Organic & Biomolecular Chemistry (v.13, #29)

Front cover (7831-7832).

Contents list (7833-7840).

Supramolecular chemistry of conjugated and conformationally rigid arylene ethynylene macrocycles (AEMs) has been the subject of increasing recent interest. AEMs are suited to function as supramolecular building blocks and hosts for small molecular guests thanks to their well-defined, non-collapsible central cavities and the potential for long range ordering through intermolecular π-stacking. Their syntheses are highly modular—albeit typically lengthy—allowing access to a great structural variety of AEM candidates for applications as carbon-rich mesogens and ligands in liquid crystals, nanoporous solids, molecular electronics, and chemical sensors. In this perspective, we highlight our recent work on the inclusion complexes and porous materials constructed from AEMs. Through this prism, we reflect on the recent advances and the remaining challenges in the supramolecular chemistry of AEMs.

Benziporphyrins were first discovered over 20 years ago. Although initially they were considered to be a chemical curiosity, a wide range of benzene-containing porphyrinoid systems are now known that exhibit intriguing spectroscopic, structural and chemical properties. These systems can often generate stable organometallic derivatives, and have been shown to have applications in the development of chemical sensors and in molecular recognition studies. The characteristics of these porphyrinoid macrocycles vary from nonaromatic to highly aromatic systems, and in a few cases antiaromatic structures are formed. The variations in aromatic character are insightful and provide a deeper understanding of aromaticity and conjugation in porphyrinoid structures. In this review, the synthesis and properties of benziporphyrinoid systems is presented with a particular emphasis on the variations in aromatic characteristics.

Synthetic applications of hypophosphite derivatives in reduction by Carole Guyon; Estelle Métay; Florence Popowycz; Marc Lemaire (7879-7906).
The development of new tools for the reduction of organic functions to reach high chemo- and stereo-selectivity is an important research domain. Although, aluminum and boron hydrides are commonly used, they suffer from environmentally and safety issues. In particular, at industrial scale, the search for more specific and efficient reagents with a lower ecological impact remains one of the main objectives of organic chemists. This review captures highlights from literature concerning phosphonic and phosphinic acid derivatives as reducing agents and evaluates their potential as alternatives, in particular to boron and aluminum hydrides.

Highly stereoselective construction of novel dispirooxindole–imidazolidines via self-1,3-dipolar cyclization of ketimines by Yan-Hua Sun; Yu Xiong; Chu-Qin Peng; Wu Li; Jun-An Xiao; Hua Yang (7907-7910).
An acid-promoted self-1,3-dipolar cycloaddition of ketimines derived from isatins and benzylamines was successfully developed to assemble unprecedented dispirooxindole–imidazolidine ring systems. Generally, excellent diastereoselectivities (only a single stereoisomer formed) and good yields (up to 94%) were obtained. Consequently, this self-1,3-dipolar cycloaddition protocol offers facile access to a novel dispiroheterocyclic skeleton.

A synthesis of putative bufopyramide has shown the structure assigned to the natural product to be incorrect. The spectroscopic data for the natural product bufopyramide matches that obtained from a synthetic sample of bufoserotonin C, confirming that the two natural products are not distinct, but instead the same compound.

The synthesis of α- and α,β-functionalized azepenes and dehydropiperidines from readily prepared α-selenonyl eneformamides or enecarbamates has been achieved through Fe-catalyzed α-substitutive deselenonation, β-regioselective lithiation/trapping, and Co-catalyzed reductive cross-coupling protocols.

An efficient synthesis of isoquinolines via rhodium-catalyzed direct C–H functionalization of arylhydrazines by Sai Zhang; Daorui Huang; Guangyang Xu; Shengyu Cao; Rong Wang; Shiyong Peng; Jiangtao Sun (7920-7923).
A highly efficient rhodium-catalyzed C–H activation of arylhydrazines and coupling with internal alkynes has been realized under mild conditions. The isoquinolines have been prepared in moderate to excellent yields in high efficiency. This methodology features the use of readily available starting materials, and a simple hydrazine moiety as a directing group, in the absence of an external metal co-oxidant under an air atmosphere. The C–H bond activation and the N–N bond cleavage have been successively realized under mild conditions.

