Organic & Biomolecular Chemistry (v.16, #35)

Front cover (6361-6361).

Inside front cover (6362-6362).

Contents list (6363-6371).

It is now well recognized that the normal cellular response in mammalian cells is critically regulated by the cyclic-AMP (cAMP) pathway through the appropriate balance of adenylyl cyclase (AC) and phosphodiesterase-4 (PDE4) activities. Dysfunctions in the cAMP pathway have major implications in various diseases like CNS disorders, inflammation and cardiac syndromes and, hence, the modulation of cAMP signalling through appropriate intervention of AC/PDE4 activities has emerged as a promising new drug discovery strategy of current interest. In this context, synthetic small molecules have had limited success so far and therefore parallel efforts on natural product leads have been actively pursued. The early promise of using the diterpene forskolin and its semi-synthetic analogs as AC activators has given way to new leads in the last decade from novel natural products like the marine sesterterpenoids alotaketals and ansellones and the 9,9′-diarylfluorenone cored selaginpulvilins, etc. and their synthesis has drawn much attention. This review captures these contemporary developments, particularly total synthesis campaigns and structure-guided analog design in the context of AC and PDE-4 modulating attributes and the scope for future possibilities.

A novel photocatalytic protocol is herein described for the preparation of functionalized phenols via radical alkylation of para-quinone methides under transition-metal-free conditions. The reaction is external oxidant free and performed at ambient temperature upon visible light irradiation, allowing the access to various desired products in satisfactory yields. The readily available 4-alkyl-1,4-dihydropyridines serve as the effective alkyl radical precursors.

Semi-syntheses of the 11-hydroxyrotenoids sumatrol and villosinol by David A. Russell; Julien J. Freudenreich; Hannah L. Stewart; Andrew D. Bond; Hannah F. Sore; David R. Spring (6395-6398).
We describe semi-syntheses of the 11-hydroxyrotenoids sumatrol (1) and villosinol (2), starting from rotenone (5), using an oxime-directed C11–H functionalisation approach. Thus, rotenone (5) was converted into rotenone oxime (6), which gave dimeric palladacycle 7 following reaction with Na2PdCl4·3H2O. Controlled, divergent, oxidation of palladacycle 7 with either Pb(OAc)4 or K2Cr2O7 afforded the 11-acetoxylated intermediates 9 and 13, respectively, which were transformed into sumatrol (1) and villosinol (2).

An efficient and highly regio- and diastereoselective synthetic method to cyclobutane-containing spiro[2.3]hexane fused with six-membered hetero-cycles has been disclosed via a thermally-induced intramolecular [2 + 2] cycloaddition of acrylamide-tethered alkylidenecyclopropanes. The DFT calculations indicate that this intramolecular cycloaddition proceeds in a concerted manner and account for the product selectivity. These reactions exhibited excellent yields and functional group tolerance under metal free conditions.

Nickel catalyzed site selective C–H functionalization of α-aryl-thioamides by Debashruti Bandyopadhyay; Annaram Thirupathi; Nagsen Munjaji Dhage; Nirmala Mohanta; S. Peruncheralathan (6405-6409).
A catalytic site selective intramolecular C–S bond forming reaction is demonstrated for the first time. The C–H bond functionalization of α-aryl-thioacetanilides was efficiently catalyzed by 2 mol% NiBr2, resulting in valuable 2-aminobenzo[b]thiophenes in moderate to good yields. Furthermore, the selective sp2 C–H bond functionalization over sp3 is exemplified.

Stereoselective synthesis of 2,6-trans-4-oxopiperidines using an acid-mediated 6-endo-trig cyclisation by Jonathan D. Bell; Alexander H. Harkiss; Christopher R. Wellaway; Andrew Sutherland (6410-6422).
An acid-mediated 6-endo-trig cyclisation of amine-substituted enones has been developed for the stereoselective synthesis of trans-6-alkyl-2-methyl-4-oxopiperidines. Performed under conditions that prevent removal of the Boc-protecting group or acetal formation, the key cyclisation was found to generate cleanly the 4-oxopiperidine products in high overall yields from a wide range of alkyl substituted enones. The synthetic utility of the trans-6-alkyl-2-methyl-4-oxopiperidines formed from this process was demonstrated with the total synthesis of the quinolizidine alkaloid, (+)-myrtine and the piperidine alkaloid, (−)-solenopsin A.

