Organic & Biomolecular Chemistry (v.12, #43)

Front cover (8564-8564).

Inside front cover (8565-8565).

Contents list (8566-8573).

Inherently chiral multi-adducts of [60]fullerene represent unique chiral molecular tectons featuring fascinating optoelectronic properties. Herein we discuss the most recent progress in the synthesis of enantiomerically pure bis- and trisadducts of C60 with the inherently chiral trans-3 and all-trans-3 addition patterns utilizing cyclo-[n]-malonate tethers derived from (−)-dimethyl-2,3-O-isopropylidene-l-tartrate. Some future perspectives regarding the investigation of these chiral building blocks in modern areas of research are discussed.

Reversible deactivation radical polymerization mediated by cobalt complexes: recent progress and perspectives by Chi-How Peng; Tsung-Yao Yang; Yaguang Zhao; Xuefeng Fu (8580-8587).
Mediation of reversible deactivation radical polymerization (RDRP) by cobalt(ii) complexes (CMRP) is the most highly developed subcategory of organometallic mediated RDRP (OMRP). Attention was paid to CMRP for its unusual high efficiency observed for the control of acrylate and vinyl acetate polymerization that produced homo- and block copolymers with narrow molecular weight distribution and a predictable molecular weight. The reactions of organic radicals with cobalt(ii) metallo-radicals and organo-cobalt(iii) complexes have a central role in the pathways that mediate this type of reversible deactivation radical polymerization. The reversible deactivation pathway dominates the polymerization when cobalt(ii) complexes can reversibly deactivate the radicals to form organo-cobalt(iii) complexes. Degenerative transfer becomes the major pathway when the cobalt(ii) species fully convert to organo-cobalt(iii) complexes and the radicals in solution rapidly exchange with radicals in organo-cobalt(iii) complexes. This review describes the polymerization behavior and control mechanisms used by cobalt complexes in the mediation of reversible deactivation radical polymerization. The emerging developments for CMRP in the aqueous phase and with photo-initiation are also described, followed by the challenges and future applications of this method.

A metal-free one-pot cascade synthesis of highly functionalized biaryl-2-carbaldehydes by Chandrasekhar Challa; Jamsheena Vellekkatt; Jaice Ravindran; Ravi S. Lankalapalli (8588-8592).
A metal-free one-pot cascade annulation of acyclic substrates dienaminodioate, cinnamaldehydes and allyl amine was achieved for the synthesis of polyfunctional biaryl-2-carbaldehydes. The reaction proceeds at room temperature by a trifluoroacetic acid mediated Diels–Alder pathway. Synthetic applications of the resulting biaryl-2-carbaldehyde have been demonstrated by conversion into an array of diverse molecules with biological and materials chemistry relevance. The present work offers a complementary route to the existing metal mediated cross-coupling methods for the preparation of biaryls.

Preparation of indium nitronates and their Henry reactions by Raquel G. Soengas; Rita Acúrcio; Artur M. S. Silva (8593-8597).
Indium nitronates were readily prepared from commercially available nitroalkanes by transmetallation of the corresponding lithium nitronates with indium salts. The Henry reaction of this indium organometallics with aldehydes afforded β-nitroalkanols in moderate to high yields. The use of chiral sugar aldehydes furnished the corresponding carbohydrate-derived β-nitroalkanols with excellent stereoselectivity.

Organocatalysts of oxidative protein folding inspired by protein disulfide isomerase by John C. Lukesh III; Kristen A. Andersen; Kelly K. Wallin; Ronald T. Raines (8598-8602).
Organocatalysts derived from diethylenetriamine effect the rapid isomerization of non-native protein disulfide bonds to native ones. These catalysts contain a pendant hydrophobic moiety to encourage interaction with the non-native state, and two thiol groups with low pKa values that form a disulfide bond with a high E°′ value.

A rhodium-catalyzed ortho-cyanation of symmetrical azobenzenes is described employing N-cyano-N-phenyl-p-toluenesulfonamide as an environmentally friendly cyanide source. The present protocol allows the synthesis of various benzonitrile derivatives in moderate to good yields and tolerates many useful functional groups.

