptor complex and zero-order on ArH, suggesting that the donor–acceptor complex was not the true reactive species. However, the acylium ion was almost invisible with a fairly low concentration under live reaction conditions. It was approved as the true reactive species through kinetic data (“kinetic capture”) in the AlCl3 promoted Friedel–Crafts acylation reaction.

Highly enantioselective synthesis of α,β-epoxy esters was achieved via one-pot organocatalytic epoxidation and consequent oxidative esterification. Excellent enantioselectivities (up to 99% ee) and good yields were obtained for a variety of α,β-epoxy esters. The method was readily scaled. Furthermore the product was applied towards the synthesis of (−)-clausenamide with excellent enantioselectivities (>99% ee).

An aza-Michael induced ring closure (aza-MIRC) tandem reaction of benzyl (2-bromoethyl)carbamate with various Michael acceptors is described. The N-Cbz-β-gem-disubstituted pyrrolidines thus obtained were proved to be versatile intermediates for the rapid access to both martinelline and spirooxindole backbones. An application of this strategy towards an expedient 4 step total synthesis of (±)-coerulescine is also presented.

An expeditious synthesis of imatinib and analogues utilising flow chemistry methods by Mark D. Hopkin; Ian R. Baxendale; Steven V. Ley (1822-1839).
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.

Anion response of organogels: dependence on intermolecular interactions between gelators by Pengchong Xue; Jiabao Sun; Qiuxia Xu; Ran Lu; Makoto Takafuji; Hirotaka Ihara (1840-1847).
Being different from common sensing molecules existing as monomer in solution, the gelators as sensing molecules self-assembled together in gels. Therefore, the interaction strength between gelators is believed as an important factor for gels to recognize selectively anions. In this paper, we choose two gelators, presenting similar binding sites for anions, but different strengths in intermolecular interaction. Moreover, their anion responsive behaviors in organogels were examined by observing phase state and measuring UV-vis and fluorescence spectra. We found that the organogel formed by 2 with strong intermolecular interaction could selectively recognize fluoride anion. However, the gels of 1 could be transformed into sol phases by addition of F, Cl, Br, AcO and H2PO4 because of the small aggregate constant of 1 in o-dichlorobenzene, presenting poor selectivity. Moreover, their UV-vis and emission spectra acting as testing methods also suggested the same conclusion.

Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization by Heiko Fittler; Olga Avrutina; Bernhard Glotzbach; Martin Empting; Harald Kolmar (1848-1857).
Herein we report a convenient strategy for the development of novel, highly-potent peptidic inhibitors of the trypsin-like serine protease matriptase based on the monocyclic variant of the sunflower trypsin inihibitor-1 (SFTI-1[1,14]). We screened SFTI-1[1,14] variants possessing incremental modifications of the parent peptide for beneficial binding properties. This compound library comprising 6 peptides and 16 triazole-containing peptidomimetics was established via structure-guided rational design and synthesized using a divergent strategy employing “copper-click” chemistry. The most favorable amino acid substitutions were combined in one framework yielding potent SFTI-1-derived matriptase inhibitor-1 (SDMI-1) and the truncated dodecapeptide variant (SDMI-2) with single-digit nanomolar inhibition constants. In silico studies indicated that the improved matriptase affinity compared to the parent peptide is caused by the successful establishment of additional favorable proton donor–acceptor interactions between basic inhibitor side chains and acidic residues on the surface of the target enzyme. SDMI-1 and 2 are potent inhibitors of the pharmaceutically relevant protease matriptase at a near physiological pH and, thus, may find applications in therapy or diagnostics.