A facile and regioselective synthesis of 1-tetralones via silver-catalyzed ring expansion by Jiajia Yu; Huijun Zhao; Shuguang Liang; Xiaoguang Bao; Chen Zhu (7924-7927).
A regioselective synthesis of 1-tetralones via silver-catalyzed ring expansion is described. A variety of 1-tetralones are furnished under mild reaction conditions from tertiary cyclobutanols regardless of the electronic properties and steric hindrance of substituents, providing a new and practical method to access diverse 1-tetralone building blocks. Preliminary experimental and DFT studies revealed that a radical-mediated sequence of C–C bond cleavage/C–C bond formation is involved.

Sphingosine-1-phosphate receptor 2 (S1PR2) plays an essential role in regulating blood–brain barrier (BBB) function during demyelinating central nervous system (CNS) disease. Increased expression of S1PR2 occurs in disease-susceptible CNS regions of female versus male SJL mice and in female multiple sclerosis (MS) patients. Here we reported a novel sensitive and noninvasive method to quantitatively assess S1PR2 expression using a C-11 labeled positron emission tomography (PET) radioligand [11C]5a for in vivo imaging of S1PR2. Compound 5a exhibited promising binding potency with IC50 value of 9.52 ± 0.70 nM for S1PR2 and high selectivity over S1PR1 and S1PR3 (both IC50 > 1000 nM). [11C]5a was synthesized in ∼40 min with radiochemistry yield of 20 ± 5% (decayed to the end of bombardment (EOB), n > 10), specific activity of 222–370 GBq μmol−1 (decayed to EOB). The biodistribution study in female SJL mice showed the cerebellar uptake of radioactivity at 30 min of post-injection of [11C]5a was increased by Cyclosporin A (CsA) pretreatment (from 0.84 ± 0.04 ID% per g to 2.21 ± 0.21 ID% per g, n = 4, p < 0.01). MicroPET data revealed that naive female SJL mice exhibited higher cerebellar uptake compared with males following CsA pretreatment (standardized uptake values (SUV) 0.58 ± 0.16 vs. 0.48 ± 0.12 at 30 min of post-injection, n = 4, p < 0.05), which was consistent with the autoradiographic results. This data suggested that [11C]5a had the capability in assessing the sexual dimorphism of S1PR2 expression in the cerebellum of the SJL mice. The development of radioligands for S1PR2 to identify a clinical suitable S1PR2 PET radiotracer, may greatly contribute to investigating sex differences in S1PR2 expression that contribute to MS subtype and disease progression and it will be very useful for detecting MS in early state and differentiating MS with other patients with neuroinflammatory diseases, and monitoring the efficacy of treating diseases using S1PR2 antagonism.

A metal and base free synthesis of primary amines has been developed at ambient temperature through ipso amination of diversely functionalized organoboronic acids, employing a combination of [bis(trifluoroacetoxy)iodo]benzene (PIFA)–N-bromosuccinimide (NBS) and methoxyamine hydrochloride as the aminating reagent. The amines were primarily obtained as their trifluoroacetate salts which on subsequent aqueous alkaline work up provided the corresponding free amines. The combination of PIFA–NBS is found to be the mildest choice compared to the commonly used strong bases (e.g. n-BuLi, Cs2CO3) for activating the aminating agent. The reaction is expected to proceed via activation of the aminating reagent followed by B–N 1,2-aryl migration.

A platform for efficient, thiol-stable conjugation to albumin's native single accessible cysteine by Mark E. B. Smith; Mikael B. Caspersen; Eifion Robinson; Maurício Morais; Antoine Maruani; João P. M. Nunes; Karl Nicholls; Malcolm J. Saxton; Stephen Caddick; James R. Baker; Vijay Chudasama (7946-7949).
Herein we report the use of bromomaleimides for the construction of stable albumin conjugates via conjugation to its native, single accessible, cysteine followed by hydrolysis. Advantages over the classical maleimide approach are highlighted in terms of quantitative hydrolysis and absence of undesirable retro-Michael deconjugation.

Due to its green-chemistry advantages, the dehydrogenative Heck reaction (DHR) has experienced enormous growth over the past few decades. In this work, two competing reaction channels were comparatively studied for the Pd(OAc)2-catalyzed DHRs of arenes with alkenes, referred to herein as the arene activation mechanism and the alkene activation mechanism, respectively, which mainly differ in the involvement of the reactants in the C–H activation step. Our calculations reveal that the commonly accepted arene activation mechanism is plausible for the desired arene–alkene cross-coupling; in contrast, the alternative alkene activation mechanism is kinetically inaccessible for the desired cross-coupling, but it is feasible for the homo-coupling of alkenes. The nature of directing groups on reactants could mainly determine the dominance of the two competing reaction routes, and therefore, influence the experimental yields. A wide range of directing groups experimentally used are examined by the density functional theory (DFT) method in this work, providing theoretical guidance for screening compatible reactants.

