Organic & Biomolecular Chemistry (v.11, #7)

Front cover (1073-1073).

Inside front cover (1074-1074).

Contents list (1075-1084).

Highly efficient and chemoselective α-iodination of acrylate esters through Morita–Baylis–Hillman-type chemistry by Vittorio Pace; Gytė Vilkauskaitė; Algirdas Šačkus; Wolfgang Holzer (1085-1088).
The chemoselective α-iodination of various simple and multi-functionalised acrylic esters is efficiently accomplished by a Morita–Baylis–Hillman protocol involving the use of N-iodophthalimide, 3-quinuclidinol and KF-Celite in acetonitrile. No degradation of the obtained compounds was observed under the optimized conditions thus, furnishing α-iodoacrylates suitable for organometallic reactions (i.e. Nozaki–Kishi–Hiyama type coupling).

We have developed gold(i)-catalyzed oxidative cyclopropanation of 1,6-enynes derived from propiolamides employing diphenyl sulfoxide as an oxidant. 1,6-Enynes having a terminal alkyne and a propiolamide tether efficiently transformed into cyclopropane carboxaldehyde derivatives.

Competition between surfactant micellization and complexation by cyclodextrin by M. Cepeda; R. Daviña; L. García-Río; M. Parajó; P. Rodríguez-Dafonte; M. Pessêgo (1093-1102).
Supramolecular property systems composed of alkyltrimethylammonium surfactants and β-cyclodextrin were studied by means of a chemical probe. Solvolysis of 4-methoxybenzenesulfonyl chloride (MBSC) was used in the mixed systems with the aim of being able to determine the concentration of uncomplexed cyclodextrin in equilibrium with the micellar system. The surfactants used enabled us to vary the length of the hydrocarbon chain between 6 and 18 carbon atoms. In all cases the existence of a significant concentration of uncomplexed CD was observable in equilibrium with the micellar system. The percentage of uncomplexed cyclodextrin increases both on increasing and decreasing the surfactant alkyl chain length, being minimal for alkyl chains between 10–12 carbon atoms. This behavior is a consequence of two simultaneous processes: complexation of surfactant monomers by the cyclodextrin and surfactant self-assembly to form micellar aggregates. By using Gibbs free energies for micellization and surfactant complexation by β-CD, we can quantitatively explain the observed behavior.

Benzothiazole-2-sulfonamides react with an excess of hydroxylamine in aqueous solutions to form 2-hydroxybenzothiazole, sulfur dioxide, and the corresponding amine. Mechanistic studies that employ a combination of structure–reactivity relationships, oxygen labeling experiments, and (in)direct detection of intermediates and products reveal that the reaction proceeds via oxygen attack, and that oxygen incorporated in the 2-hydroxybenzothiazole product derives from hydroxylamine. The reaction, which is performed under mild conditions, can be used as a deprotection method for cleavage of benzothiazole-2-sulfonyl-protected amino acids.

First syntheses of the biologically active fungal metabolites pestalotiopsones A, B, C and F by Andrew Michael Beekman; Edwin Castillo Martinez; Russell Allan Barrow (1109-1115).
A synthetic approach accessing the pestalotiopsones, fungal chromones possessing a rare skeletal subtype, is reported for the first time. The synthesis of pestalotiopsone A (1) has been achieved in 7 linear steps (28%), from commercially available 3,5-dimethoxybenzoic acid and subsequently the first syntheses of pestalotiopsone B (2), C (3) and F (4) were performed utilising this chemistry. The key steps include a newly described homologation of a substituted benzoic acid to afford phenylacetate derivatives utilising Birch reductive alkylation conditions, a microwave mediated chromanone formation proceeding through an oxa-Michael cyclisation, and an IBX induced dehydrogenation to the desired chromone skeleton. The synthetic natural products were completely characterised for the first time, confirming their structures and their biological activities evaluated against a panel of bacterial pathogens.