Novel anilinocoumarin derivatives as agents against hepatitis C virus by the induction of IFN-mediated antiviral responses by Huang-Kai Peng; Wei-Chun Chen; Jin-Ching Lee; Shiang-Yu Yang; Cherng-Chyi Tzeng; Ying-Ting Lin; Shyh-Chyun Yang (1858-1866).
The hepatitis C virus (HCV) is the main cause of progressive liver disease, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Novel anilinocoumarins were synthesized, and their efficacy against HCV replication was evaluated. We demonstrated that 3-(3′,4′,5′-trimethoxyanilin-1′-yl)methylaminocoumarin (6) exhibited strong anti-HCV activity at protein and RNA levels at non-toxic concentrations, with an EC50 value of 12 ± 0.3 μM and a selective index (SI) value of 10. Combined treatment of compound 6 and interferon-α (IFN) or telaprevir induced a significant decrease in HCV RNA levels, respectively. We also found that the anti-HCV replication effect of compound 6 was due to the induction of IFN-mediated antiviral responses. This is the first report demonstrating that coumarins inhibit viral replication through an IFN-mediated anti-viral response. Collectively, compound 6 possessed potent activities against HCV replication and could be a new lead compound with higher selectivity and less toxicity.

An efficient and direct use of formamides as amino group sources for the synthesis of α-ketoamides was developed under metal-free conditions. The reaction was based on the oxidative coupling of acetophenones with formamides and generated the desired products in good yields in the presence of t-BuOOH/I2/PhCO2H.

Trifluoroethanol solvent facilitates selective N-7 methylation of purines by Honorine Lebraud; Celine Cano; Benoit Carbain; Ian R. Hardcastle; Ross W. Harrington; Roger J. Griffin; Bernard T. Golding (1874-1878).
Purines protected at N-9 by p-methoxybenzyl are methylated or ethylated in 2,2,2-trifluoroethanol at N-7 by trimethyl- or triethyl-oxonium borofluorate, respectively. Subjecting the resulting cationic species to microwave irradiation releases an N7-methyl- or ethyl-purine. This one-pot procedure is an efficient regiospecific method applicable to diverse substrates.

A series of tolyl 2-azido-2-deoxy-thio-glucoside donors with different combinations of protecting groups were prepared. These donors were used in glycosylation reactions to test the correlations between the stereoselectivity and the pattern of the protecting groups. Acetyl groups showed a position dependent stereo-directing effect. A remote participating mechanism is proposed to explain the observed results.

Direct evidence has been obtained to confirm the unusual nucleophilic attack of an alkoxide at the S-center of sp3-hybridized sulfonyl esters. The unusual reaction pathway leads to S–O bond scission which is crucial for the regio- and stereoselective conversion of 2,3-di-O-sulfonates of 4,6-O-benzylidene-β-d-galactopyranosides into β-d-idopyranosides. In addition, strong evidence has been provided to clarify the role of the alkali counter-cation in the transformation. The cation is believed to influence the reaction rate via coordination to an oxygen in the sulfonate ester; the presence of a neighboring ring oxygen oriented in a cis-relationship greatly enhances reactivity of the sulfonyl ester.

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF–VEGFR interaction by María Isabel García-Aranda; Susana González-López; Clara María Santiveri; Nathalie Gagey-Eilstein; Marie Reille-Seroussi; Mercedes Martín-Martínez; Nicolas Inguimbert; Michel Vidal; María Teresa García-López; María Angeles Jiménez; Rosario González-Muñiz; María Jesús Pérez de Vega (1896-1905).
The design, synthesis, conformational studies and binding affinity for VEGF receptors of a collection of linear and cyclic peptide analogues of the N-terminal α-helix fragments 13–25 of VEGF and 1–13 of Vammin are described. Linear 13(14)-mer peptides were designed with the help of an AGADIR algorithm and prepared following peptide solid-phase synthetic protocols. Cyclic peptide derivatives were prepared on-resin from linear precursors with conveniently located Glu and Lys residues, by the formation of amide linkages. Conformational analysis, CD and NMR, showed that most synthesized peptides have a clear tendency to be structured as α-helices in solution. Some of the peptides were able to bind a VEGFR-1 receptor with moderate affinity. In addition to the described key residues (Phe17, Tyr21 and Tyr25), Val14 and Val20 seem to be relevant for affinity.

Back cover (1907-1908).