On the interaction between the imidazolium cation and aromatic amino acids. A computational study by Ana A. Rodríguez-Sanz; Enrique M. Cabaleiro-Lago; Jesús Rodríguez-Otero (7961-7972).
Complexes formed by the imidazolium cation and the aromatic amino acids, phenylalanine, tyrosine, tryptophan, and histidine have been studied by using computational methods. Complexation energies estimated at the MP2.X level amount to −123.3, −124.6, −131.5 and −145.5 kJ mol−1 for Phe, Tyr, Trp and His, respectively. The results obtained for Phe, Tyr and Trp complexes are similar, with the most stable minima corresponding to structures with the imidazolium cation stacked over the rings. The cation forms hydrogen bonds with the amino acid while establishing cation⋯π contacts with the aromatic rings. Extended structures with the amino acids in zwitterionic form are almost equally stable, though. The interaction is controlled by electrostatics and induction, though the preference for the stacked minima is due to larger contributions from induction and dispersion despite the energy cost of folding the amino acid. His complexes exhibit a totally different behaviour, and no structures displaying cation⋯π interactions are found among the most stable minima. Most favourable complexes of His show the cation hydrogen bonded to the amino acid in extended zwitterionic form. Overall, Phe, Tyr and Trp complexes can show parallel structures in competition with similarly stable zwitterionic ones, while His only shows zwitterionic minima, with a stability even larger than any of the other aromatic amino acids, though lacking participation of the π cloud in the interaction.

DMSO/I2 mediated C–C bond cleavage of α-ketoaldehydes followed by C–O bond formation: a metal-free approach for one-pot esterification by Vunnam Venkateswarlu; K. A. Aravinda Kumar; Sorav Gupta; Deepika Singh; Ram A. Vishwakarma; Sanghapal D. Sawant (7973-7978).
A novel and efficient I2/DMSO mediated metal-free strategy is presented for the direct C–C bond cleavage of aryl-/heteroaryl- or aliphatic α-ketoaldehydes by C2-decarbonylation and C1-carbonyl oxidation to give the corresponding carboxylic acids followed by esterification in one pot, offering excellent yields in both the steps. Here, DMSO acts as the oxygen source/oxidant and this reaction works very well under both conventional heating and microwave irradiation. This is a very simple and convenient protocol.

Synthesis and evaluation of galacto-noeurostegine and its 2-deoxy analogue as glycosidase inhibitors by Stéphane Salamone; Lise L. Clement; Agnete H. Viuff; Ole Juul Andersen; Frank Jensen; Henrik H. Jensen (7979-7992).
An epimer of the known glycosidase inhibitor noeurostegine, galacto-noeurostegine, was synthesised in 21 steps from levoglucosan and found to be a potent, competitive and highly selective galactosidase inhibitor of Aspergillus oryzaeβ-galactosidase. Galacto-noeurostegine was not found to be an inhibitor of green coffee bean α-galactosidase, yeast α-glucosidase and E. coliβ-galactosidase, whereas potent but non-competitive inhibition against sweet almond β-glucosidase was established. The 2-deoxy-galacto-noeurostegine analogue was also prepared and found to be a less potent inhibitor of the same enzymes.

A chiral phosphoric acid-catalyzed asymmetric reaction of 2-indolylmethanols with 3-alkylindoles has been established, which constructed a biologically important 2,2′-bisindolylmethane scaffold in high yields and good enantioselectivities (up to 98% yield, 94 : 6 er). This protocol not only provides an efficient method for constructing a 2,2′-bisindolylmethane framework in an enantioselective form, but also promotes the development of 2-indolylmethanol-involved catalytic asymmetric transformations.