A highly enantioselective intramolecular 6-exo-trig aza-Michael addition was developed to afford chiral 3-substituted 1,2-oxazinanes in high yields (up to 99% yield) and good enantioselectivities (up to 98/2 er). These reactions were enabled by a quinine-derived primary–tertiary diamine as a catalyst and pentafluoropropionic acid (PFP) as a co-catalyst.

A design strategy for small molecule-based targeted MRI contrast agents: their application for detection of atherosclerotic plaques by Shimpei Iwaki; Kazuya Hokamura; Mikako Ogawa; Yasuo Takehara; Yasuaki Muramatsu; Takehiro Yamane; Kazuhisa Hirabayashi; Yuji Morimoto; Kohsuke Hagisawa; Kazuhide Nakahara; Tomoko Mineno; Takuya Terai; Toru Komatsu; Tasuku Ueno; Keita Tamura; Yusuke Adachi; Yasunobu Hirata; Makoto Arita; Hiroyuki Arai; Kazuo Umemura; Tetsuo Nagano; Kenjiro Hanaoka (8611-8618).
Gadolinium(iii) ion (Gd3+) complexes are widely used as contrast agents in magnetic resonance imaging (MRI), and many attempts have been made to couple them to sensor moieties in order to visualize biological phenomena of interest inside the body. However, the low sensitivity of MRI has made it difficult to develop practical MRI contrast agents for in vivo imaging. We hypothesized that practical MRI contrast agents could be designed by targeting a specific biological environment, rather than a specific protein such as a receptor. To test this idea, we designed and synthesized a Gd3+-based MRI contrast agent, 2BDP3Gd, for visualizing atherosclerotic plaques by linking the Gd3+-complex to the lipophilic fluorophore BODIPY to stain lipid-rich environments. We found that 2BDP3Gd was selectively accumulated into lipid droplets of adipocytes at the cellular level. Atherosclerotic plaques in the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits were clearly visualized in T1-weighted MR images after intravenous injection of 2BDP3Gdin vivo.

Pd(ii)-catalyzed ligand controlled synthesis of pyrazole-4-carboxylates and benzo[b]thiophene-3-carboxylates by Yogesh Daulat Dhage; Hiroki Daimon; Cheng Peng; Taichi Kusakabe; Keisuke Takahashi; Yuichiro Kanno; Yoshio Inouye; Keisuke Kato (8619-8626).
Cyclization–carbonylation of α,β-alkynic hydrazones and (o-alkynylphenyl) (methoxymethyl) sulfides with Pd(tfa)2 in DMSO/MeOH afforded methyl pyrazole-4-carboxylates and benzo[b]thiophene-3-carboxylates, respectively, in good yields. A simple change of the ligand (solvent) allowed controlled, effective switching between cyclization–carbonylation–cyclization-coupling (CCC-coupling) reactions and cyclization–carbonylation reactions.

Synthesis of fluorescent 2,3,5,6-tetraalkynylpyridines by site-selective Sonogashira-reactions of 2,3,5,6-tetrachloropyridines by Peter Ehlers; Andranik Petrosyan; Antje Neubauer; Timo Bröse; Stefan Lochbrunner; Tariel V. Ghochikyan; Ashot S. Saghyan; Peter Langer (8627-8640).
4-Substituted 2,3,5,6-tetraalkynylpyridines were prepared by tetra-fold Sonogashira reactions of the corresponding 2,3,5,6-tetrachloropyridines. 2,6-Dialkynyl-3,5-dichloropyridines were prepared by site-selective Sonogashira reactions from various 4-unsubstituted and 4-substituted tetrachloropyridines. Subsequent two-fold Sonogashira reactions of the products allowed for the synthesis of various 2,3,5,6-tetraalkynylpyridines containing different alkynyl groups. The products exhibit interesting UV/Vis and fluorescence properties. The position of absorption and emission bands can be tuned by systematic variation of the type of alkynyl substituent and by the type of substituent located at position 4 of the pyridine moiety. The presence of electron withdrawing substituents or of an alkynyl group at position 4 as well as the presence of donor substituted alkynyl groups at positions 2, 3, 5 and 6 resulted in high fluorescence quantum yields of up to 0.6, presumably due to the push–pull substitution pattern of the molecules.

