Organic & Biomolecular Chemistry (v.11, #8)

Front cover (1261-1261).

Inside front cover (1262-1262).

Contents list (1263-1270).

Iron-catalysed carbon–carbon single bond activation by Johannes E. M. N. Klein; Bernd Plietker (1271-1279).
In search of recent challenges in synthetic organic chemistry transformations of substrates possessing formally unreactive bonds have been thoroughly addressed. Amongst those reactions a small number of iron-catalysed reactions have emerged and will be presented showcasing that only a mere starting-point has been reached and many opportunities are to be found in this area.

The HKR of racemic anti- or syn-3-substituted epoxy esters catalyzed by a Co(iii)salen complex provides ready access to the corresponding enantioenriched 3,4-disubstituted γ-butyrolactones and 3-substituted epoxy esters. This strategy has been successfully employed in the formal synthesis of biologically active 3,4-disubstituted piperidine derivatives, (−)-paroxetine and Ro 67-8867 and a natural product, (+)-eldanolide.

Asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with β-nitroalkenes catalyzed by chiral bifunctional thioureas by Ren-Qiang Mei; Xiao-Ying Xu; Lin Peng; Fan Wang; Fang Tian; Li-Xin Wang (1286-1289).
The first asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with nitroolefins catalyzed by chiral bifunctional thioureas was reported and 2,3-dihydrofuro[3,2-c]-coumarin adducts have been obtained in moderate yields (53–75%) and good enantioselectivities (64–90% ee).

A concise synthetic protocol for aryl functionalized phenanthrolines has been developed. It was demonstrated that 3,8-diphenyl-1,10-phenanthroline (7a) is competent in promoting transition-metal-free direct arylation and 2,3,8,9-tetraphenyl-1,10-phenanthroline (8a) is a highly efficient ligand in the in situ Pd-catalysed Heck reaction.

Synthesis and characterization of pH-sensitive, biotinylated MRI contrast agents and their conjugates with avidin by Sandip M. Vibhute; Jörn Engelmann; Tatjana Verbić; Martin E. Maier; Nikos K. Logothetis; Goran Angelovski (1294-1305).
Responsive or smart contrast agents (SCAs) provide new opportunities in magnetic resonance imaging (MRI) to examine a number of physiological and pathological events. However, their application in vivo remains challenging. Therefore, much research is focused on the optimization of their properties, to enable their use in additional imaging modalities, pre-targeted delivery, or to increase the local concentration of the agent. The key feature in the SCA synthetic modification is the retention of their physicochemical properties related to the specific MR response. Here, we report the preparation and characterization of pH sensitive SCAs appended with a phosphonate pendant arm and either an aliphatic (GdL1) or aromatic linker (GdL2). The longitudinal relaxivity of GdL1 and GdL2 increases by 146% and 31%, respectively, while the pH decreases from 9 to 5. These two SCAs were converted to the biotinylated systems GdL3 and GdL4 and their interaction with avidin was investigated. The binding affinity with avidin was assessed with a fluorescence displacement assay and with MRI phantom experiments in a 3T MRI scanner. The fluorometric assay and MRI E-titrations revealed a 3 : 1 binding mode of GdL3–4 to avidin with the binding affinity as high as that of the parent avidin–biotin complex. The high binding affinity was confirmed with MRI by a competitive assay. The avidin–GdL3–4 complexes thus obtained exhibit changes in both r1 and r2 that are pH dependent. The results reveal a new pathway for the modification and improvement of SCAs to make them more suitable for in vivo application.