Asymmetric synthesis of warfarin and its analogs catalyzed by C2-symmetric squaramide-based primary diamines by Sergei V. Kochetkov; Alexander S. Kucherenko; Sergei G. Zlotin (6423-6429).
Novel C2-symmetric N,N′-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,β-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.

Chloroform as a carbon monoxide source in palladium-catalyzed synthesis of 2-amidoimidazo[1,2-a]pyridines by P. R. Nitha; Manu M. Joseph; Greeshma Gopalan; Kaustabh Kumar Maiti; K. V. Radhakrishnan; Parthasarathi Das (6430-6437).
A palladium-catalyzed aminocarbonylation strategy exploiting chloroform as a CO source has been developed for the synthesis of biologically potent 2-amidoimidazopyridine scaffolds. The aminocarbonylation reaction was found to be general with a range of amines and substituted imidazopyridines. Preliminary biological evaluation of cytotoxicity on selected examples provides scope for future investigations.

Pd-Catalyzed C(sp2)–H aminocarbonylation using the Langlois reagent as a carbonyl source by Xiao-Fang Li; Lin-Feng Shi; Xing-Guo Zhang; Xiao-Hong Zhang (6438-6442).
A Pd-catalyzed C(sp2)–H aminocarbonylation of aryl carboxamides assisted by an N,S-bidentate directing group was developed, in which cheap and stable sodium trifluoromethanesulfinate was first utilized as a carbonyl source. The reaction can be applicable to a wide range of carboxamides with good functional group tolerance and afford isoindole-1,3-diones in moderate to good yields.

Attaching an additional binding site directed moiety or a ligand to an ATP-binding site inhibitor has been used as a strategy to increase kinase binding affinity and specificity. The moieties typically used here as the second binding partner are varied from simple organic groups to ligands such as peptides derived from substrate binding site sequences. So far these hetero-bivalent ligands were developed targeting additional binding sites closer to the ATP-binding pocket. Here we report a unique expansion of this hetero-bivalent idea by: (I) targeting a new binding site much farther away from ATP-binding site, (II) using a peptide uniquely derived from a portion of the same kinase sequence that has been reported to turn and bind to the above distance binding pocket (used as the second binding ligand), and (III) optimizing a much longer and flexible linker (to connect ATP-binding site inhibitor and above mentioned second peptide sequence) with multistep, yet complete on-bead synthesis approach. We converted a very weak EphA3-kinase ATP-binding site inhibitor-PP2 into a potent hetero-bivalent ligand by tethering to a unique 5-mer peptide sequence that derived from the linker region of EphA3 that connects kinase and sterile alpha motif (SAM) domains. Our design highlight the use of distance binding pockets to ATP-binding site as the second targeted site, while introducing the idea of extracting natural peptide sequences that already exist within the same kinase sequence, by a careful screening of available crystal structures.