Regioselective π-extension of indoles with rhodium enalcarbenoids – synthesis of substituted carbazoles by Kuldeep Singh Rathore; Mandeep Harode; Sreenivas Katukojvala (8641-8645).
An efficient Rh(ii) carboxylate and Brønsted acid catalyzed direct π-extension of indoles to 4-substituted carbazoles is developed. The reaction involves a regioselective C-3 functionalization of indole by a rhodium enalcarbenoid and a Brønsted acid assisted cyclocondensation. In addition a twofold regioselective π-extension of pyrroles to 4,8-disubstituted carbazoles has also been developed. The utility of the methodology was demonstrated with the synthesis of analogues of an hepatitis C virus replication inhibitor and a secreted phospholipase A2 (sPLA2) inhibitor.

Scalarane sesterterpenes from Thorectidae sponges as inhibitors of TDP-43 nuclear factor by Carmen Festa; Chiara Cassiano; Maria Valeria D'Auria; Cécile Debitus; Maria Chiara Monti; Simona De Marino (8646-8655).
The analysis of two Thorectidae sponge samples, Hyrtios sp. and Petrosaspongia sp., collected at Fiji Islands, led to the isolation of five new scalarane derivatives along with fifteen known compounds. Their structures were elucidated on the basis of NMR and MS spectroscopic data. The small library of natural scalarane derivatives was investigated for their ability to modulate the activity of trans-activation response DNA-binding protein of 43 kDa (TDP-43), a key factor in several neurodegenerative conditions and the study resulted in the identification of potent inhibitors of TDP-43 protein.

Highly enantioselective phosphination and hydrophosphonylation of azomethine imines: using chiral squaramide as a hydrogen bonding organocatalyst by Ling-Pei Kong; Nai-Kai Li; Shao-Yun Zhang; Xiang Chen; Min Zhao; Ya-Fei Zhang; Xing-Wang Wang (8656-8670).
Enantioselective phosphination and hydrophosphonylation reactions between azomethine imines and diarylphosphine oxides or dialkyl phosphites were respectively developed by the use of a chiral squaramide as the hydrogen bonding organocatalyst, which afforded two types of phosphorus containing product in high yields with good to excellent enantioselectivities.

The presence of 5′,8-cyclo-2′-deoxyadenosine (5′S)-cdA induces modifications in the geometry of the DNA duplex in the 5′-end direction of the strand and in the 3′-end direction of the complementary strand. As a consequence, the enzymes are probably not able to adjust their active sites in this rigid structure. Additionally, clustered DNA damage sites, a signature of ionising radiation, pose a severe challenge to a cell's repair machinery, particularly base excision repair (BER). To date, clusters containing a DNA base lesion, (5′S)-cdA, which is repaired by nucleotide excision repair, have not been explored. We have therefore investigated whether bistranded clusters containing (5′S)-cdA influence the repairability of an opposed AP site lesion, which is repaired by BER. Using synthetic oligonucleotides containing a bistranded cluster with (5′S)-cdA and an AP site at different interlesion separations, we have shown that in the presence of (5′S)-cdA on the 5′-end side, repair of the AP site by the BER machinery is retarded when the AP site is ≤8 bases from the (5′S)-cdA. However, if (5′S)-cdA is located on the 3′-end side with respect to the AP site, the effect on its repair is much weaker and totally disappears for distances ≥8 bases.

Regioselective ruthenium catalysed H–D exchange using D2O as the deuterium source by Lorenzo Piola; José A. Fernández-Salas; Simone Manzini; Steven P. Nolan (8683-8688).
An efficient and convenient ruthenium catalysed method for a regiospecific H/D exchange using D2O is described. Organic moieties such as pyridine, oxazole, imidazole, pyrazole, ester, ketone and carboxylic acid have been found effective directing groups in this transformation. In addition, the deuteration of the enantiopure (S)-Ketoprofen leads to the incorporation of three deuterium atoms with retention of molecular chirality.