Bullvalene is an organic molecule that spontaneously undergoes Cope rearrangements, resulting in a reconfiguration of its carbon framework. During our study of oligosubstituted bullvalenes, which are structurally dynamic shapeshifting molecules, we found that we could isolate one metastable isomer from the interconverting population of 1680 constitutional isomers (852 structures if enantiomeric pairs are counted once). The preferential formation and unexpected stability of this isomer led to many questions, which we have addressed in this report. (1) What is its structure? (2) How many rearrangements are required to form this isomer from the initial bullvalene structure? (3) Why is it the preferred isomer? (4) What is the role of the substituents in its energetic preference? Our answers required synthesis, HPLC isolation, NMR characterizations, network construction and analysis, and computational (DFT) studies. The results of these efforts revealed the remarkable interconversion network of bullvalene rearrangements. The formation of this metastable isomer is preferred by both thermodynamic and kinetic factors and the ester substituent amplifies the energy difference between various structural isomers of oligosubstituted bullvalenes. The shapeshifting nature of oligosubstituted bullvalene is a useful and unusual property that has many potential applications. Insights into their rearrangements, energy landscape and substituent effect will be important knowledge for the development of these molecules towards materials, sensors and biologically active compounds.

Analysis of guest binary mixtures by tert-butylcalix[6]arene using host memory of previously bound guests by Goulnaz D. Safina; Marat A. Ziganshin; Aidar T. Gubaidullin; Valery V. Gorbatchuk (1318-1325).
A new principle of quantitative and qualitative analysis of binary organic mixtures is offered, which is based on an ability of calixarene receptor for specific polymorphic transitions related to the composition of the analyzed guest mixture. The ability of tert-butylcalix[6]arene to remember selectively some guests bound from headspace both of pure liquids and their binary mixtures is used. The image of guest mixture remains written in metastable polymorphs of host after partial or complete guest elimination from clathrates. The memory was read using differential scanning calorimetry as the enthalpy of exothermic polymorphic transition of host collapse. This enthalpy monotonously changes with the variation of guests’ ratio in mixture, unlike the enthalpies of endothermic pseudopolymorphic transitions of guest release. So, the composition of volatile binary mixture can be estimated using only one receptor and only one its parameter even in absence of preferential binding from a binary mixture of guests. This is an example of a genuine molecular recognition.

Two rotaxanes incorporating a 3,5-bis(triazole)-pyridinium axle component have been prepared using either an anion templated amide condensation or ring closing metathesis (RCM) clipping strategy. The respective yields of interlocked receptor were found to be significantly higher when the RCM clipping synthetic route was used. Proton NMR titration experiments in competitive 1 : 1 CDCl3–CD3OD solvent media reveal that the rotaxane prepared by the clipping procedure is selective for halide anions over larger, more basic oxoanions. Interestingly, the interlocked host displays an unusual preference for bromide over other halide anions.

Synthesis and evaluation of novel ellipticines as potential anti-cancer agents by Fiona M. Deane; Elaine C. O'Sullivan; Anita R. Maguire; Jayne Gilbert; Jennette A. Sakoff; Adam McCluskey; Florence O. McCarthy (1334-1344).
Drugs that inhibit DNA topoisomerase I and DNA topoisomerase II have been widely used in cancer chemotherapy. We report herein the results of a focused medicinal chemistry effort around novel ellipticinium salts which target topoisomerase I and II enzymes with improved solubility. The salts were prepared by reaction of ellipticine with the required alkyl halide and evaluated for DNA intercalation, topoisomerase inhibition and growth inhibition against 12 cancer cell lines. Results from the topoisomerase I relaxation assay indicated that all novel ellipticine derivatives behaved as intercalating agents. At a concentration of 100 μM, specific topoisomerase I inhibition was not observed. Two of the derivatives under investigation were found to fully inhibit the DNA decatenation reaction at a concentration of 100 μM, indicative of topoisomerase II inhibition. N-Alkylation of ellipticine was found to enhance the observed growth inhibition across all cell lines and induce growth inhibition comparable to that of Irinotecan (CPT-11; GI50 1–18 μM) and in some cell lines better than Etoposide (VP-16; GI50 = 0.04–5.2 μM). 6-Methylellipticine was the most potent growth inhibitory compound assessed (GI50 = 0.47–0.9 μM). N-Alkylation of 6-methylellipticine was found to reduce this response with GI50 values in the range of 1.3–28 μM.