Unveiling sequential late-stage methyltransferase reactions in the meleagrin/oxaline biosynthetic pathway by Sean A. Newmister; Stelamar Romminger; Jennifer J. Schmidt; Robert M. Williams; Janet L. Smith; Roberto G. S. Berlinck; David H. Sherman (6450-6459).
Antimicrobial and anti-proliferative meleagrin and oxaline are roquefortine C-derived alkaloids produced by fungi of the genus Penicillium. Tandem O-methylations complete the biosynthesis of oxaline from glandicoline B through meleagrin. Currently, little is known about the role of these methylation patterns in the bioactivity profile of meleagrin and oxaline. To establish the structural and mechanistic basis of methylation in these pathways, crystal structures were determined for two late-stage methyltransferases in the oxaline and meleagrin gene clusters from Penicillium oxalicum and Penicillium chrysogenum. The homologous enzymes OxaG and RoqN were shown to catalyze penultimate hydroxylamine O-methylation to generate meleagrin in vitro. Crystal structures of these enzymes in the presence of methyl donor S-adenosylmethionine revealed an open active site, which lacks an apparent base indicating that catalysis is driven by proximity effects. OxaC was shown to methylate meleagrin to form oxaline in vitro, the terminal pathway product. Crystal structures of OxaC in a pseudo-Michaelis complex containing sinefungin and meleagrin, and in a product complex containing S-adenosyl-homocysteine and oxaline, reveal key active site residues with His313 serving as a base that is activated by Glu369. These data provide structural insights into the enzymatic methylation of these alkaloids that include a rare hydroxylamine oxygen acceptor, and can be used to guide future efforts towards selective derivatization and structural diversification and establishing the role of methylation in bioactivity.

Campestarenes: new building blocks with 5-fold symmetry by Seong Nam; David C. Ware; Penelope J. Brothers (6460-6469).
Campestarene is a planar, shape-persistent macrocycle with 5-fold symmetry. A range of derivatives bearing peripheral functional groups suitable for generating supramolecular interactions has been designed and synthesised for potential applications in creating 2D quasicrystal molecular assemblies. The new campestarene derivatives bear ester, carboxylic acid, methoxy, bromo, 4-pyridyl, 4-cyanophenyl and 4-phenyl carboxylic acid groups, including further derivatives of the latter two bearing alkyl chains on the phenyl groups to improve solubility. The campestarene derivatives were prepared by reductive condensation of phenol precursors bearing nitro and formyl groups using Na2S2O4. The target functional groups were installed either by pre-cyclisation derivatisation or by synthesis of methoxy-substituted campestarene and subsequent derivatisation. The cyclisation reaction is tolerant of the functional groups introduced. The ten new campestarene derivatives were characterised by NMR spectroscopy and MALDI-TOF MS, although the poor solubility of some examples precluded their detailed characterisation.

Enantioselective 1,4-Michael addition reaction of pyrazolin-5-one derivatives with 2-enoylpyridines catalyzed by Cinchona derived squaramides by Vivek Sharma; Anmolpreet Kaur; Subash Chandra Sahoo; Swapandeep Singh Chimni (6470-6478).
The bifunctional nature of the cinchonidine squaramides has been successfully employed to catalyze the enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones with 2-enoylpyridines under mild reaction conditions. Through this methodology, a broad range of optically active heterocyclic derivatives bearing both pyrazole and pyridine motifs have been synthesized in yields up to 88% and enantiomeric excess up to 96%.

Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid by Anna D. Peters; Catriona McCallion; Andrew Booth; Julie A. Adams; Karen Rees-Unwin; Alain Pluen; John Burthem; Simon J. Webb (6479-6490).
A bis(cyclam)-capped cholesterol lipid designed to bind C–X–C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C–X–C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 μM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.

Nickel-catalysed radical tandem cyclisation/arylation: practical synthesis of 4-benzyl-3,3-difluoro-γ-lactams by Wen-Peng Mai; Fei Wang; Xiao-Feng Zhang; Shi-Min Wang; Qun-Peng Duan; Kui Lu (6491-6498).
Enabled by nickel catalysis, a practical access to the synthesis of 4-benzyl-3,3-difluoro-γ-lactams has been developed via radical tandem cyclisation/arylation. This method features a nickel catalyst, high reaction efficiency, and good substrate tolerance and scope. This protocol proceeds through an intramolecular radical addition to form a primary alkyl radical followed by intermolecular Suzuki-type coupling.