Profiling substrate specificity of two series of phenethylamine analogs at monoamine oxidase A and B by Egon Heuson; Morten Storgaard; Tri H. V. Huynh; Franck Charmantray; Thierry Gefflaut; Lennart Bunch (8689-8695).
The membrane bound enzyme monoamine oxidase exist in two splice variants designated A and B (MAO-A and MAO-B) and are key players in the oxidative metabolism of monoamines in mammalians. Despite their importance and being a prevalent target for the development of inhibitors as drugs, no systematic study of substrate specificity has been reported. In this study we present a systematic study of the MAO-A and MAO-B substrate specificity profile by probing two series of phenethylamine analogs. Km and kcat values were determined for four N-alkyl analogs 2–5 and four aryl halide analogs 6–9 at MAO-A and MAO-B. A following in silico study disclosed a new adjacent compartment to the MAO-B substrate pocket defined by amino acids Tyr188, Tyr435, Tyr398, Thr399, Cys172 and Gly434. This new insight is important for the understanding of the substrate specificity of the MAO-B enzyme and will be relevant for future drug design within the field of monoamines.

Utilizing electrostatic interactions to facilitate F-18 radiolabeling of poly(amido)amine (PAMAM) dendrimers by Dong Zhou; Sung Hoon Kim; Vincent M. Carroll; Carmen S. Dence; John A. Katzenellenbogen (8696-8701).
The development of methods for the facile conjugation and radiolabeling of poly(amido)amine (PAMAM) dendrimers would be of great benefit in evaluating biomedical applications of these intriguing molecularly defined polymers. Two anionic N-hydroxysuccinimide (NHS) esters (7 and 10) were developed and radiolabeled with fluorine-18 using Cu(i)-catalyzed click reactions. The radiolabeling of a primary amine-terminated PAMAM generation-6 (G6) dendrimer with [18F]7 or [18F]10 was complete in water or methanol within 5 min at room temperature. This highly efficient conjugation reaction benefits from a high, localized concentration of these NHS esters on the surface of PAMAM dendrimers, due to the electrostatic attraction between the anionic NHS esters and the positively-charged PAMAM dendrimers. The large medium effect (pH, salt, solvent) observed for these conjugation reactions is consistent with this mechanism. This novel strategy of utilizing electrostatic interactions provides a novel, facile, and efficient method for the conjugation and radiolabeling of PAMAM dendrimers that also has potential for radiolabeling other appropriate nanoparticles.

Pyridoxine-derived bicyclic amido-, ureido-, and carbamato-pyridinols: synthesis and antiangiogenic activities by Hyunji Lee; Dong-Guk Kim; Suhrid Banskota; You Kyoung Lee; Tae-gyu Nam; Jung-Ae Kim; Byeong-Seon Jeong (8702-8710).
We recently developed an efficient and practical synthesis for a novel series of pyridoxine-derived 6-amido-2,4,5-trimethylpyridin-3-ols and found that this novel scaffold has outstanding activity to inhibit angiogenesis measured by the quantitative chick embryo chorioallantoic membrane (CAM) assay. As an effort to extend the scope of the amidopyridinol scaffold, we here report the synthesis and antiangiogenic activities of a series of bicyclic versions of the amidopyridinol including five- and six-membered cyclic amide-, cyclic urea-, and cyclic carbamate-fused pyridinols. The six membered bicyclic derivatives were prepared by the reported procedures, and the five-membered ring-fused ones were synthesized by new synthetic methods developed in this study. CAM assays showed that both six- and five-membered lactam-fused pyridinols have activities comparable to sunitinib malate, the positive control, in inhibition of vascular endothelial growth factor-induced angiogenesis. On the other hand, the urea and the carbamate derivatives showed modest to moderate antiangiogenic activities. In summary, some bicyclic aminopyridinols can provide a good platform for structural exploitation in future medicinal chemistry work.