Synthesis and properties of 2′-O-neopentyl modified oligonucleotides by Gérald Mathis; Stéphane Bourg; Samia Aci-Sèche; Jean-Christophe Truffert; Ulysse Asseline (1345-1357).
2′-O-Neopentyldeoxyuridine (Un) was synthesized and incorporated into a series of oligodeoxyribonucleotides. Single and triple incorporations in various arrangements were performed. The Watson and Crick pairing properties with complementary DNA and RNA were investigated by UV melting curves, CD spectroscopy, and molecular dynamic simulations. The results were compared to those obtained with DNA–DNA and DNA–RNA duplexes involving dU at the same positions. Oligonucleotides containing Un clearly demonstrated their ability to form duplexes with both complementary DNA and RNA but with higher stabilities for the DNA–RNA duplexes similar to the one of the parent DNA–RNA duplex. Investigations into the thermodynamic properties of these 17-base-pair duplexes revealed ΔG values (37 °C) that are in line with the measured Tm values for both the DNA–DNA and DNA–RNA duplexes. CD spectroscopic structural investigations indicated that the conformations of the DNA–DNA and DNA–RNA duplexes involving Un are similar to those of the dT–rA and dU–rA containing duplexes. Only small changes in intensities and weak blue shifts were observed when three Uns were incorporated into the duplexes. The results of the molecular dynamic simulations showed, for the six duplexes involving the modified nucleoside Un, calculated curvatures similar to those of the corresponding unmodified duplexes without base-pair disruption. The neopentyl group is able to be accommodated in the minor grooves of both the DNA–DNA and RNA–DNA duplexes. However, molecular dynamic simulations indicated that the Uns adopt a C2′-exo sugar pucker conformation close to an A-helix type without perturbing the C2′-endo sugar pucker conformations of their 2′-deoxynucleoside neighbours. These results confirm the potential of 2′-O-neopentyldeoxyuridine as a nucleoside surrogate for oligonucleotide based therapeutic strategies.

A concise one-pot synthesis of trifluoromethyl-containing 2,6-disubstituted 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines by Russell J. Johnson; Donogh J. R. O'Mahony; William T. Edwards; Matthew A. J. Duncton (1358-1366).
5,6,7,8-Tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines with appended trifluoromethyl groups are valuable chemotypes in medicinal chemistry due to the presence of a partially-saturated bicyclic ring and metabolically-stable CF3 group. 1H NMR studies were used to optimize the preparation of such compounds, using a three-step/one-pot procedure, to provide novel 2,6-disubstitued derivatives with a tertiary-substituent. Racemic 2,6-disubstituted tetrahydroquinolines were separated by chiral HPLC to provide single enantiomers.

We report a new synthetic sequence for the preparation of silylated 2,2-difluorostyrene derivatives. This new route has numerous advantages over the previous one including enhanced scope, higher yields, ease of purification, and significant reduction of the amount of desilylated side-products. An unexpected transformation of a silylated 2,2-difluorostyrene derivative is also presented.

Chemoenzymatic total synthesis of hyperiones A and B by Chicco Manzuna Sapu; Jan Deska (1376-1382).
The first asymmetric total synthesis of hyperiones A and B, two norlignans from Hypericum chinense, has been accomplished following a chemoenzymatic approach. Key features of this synthesis include the lipase-catalyzed enantioselective desymmetrization of a prochiral allenic diol and a silver-mediated cycloisomerization of the resulting axially chiral product to furnish the furan core structure. Two alternative pathways, a ruthenium-catalyzed redox isomerization on the one side and a platinum-catalyzed hydrogenation on the other, are described to finally obtain the desired norlignans.

An unexpected N-glycosidation reaction of anthracen-1-amine with glycals was identified, and its use in the synthesis of C1′ N-linked analogues of natural product marmycin A was explored. The structures of all these products were determined by 1D and 2D NMR, CD spectra, and X-ray crystal analysis. These products were then subjected to Friedel–Crafts acylation, Dess–Martin oxidation and nucleophilic addition leading to novel natural product analogues bearing a quaternary carbon center.