A glycoluril dimer–triptycene hybrid receptor: synthesis and molecular recognition properties by Wenjin Liu; Xiaoyong Lu; Zihui Meng; Lyle Isaacs (6499-6506).
The strategic combination of the methylene bridged glycoluril dimer and triptycene skeletons delivers acyclic water soluble hybrid receptor 1 which is analogous to cucurbit[6]uril. The molecular recognition properties of host 1 toward hydrophobic cationic guests are investigated in detail by a combination of 1H NMR spectroscopy and isothermal titration calorimetry (ITC) studies. The fluorescence emission of 1 can be selectively and efficiently quenched upon the formation of 1·26 and 1·28 complexes.

Based on the electronic properties of different hybridized oxygen atoms (sp3versus sp2) in the structure of O,O-acetals containing an enol ether moiety, the chemoselective formation of oxocarbenium ions was realized to furnish diversified chiral heterocyclic compounds with excellent stereoselectivities by reacting with different types of nucleophiles. Additionally, an unexpected intramolecular oxocarbenium ion transfer was also reported to form polycyclic products containing the O,O-acetal functional group.

Classical molecular dynamics and metadynamics simulations decipher the mechanism of CBP30 selectively inhibiting CBP/p300 bromodomains by Qianqian Wang; Xiaoli An; Jiahui Xu; Yuwei Wang; Liang Liu; Elaine Lai-Han Leung; Xiaojun Yao (6521-6530).
The selective modulation of individual bromodomains (BDs) by small molecules represents an important strategy for the treatment of various cancers, considering that the BD-containing proteins share common BD structures and distinct pharmacological functions. Small molecule inhibitors targeting BDs outside of the bromodomain and extraterminal domain (BET, including BRD2–4 and BRDT) family are particularly lacking. CBP30 exhibited excellent selectivity for the transcriptional coactivators CBP (CREB binding protein) and p300 bromodomains, providing a new opportunity for designing selective non-BET inhibitors. Here, we performed classical molecular dynamics (cMD) and metadynamics simulations to reveal the selective mechanism of CBP30 binding with CBP/p300 and BRD4-BD1/BD2 bromodomains. The cMD simulations combined with binding free energy calculations were performed to compare the overall features of CBP30 binding with CBP/p300 and BRD4-BD1/BD2 bromodomains. Arg1173/1137, as the unique residue for CBP/p300, was responsible for the selective binding to CBP30 via cation–π and hydrogen bond interactions. Metadynamics simulation, together with unbinding free energy profiles, suggested that the dissociation pathways of CBP30 from CBP/p300 and BRD4-BD1/BD2 bromodomains were different, with the unbinding of the former being more difficult. These findings will be helpful for novel CBP/p300-inhibitor design and rational structural modification of existing inhibitors to increase their selectivity.

Facile synthesis and fundamental properties of an N-methylguanidine-bridged nucleic acid (GuNA[NMe]) by Naohiro Horie; Shinji Kumagai; Yutaro Kotobuki; Takao Yamaguchi; Satoshi Obika (6531-6536).
An N-methylguanidine-bridged nucleic acid (GuNA[NMe]), a guanidine-bridged nucleic acid (GuNA) bearing a methyl substituent at the bridge, was successfully synthesised and incorporated into oligonucleotides. By employing an acetyl protecting group, GuNA[NMe]-modified oligonucleotides bearing acid-sensitive purine nucleobases were successfully prepared. The obtained GuNA[NMe]-modified oligonucleotides exhibit excellent binding affinity towards the complementary single-stranded RNA and DNA. Furthermore, even a single GuNA[NMe] modification provides robust enzymatic stability, similar to that achieved by the well-established phosphorothioate backbone modification. These data indicate that such a GuNA[NMe] represents a valuable modification for the development of therapeutic oligonucleotides.