Q2DSTD NMR deciphers epitope-mapping variability for peptide recognition of integrin αvβ6 by Jessica L. Sorge; Jane L. Wagstaff; Michelle L. Rowe; Richard A. Williamson; Mark J. Howard (8001-8007).
Integrin αvβ6 is a cell surface arginine-glycine-aspartic acid (RGD)-specific heterodimeric glycoprotein that is only expressed on epithelia during processes of tissue remodelling, including cancer. The specificity and molecular nature of interactions toward this integrin are poorly understood and new insights into such processes are important to cell biologists and pharmaceutical drug discovery. This study demonstrates the application of quantitative two-dimensional saturation transfer (Q2DSTD) NMR to obtain precise details of peptide interactions with integrin αvβ6 and their correlation to specificity for the integrin. This approach highlights subtle but significant differences in ligand contact by three related 21-mer peptides: FMDV2, an αvβ6 specific peptide and DBD1 and LAP2T1 peptides that bind many αv integrins in addition to αvβ6. FMDV2 and DBD1 differ only by the cyclisation of DBD1; a process that removes αvβ6 specificity. Q2DSTD NMR demonstrates these peptides experience significantly different interactions with the integrin; FMDV contacts primarily through four residues: 6Leu, 10Leu, 12Val and 13Leu, whereas DBD1 and LAP2T1 have more widespread contacts across their sequences. Q2DSTD NMR combined two-dimensional STD with quantitation by considering the relaxation of the ligand (CRL) to provide precise ligand contact information. This study also examines the role of CRL in the Q2DSTD process and how quantitation modifies STD data and unravels epitope-mapping variability to provide precise results that differentiate interactions at the atomic level for each peptide.

Probing heterobivalent binding to the endocytic AP-2 adaptor complex by DNA-based spatial screening by F. Diezmann; L. von Kleist; V. Haucke; O. Seitz (8008-8015).
The double helical DNA scaffold offers a unique set of properties, which are particularly useful for studies of multivalency in biomolecular interactions: (i) multivalent ligand displays can be formed upon nucleic acid hybridization in a self-assembly process, which facilitates spatial screening (ii) valency and spatial arrangement of the ligand display can be precisely controlled and (iii) the flexibility of the ligand display can be adjusted by integrating nick sites and unpaired template regions. Herein we describe the use of DNA-based spatial screening for the characterization of the adaptor complex 2 (AP-2), a central interaction hub within the endocytic protein network in clathrin-mediated endocytosis. AP-2 is comprised of a core domain and two, so-called appendage domains, the α- and the β2-ear, which associate with cytoplasmatic proteins required for the formation or maturation of clathrin/AP-2 coated pits. Each appendage domain has two binding grooves which recognize distinct peptide motives with micromolar affinity. This provides opportunities for enhanced interactions with protein molecules that contain two (or more) different peptide motives. To determine whether a particular, spatial arrangement of binding motifs is required for high affinity binding we probed the distance-affinity relationships by means of DNA-programmed spatial screening with self-assembled peptide-DNA complexes. By using trimolecular and tetramolecular assemblies two different peptides were positioned in 2–22 nucleotide distance. The binding data obtained with both recombinant protein in well-defined buffer systems and native AP-2 in brain extract suggests that the two binding sites of the AP-2 α-appendage can cooperate to provide up to 40-fold enhancement of affinity compared to the monovalent interaction. The distance between the two recognized peptide motives was less important provided that the DNA duplex segments were connected by flexible, single strand segments. By contrast, the experiments with a more rigid, duplex-spaced assembly revealed marked distance dependencies. Consequences for the function of adaptor proteins are discussed.

1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity by Mohammed K. Abdel-Hamid; Kylie A. Macgregor; Luke R. Odell; Ngoc Chau; Anna Mariana; Ainslie Whiting; Phillip J. Robinson; Adam McCluskey (8016-8028).
Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.

Paleo-soraphens: chemical total syntheses and biological studies by Hai-Hua Lu; Bettina Hinkelmann; Thomas Tautz; Jun Li; Florenz Sasse; Raimo Franke; Markus Kalesse (8029-8036).
The soraphens are natural products that exhibit a molecular structure different from what would have been expected by following its polyketidal assembly line. The most significant differences are the presence of a hemiketal instead of a trisubstituted double bond and a double bond at C9 and C10 where a saturated carbon chain was expected. We were interested in the biological activity of the soraphens with architectures as described by the polyketide synthase since we hypothesized that these modifications reflect the evolutionary optimization of the soraphens. Herein we describe four additional derivatives of the so-called paleo-soraphens and their biological profiling to provide a picture of the hypothetical evolutionary optimization of this family of natural products. The syntheses required a unified and convergent strategy and their biological profiling was performed with the aid of impedance measurements. The results of these biological experiments are consistent with the proposed evolutionary optimization of the soraphens.