A reactive tagging methodology was used to select the species most reactive to an acylation reagent from a solid phase library of beta hairpin peptides. Hits bearing an electron-rich aromatic residue across strand from a reactive histidine were found to competitively become N-acylated. In addition to displaying rapid N-acylation rates the hit peptide was additionally deacylated in the presence of a nucleophile, thus closing a putative catalytic cycle. Variants of the hit peptide were studied to elucidate both the magnitude (up to 18 000-fold over background, kcat/kuncat = 94 000 000, or 45-fold over Boc-histidine methyl ester) and mechanism of acyl transfer catalysis. A combination of CH–π, cation–π and HisH+–O interactions in the cationic imidazole transition state is implicated in the rate acceleration, in addition to the fidelity of the beta hairpin fold. Moreover, NMR structural data on key intermediates or models thereof suggest that a key feature of this catalyst is the ability to access several different stabilizing conformations along the catalysis reaction coordinate.

The conformations of a series of benziporphyrins, naphthiporphyrins, oxybenziporphyrins, and related structures were minimized using DFT-B3LYP/6-311++G(d,p). The relative stabilities of the tautomers for each series were calculated using M06-2X and B3LYP-D functionals, and bond lengths were obtained. The diatropic properties of each species were assessed by calculating nucleus independent chemical shifts (NICS) and the related NICSzz values. Although benziporphyrin and naphthiporphyrin tautomers essentially exhibit no aromatic properties, mono- and diprotonated species show weakly diatropic characteristics in agreement with experimental observations. Benziphlorins, intermediates in the MacDonald “3 + 1” synthesis of benziporphyrins, were also examined and tautomers with methylene units adjacent to the benzene ring were shown to be far more stable than tautomers with a CH2 bridge between two pyrrolic units. 2-Hydroxybenziporphyrin was shown to be significantly less stable than the aromatic tautomer oxybenziporphyrin, although diprotonation leads to a species with somewhat reduced diatropicity. Related systems were also analyzed and the results demonstrate that benziporphyrins and naphthiporphyrins range from structures with no measurable macrocyclic aromaticity to strongly aromatic systems that exhibit large diamagnetic ring currents.

This study presents a showcase for the novel Quantum Chemistry Electron Ionization Mass Spectrometry (QCEIMS) method on five FDA-approved drugs. The method allows a first-principles electronic structure-based prediction of EI mass spectra in principle for any molecule. The systems in this case study are organic substances of nominal masses between 404 and 853 atomic mass units and cover a wide range of functional groups and organic molecular structure motifs. The results demonstrate the widespread applicability of the QCEIMS method for the unbiased computation of EI mass spectra even for larger molecules. Its strengths compared to standard (static) or database driven approaches in such cases are highlighted. Weak points regarding the required computation times or the approximate character of the employed QC methods are also discussed. We propose QCEIMS as a viable and robust way of predicting EI mass spectra for sizeable organic molecules relevant to medicinal and pharmaceutical chemistry.

Selective chromo-fluorogenic detection of DFP (a Sarin and Soman mimic) and DCNP (a Tabun mimic) with a unique probe based on a boron dipyrromethene (BODIPY) dye by Andrea Barba-Bon; Ana M. Costero; Salvador Gil; Ramón Martínez-Máñez; Félix Sancenón (8745-8751).
A novel colorimetric probe (P4) for the selective differential detection of DFP (a Sarin and Soman mimic) and DCNP (a Tabun mimic) was prepared. Probe P4 contains three reactive sites; i.e. (i) a nucleophilic phenol group able to undergo phosphorylation with nerve gases, (ii) a carbonyl group as a reactive site for cyanide; and (iii) a triisopropylsilyl (TIPS) protecting group that is known to react with fluoride. The reaction of P4 with DCNP in acetonitrile resulted in both the phosphorylation of the phenoxy group and the release of cyanide, which was able to react with the carbonyl group of P4 to produce a colour modulation from pink to orange. In contrast, phosphorylation of P4 with DFP in acetonitrile released fluoride that hydrolysed the TIPS group in P4 to yield a colour change from pink to blue. Probe P4 was able to discriminate between DFP and DCNP with remarkable sensitivity; limits of detection of 0.36 and 0.40 ppm for DCNP and DFP, respectively, were calculated. Besides, no interference from other organophosphorous derivatives or with presence of acid was observed. The sensing behaviour of P4 was also retained when incorporated into silica gel plates or onto polyethylene oxide membranes, which allowed the development of simple test strips for the colorimetric detection of DCNP and DFP in the vapour phase. P4 is the first probe capable of colorimetrically differentiating between a Tabun mimic (DCNP) and a Sarin and Soman mimic (DFP).