A chemically engineered, stable oligomer mimic of amyloid β42 containing an oxime switch for fibril formation by Masashi Yamamoto; Kiyomichi Shinoda; Jizhi Ni; Daisuke Sasaki; Motomu Kanai; Youhei Sohma (6537-6542).
Toxic aggregation of monomeric amyloid β (Aβ) into oligomers followed by the formation of fibrils is a causative process in the pathogenesis of Alzheimer's disease. The mechanism for furnishing the toxicity of Aβ aggregates is elusive, however, mainly due to the transient, unstable properties of the oligomer states. Oligomer mimics stabilized by chemical protein engineering are potentially useful tools for elucidating the pathogenicity of Aβ aggregates. Here we report a stable Aβ oligomer mimic that is transformed into fibrils by a chemical stimulus, i.e., an oxime exchange reaction. A derivative of Aβ42[Met35(O)], compound 2, containing an oxime tether between residues 23 and 28 (a salt-bridge surrogate between Asp23 and Lys28 of the Aβ42 oligomer), rapidly and homogeneously formed stable, relatively large oligomers with preserved amyloid-like properties, such as the propensity to form β-sheets and toxicity. Chemical cleavage of the tether via an oxime exchange reaction induced transformation of the oligomers into the fibril state. These results demonstrate that the oxime bond formation/cleavage can switch the aggregation state of the mimic by functionally surrogating the salt-bridge of Aβ42. This novel system temporally dissects the dynamic process of Aβ aggregation, and thus might offer a unique molecular tool for exploring the properties of Aβ oligomers and fibrils.

Synthesis of furo[3,2-b:4,5-b′]diindoles and their optical and electrochemical properties by Huy Do Hoang; Julia Janke; Aneta Amirjanyan; Tariel Ghochikyan; Anika Flader; Alexander Villinger; Peter Ehlers; Stefan Lochbrunner; Annette-Enrica Surkus; Peter Langer (6543-6551).
An efficient two-step palladium catalyzed synthesis of furo[3,2-b:4,5-b′]diindoles, a hitherto unknown symmetrical heterocyclic core structure, was developed. The synthesis is based on a regioselective Suzuki–Miyaura cross coupling reaction of tetrabromofuran and subsequent double N-arylation. Selected compounds were studied with regard to their optical and electrochemical properties. The compounds show fluorescence with high quantum yields and non-reversible oxidation events. The compounds possess similar HOMO–LUMO band gaps compared to their sulfur and nitrogen analogs. Variation of the substituents hardly affects the HOMO–LUMO gap, but allows for some fine-tuning of the electron affinity and ionization potential as well as quantum yields. The compounds prepared represent interesting candidates for the development of organic electronic materials.

Synthesis and characterization of various 5′-dye-labeled ribonucleosides by Coralie De Schutter; Vincent Roy; Patrick Favetta; Corentin Pavageau; Stéphane Maisonneuve; Nicolas Bogliotti; Juan Xie; Luigi A. Agrofoglio (6552-6563).
Hitherto unknown chromophoric nucleosides are reported. This novel set of visibly coloured dye-labeled 5′-nucleosides, including 1,2,4,5-tetrazine, dicyanomethylene-4H-pyran, benzophenoxazinone, 9,10-anthraquinone and azobenzene chromophores, were prepared mainly under Cu-catalyzed azide–alkyne cycloaddition (CuAAC). The design criteria are outlined. Several derivatives possess in supplement a fluorescence property. The absorption and fluorescence spectra of all coloured nucleosides were recorded to study their potential as visible-range probes. Such nucleodyes are of great interest for future competitive lateral flow test MIP-based strips.

Synthesis of oxindoles through trifluoromethylation of N-aryl acrylamides by photoredox catalysis by Maojian Lu; Zhiji Liu; Jinwang Zhang; Yu Tian; Honggui Qin; Mingqiang Huang; Shirong Hu; Shunyou Cai (6564-6568).
Mild and direct intramolecular oxidative aryltrifluoromethylations of activated alkenes have been established through visible light photocatalysis, affording a range of CF3-containing oxindoles or isoquinolinediones in the presence of an organic fluorophore-type photocatalyst 4CzIPN, oxygen and visible light irradiation under strong oxidant and transition metal free conditions. A variety of frequently encountered functional groups are well tolerated in this transformation.