Cu-catalyzed direct C–H bond functionalization: a regioselective protocol to 5-aryl thiazolo[3,2-b]-1,2,4-triazoles by Zengyang Xie; Xiaojun Zhu; Yangfan Guan; Dunru Zhu; Hongwen Hu; Chen Lin; Yi Pan; Juli Jiang; Leyong Wang (1390-1398).
An efficient, regioselective C-5 arylation of thiazolo[3,2-b]-1,2,4-triazoles catalyzed by a simple copper catalyst was developed. This arylation proceeded smoothly and tolerated a variety of functional groups (44 examples). A wide range of functionalized thiazolo[3,2-b]-1,2,4-triazole derivatives were obtained in high yields (up to 99% yield). Possible catalytic cycles of the arylation were also discussed.

Reactions of nitric oxide and nitrogen dioxide with coenzyme Q: involvement of the isoprenic chain by Paola Astolfi; Laurence Charles; Didier Gigmes; Lucedio Greci; Corrado Rizzoli; Federico Sorana; Pierluigi Stipa (1399-1406).
The formation of a di-tert-alkyl nitroxide has been observed by Electron Spin Resonance during the exposure of coenzyme CoQ10, in both the oxidized and reduced forms, to nitrogen dioxide (˙NO2) or to nitric oxide (˙NO) in the presence of oxygen. The same kind of nitroxide has been observed also with CoQ1, CoQ3 or with 1-phenyl-3-methyl-2-butene, chosen as model compounds. In all cases, the formation of the nitroxide may be justified only by admitting the involvement of the isoprenic chain of the coenzymes and in particular the addition of ˙NO2 to the double bond. A mechanism which accounts for the formation of the nitroxide as well as the other compounds observed in the reactions is proposed and confirmed by a spectroscopic investigation (FT-IR, 1H NMR, X-ray analysis) and by ESI-MS.

Comprehensive studies on the tautomerization of glycine: a theoretical study by Chang Kon Kim; Byung-Ho Park; Hai Whang Lee; Chan Kyung Kim (1407-1413).
The tautomerization process of glycine between the neutral (NE) and zwitterionic (ZW) forms in aqueous solution was explored theoretically using the conductor-like polarizable continuum model (CPCM) by adopting the PAULING cavity model at the B3LYP, MP2 and CCSD levels with the 6-311+G(d,p) basis set. The tautomerization of glycine is unable to be predicted satisfactorily within the equilibrated framework of the CPCM method. Instead, in this study, three plausible non-equilibrated solvation situations were assumed: (S-1) one water molecule attached to the transferring proton in the ZW moves together with the transferring proton; (S-2) one water molecule attached to the transferring proton in the ZW remains motionless at a fixed position near the NH2 fragment at the TS structure; and (S-3) proton transfer occurs without changing the position of the surrounding water molecules from their initial state, the ZW form, in the eight water clusters. Although the calculation of (S-3) failed, the Gibbs free energies of activation for tautomerization from the ZW to NE, ΔG(ZW → NE), was well consistent with the experimental findings in the hypothetical non-equilibrated solvation states of (S-1) and (S-2). This suggests that non-equilibrium solvation is essential to explain the observed experimental data.

The excited-state proton transfer (ESPT) via proton transfer wires in green fluorescent protein (GFP) plays an important role on the spectroscopic of GFP. In this work, we use the proton transfer wires and the chromophore complex to simulate the tautomer structures of neutral state and the intermediate state in wt-GFP. And we employ the time-dependent density functional theory combined with the sum-over-states method to calculate the one- and two-photon absorption properties of these complexes in GFP. We obtain the large stokes shift from 383 nm to 500 nm in GFP when simulating the ESPT process by these isomerous H-bonding complexes. We find that the TPA spectrum of the H-bonding complex of the intermediate state agrees more with experimental measurement than that of the H-bonding complex of the neutral state. The TPA spectrum of GFP might be mainly dominated by the structure which is similar to the H-bonding complex of intermediate state. Further, we simulate another kind of complex which possess short-strong hydrogen bonds in proton transfer wires, and find that TPA properties of these complexes are much stronger than that of the complexes with the long distance proton wires from GFP.

Back cover (1423-1424).