Thiophene-benzoquinones: synthesis, crystal structures and preliminary coordination chemistry of derived anilate ligands by Matteo Atzori; Flavia Pop; Thomas Cauchy; Maria Laura Mercuri; Narcis Avarvari (8752-8763).
2,5-Bis(thiophene) and 2,5-bis(ethylenedioxy-thiophene) (EDOT) derivatives of 3,6-diethoxy-1,4-benzoquinone (para isomers) were prepared by Stille coupling between the 2,5-dibromo-3,6-diethoxy-1,4-benzoquinone precursors and (n-Bu)3Sn-R (R = 2-thiophenyl or 3,4-ethylenedioxy-2-thiophenyl) reagents. In a parallel series of experiments 2,6-bis(thiophene) and 2,6-EDOT-3,5-diethoxy-1,4-benzoquinone (meta isomers) were synthesized by the same strategy. The four compounds were structurally characterized. The thiophene derivatives show essentially planar conformation thanks to the conjugation and establishment of S⋯O 1,5-nonbonded interactions, while in the EDOT derivatives the thiophene moieties are twisted with respect to the benzoquinone ring because of the steric hindrance. TD-DFT calculations were performed on both para and meta thiophene isomers in order to explain the differences observed in the UV-Vis absorption spectra. The 2,5-derivatives are valuable precursors for thiophene containing anilate (An) ligands, as the first examples of electron rich substituent based anilates. The Cu(ii) complex [Cu(Th2An)(tbbpy)]·2H2O (Th2An = thiophene-anilate; tbbpy = 4,4′-bis(tert-butyl)-2,2′-bipyridine) was isolated and structurally characterized. The metal center lies within a square planar coordination geometry, while the ligands engage in a set of intermolecular contacts.

Anti-hepatitis B virus activities and absolute configurations of sesquiterpenoid glycosides from Phyllanthus emblica by Jun-Jiang Lv; Ya-Feng Wang; Jing-Min Zhang; Shan Yu; Dong Wang; Hong-Tao Zhu; Rong-Rong Cheng; Chong-Ren Yang; Min Xu; Ying-Jun Zhang (8764-8774).
During the process exploring anti-viral compounds from Phyllanthus species, eight new highly oxygenated bisabolane sesquiterpenoid glycoside phyllaemblicins G1–G8 (1–8) were isolated from Phyllanthus emblica, along with three known compounds, phyllaemblicin F (9), phyllaemblic acid (10) and glochicoccin D (11). Phyllaemblicin G2 (2), bearing a tricyclo [3.1.1.1] oxygen bridge ring system, is an unusual sesquiterpenoid glycoside, while phyllaemblicins G6–G8 (6–8) are dimeric sesquiterpenoid glycosides with two norbisabolane units connecting through a disaccharide. All the structures were elucidated by the extensive analysis of HRMS and NMR data. The relative configuration of phyllaemblicin G2 was constructed based on heteronuclear coupling constants measurement, and the absolute configurations for all new compounds were established by calculated electronic circular dichroism (ECD) using time dependent density functional theory. The sesquiterpenoid glycoside dimers 6–9 displayed potential anti-hepatitis B virus (HBV) activities, especially for the new compound 6 with IC50 of 8.53 ± 0.97 and 5.68 ± 1.75 μM towards the HBV surface antigen (HBsAg) and HBV excreted antigen (HBeAg) secretion, respectively.

Robust asymmetric synthesis of unnatural alkenyl amino acids for conformationally constrained α-helix peptides by Boris Aillard; Naomi S. Robertson; Adam R. Baldwin; Siobhan Robins; Andrew G. Jamieson (8775-8782).
The efficient asymmetric synthesis of unnatural alkenyl amino acids required for peptide ‘stapling’ has been achieved using alkylation of a fluorine-modified NiII Schiff base complex as the key step.

Back cover (8783-8784).