Pyrido[1,2-a]pyrimidinium ions – a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties by Susanta Kumar Manna; Arabinda Mandal; Suresh Kumar Mondal; Arup Kr Adak; Akash Jana; Somnath Das; Sourav Chattopadhyay; Somenath Roy; Shyamal Kr Ghorai; Shubhankar Samanta; Maidul Hossain; Mahiuddin Baidya (8037-8047).
A novel class of bridgehead nitrogen heterocycles, pyrido[1,2-a]pyrimidinium ions, has been readily synthesized by a two-step one-pot reaction in high yields (up to 93%). These ionic compounds are bench stable and moisture tolerant and have highly fluorescent properties (quantum yield up to 0.65). A characteristic bright bluish fluorescence was observed in polar solvents such as acetonitrile and fluorescent intensity gradually diminishes with decreasing the polarity of the medium, which becomes almost negligible in toluene. These compounds also show interesting bioactivity. DNA interaction, imaging, and viability experiments with human leukemic Jurkat and KG-1A cells revealed that they are potential candidates for cancer diagnosis.

Treatment of (ortho-trimethysilyl)aryl phenylsulfonates with a soluble fluoride source initiates a Truce-Smiles rearrangement leading to the formation of functionalized bi-aryls. This new carbon–carbon bond-forming reaction proceeds without recourse to transition metal catalysis, under mild reaction conditions and with good functional group compatibility.

Influence of receptor flexibility on intramolecular H-bonding interactions by Hongmei Sun; Kai Guo; Haifeng Gan; Xin Li; Christopher A. Hunter (8053-8066).
Atropisomers of a series of zinc tetraphenyl porphyrins were synthesized and used as supramolecular receptors. Rotation around the porphyrin-meso phenyl bonds is restricted by installing ortho-chlorine substituents on the phenyl groups. The chlorine substituents allowed chromatographic separation of atropisomers, which did not interconvert at room temperature. The porphyrin meso phenyl groups were also equipped with phenol groups, which led to the formation of intramolecular H-bonds when the zinc porphyrins were bound to pyridine ligands equipped with ester or amide side arms. Binding of the pyridine ligands with the conformationally locked chloroporphyrins was compared with the corresponding unsubstituted porphyrins, which are more flexible. The association constants of 150 zinc porphyrin–pyridine complexes were measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). These association constants were then used to construct 120 chemical double mutant cycles to quantify the influence of chlorine substitution on the free energy of intramolecular H-bonds formed between the phenol side arms of the porphyrins and the ester or amide side arms of the pyridine ligands. Conformational restriction leads to increases in the stability of some complexes and decreases in the stability of others with variations in the free energy contribution due to intramolecular H-bonding of −5 to +6 kJ mol−1.

When adorned with n-octyl chains azobenzene is able to disrupt a variety of calcein-loaded phospholipid liposomes. The levels of lysis observed are dependent both on the lipid headgroup and the conformation of the azobenzene compound. In all cases studied, it has been shown that the cis-conformer is more membrane-interactive than the trans-conformer, suggesting that this class of molecule could be optimised for photo-dynamic therapy applications against infectious pathogens.

Phenalenones: insight into the biosynthesis of polyketides from the marine alga-derived fungus Coniothyrium cereale by Mamona Nazir; Fayrouz El Maddah; Stefan Kehraus; Ekaterina Egereva; Jörn Piel; Alexander O. Brachmann; Gabriele M. König (8071-8079).
The marine alga-derived fungus Coniothyrium cereale is a prolific producer of phenalenones. These polyketides were shown to possess antimicrobial effects and inhibitory activity towards the protease human leucocyte elastase (HLE). The current study focused on the biosynthesis of eight different structural types of phenalenones, comprising the natural products rousselianone A′ (1), coniosclerodin (3), cereolactam (12), cereoaldomine (15), and trypethelone (16). Solid agar cultures of C. cereale were used to follow up the incorporation of [1-13C] labeled acetate into these metabolites. Taking the respective mechanisms of polyketide metabolism into account, the labeling pattern was interpreted, thus providing a hypothesis for the biosynthetic formation of the phenalenones. The polyketide skeleton of the phenanthrene-based compound cereolactam is proposed to be formed through degradation of a heptaketide by loss of two carbon atoms.

Correction: Synthesis of 2-deoxy-2,2-difluoro-α-maltosyl fluoride and its X-ray structure in complex with Streptomyces coelicolor GlgEI-V279S by Sandeep Thanna; Jared J. Lindenberger; Vishwanath V. Gaitonde; Donald R. Ronning; Steven J. Sucheck (8080-8080).
Correction for ‘Synthesis of 2-deoxy-2,2-difluoro-α-maltosyl fluoride and its X-ray structure in complex with Streptomyces coelicolor GlgEI-V279S’ by Sandeep Thanna et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c5ob00867k.

Back cover (8081-8082).