We have developed new triazine-based esterifying reagents comprising pyridines that can act as a nucleophilic catalyst. 1-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-3,5-lutidinium chloride (DMT-3,5-LUT) was found to exhibit a superior reactivity for the dehydrating condensation reaction between carboxylic acids and alcohols. The reaction of DMT-3,5-LUT with carboxylic acids produces intermediacy of acyloxytriazines, which is known to exhibit moderate reactivity toward alcohols, with concomitant liberation of 3,5-lutidine. The subsequent chemical transformation of the acyloxytriazines and alcohols into esters can be accelerated by the action of 3,5-lutidine as a nucleophilic catalyst. The detailed reaction mechanism revealed by a time-course analysis of the reactions is also discussed.

Rationalisation of a mechanism for sensing single point variants in target DNA using anthracene-tagged base discriminating probes by Jean-Louis H. A. Duprey; Dario M. Bassani; Eva I. Hyde; Gediminas Jonusauskas; Christian Ludwig; Alison Rodger; Neil Spencer; Joseph S. Vyle; John Wilkie; Zheng-Yun Zhao; James H. R. Tucker (6576-6585).
The labelling of DNA oligonucleotides with signalling groups that give a unique response to duplex formation depending on the target sequence is a highly effective strategy in the design of DNA-based hybridisation sensors. A key challenge in the design of these so-called base discriminating probes (BDPs) is to understand how the local environment of the signalling group affects the sensing response. The work herein describes a comprehensive study involving a variety of photophysical techniques, NMR studies and molecular dynamics simulations, on anthracene-tagged oligonucleotide probes that can sense single base changes (point variants) in target DNA strands. A detailed analysis of the fluorescence sensing mechanism is provided, with a particular focus on rationalising the high dependence of this process on not only the linker stereochemistry but also the site of nucleobase variation within the target strand. The work highlights the various factors and techniques used to respectively underpin and rationalise the BDP approach to point variant sensing, which relies on different responses to duplex formation rather than different duplex binding strengths.

An experimental and computational study on isomerically pure, soluble azaphthalocyanines and their complexes and boron azasubphthalocyanines of a varying number of aza units by Martin Liebold; Eugen Sharikow; Elisabeth Seikel; Lukas Trombach; Klaus Harms; Petr Zimcik; Veronika Novakova; Ralf Tonner; Jörg Sundermeyer (6586-6599).
Herein, we present a series of isomerically pure, peripherally alkyl substituted, soluble and low aggregating azaphthalocyanines as well as their new, smaller hybrid homologues, azasubphthalocyanines. The focus lies on the effect of the systematically increasing number of aza building blocks [–N] replacing the non-peripheral [–CH] units and their influence on the physical and photophysical properties of these chromophores. The absolute and relative HOMO–LUMO energies of azaphthalocyanines were analyzed using UV-Vis and CV and compared to the density functional theory calculations (B3LYP, TD-DFT). The lowering of the HOMO level is revealed as the determining factor for the trend in the adsorption energies by electronic structure analysis. Crystals of substituted subphthalocyanines, N2-Pc*H2 and N4-[Pc*Zn·H2O], were obtained out of DCM. For the synthesis of the valuable tetramethyltetralin phthalocyanine building block a new highly efficient synthesis involving a nearly quantitative CoII catalyzed aerobic autoxidation step is introduced replacing inefficient KMnO4/pyridine as the oxidant.

Reduction of aromatic nitriles into aldehydes using calcium hypophosphite and a nickel precursor by Rim Mouselmani; Ali Hachem; Ali Alaaeddine; Estelle Métay; Marc Lemaire (6600-6605).
Herein we report the reduction of aromatic nitriles into aldehydes with calcium hypophosphite in the presence of base and nickel(ii) complex in a water/ethanol mixture. This catalytic system reduced efficiently a series of aromatic nitriles bearing different functional groups such as –Cl, –CF3, –Br, –CH3, –OCH3, –COOCH2CH3, –OH and –CHO. The corresponding aldehydes were isolated in moderate to excellent yields (30–94%).

Back cover (6607-6608).