Efficient synthesis of diverse heterobifunctionalized clickable oligo(ethylene glycol) linkers: potential applications in bioconjugation and targeted drug delivery by Lalit N. Goswami; Zachary H. Houston; Saurav J. Sarma; Satish S. Jalisatgi; M. Frederick Hawthorne (1116-1126).
Herein we describe the sequential synthesis of a variety of azide-alkyne click chemistry-compatible heterobifunctional oligo(ethylene glycol) (OEG) linkers for bioconjugation chemistry applications. Synthesis of these bioorthogonal linkers was accomplished through desymmetrization of OEGs by conversion of one of the hydroxyl groups to either an alkyne or azido functionality. The remaining distal hydroxyl group on the OEGs was activated by either a 4-nitrophenyl carbonate or a mesylate (–OMs) group. The –OMs functional group served as a useful precursor to form a variety of heterobifunctionalized OEG linkers containing different highly reactive end groups, e.g., iodo, –NH2, –SH and maleimido, that were orthogonal to the alkyne or azido functional group. Also, the alkyne- and azide-terminated OEGs are useful for generating larger discrete poly(ethylene glycol) (PEG) linkers (e.g., PEG16 and PEG24) by employing a Cu(i)-catalyzed 1,3-dipolar cycloaddition click reaction. The utility of these clickable heterobifunctional OEGs in bioconjugation chemistry was demonstrated by attachment of the integrin (αvβ3) receptor targeting peptide, cyclo-(Arg-Gly-Asp-d-Phe-Lys) (cRGfKD) and to the fluorescent probe sulfo-rhodamine B. The synthetic methodology presented herein is suitable for the large scale production of several novel heterobifunctionalized OEGs from readily available and inexpensive starting materials.

Assessment of a putative proton relay in Arabidopsis cinnamyl alcohol dehydrogenase catalysis by Choonseok Lee; Diana L. Bedgar; Laurence B. Davin; Norman G. Lewis (1127-1134).
Extended proton relay systems have been proposed for various alcohol dehydrogenases, including the Arabidopsis thaliana cinnamyl alcohol dehydrogenases (AtCADs). Following a previous structural biology investigation of AtCAD5, the potential roles of three amino acid residues in a putative proton relay system, namely Thr49, His52 and Asp57, in AtCAD5, were investigated herein. Using site-directed mutagenesis, kinetic and isothermal titration calorimetry (ITC) analyses, it was established that the Thr49 residue was essential for overall catalytic conversion, whereas His52 and Asp57 residues were not. Mutation of the Thr49 residue to Ala resulted in near abolition of catalysis, with thermodynamic data indicating a negative enthalpic change (ΔH), as well as a significant decrease in binding affinity with NADPH, in contrast to wild type AtCAD5. Mutation of His52 and Asp57 residues by Ala did not significantly change either catalytic efficiency or thermodynamic parameters. Therefore, only the Thr49 residue is demonstrably essential for catalytic function. ITC analyses also suggested that for AtCAD5 catalysis, NADPH was bound first followed by p-coumaryl aldehyde.

A convenient chemical-microbial method for developing fluorinated pharmaceuticals by Tara V. Bright; Fay Dalton; Victoria L. Elder; Cormac D. Murphy; Neil K. O'Connor; Graham Sandford (1135-1142).
A significant proportion of pharmaceuticals are fluorinated and selecting the site of fluorine incorporation can be an important beneficial part a drug development process. Here we describe initial experiments aimed at the development of a general method of selecting optimum sites on pro-drug molecules for fluorination, so that metabolic stability may be improved. Several model biphenyl derivatives were transformed by the fungus Cunninghamella elegans and the bacterium Streptomyces griseus, both of which contain cytochromes P450 that mimic oxidation processes in vivo, so that the site of oxidation could be determined. Subsequently, fluorinated biphenyl derivatives were synthesised using appropriate Suzuki–Miyaura coupling reactions, positioning the fluorine atom at the pre-determined site of microbial oxidation; the fluorinated biphenyl derivatives were incubated with the microorganisms and the degree of oxidation assessed. Biphenyl-4-carboxylic acid was transformed completely to 4′-hydroxybiphenyl-4-carboxylic acid by C. elegans but, in contrast, the 4′-fluoro-analogue remained untransformed exemplifying the microbial oxidation – chemical fluorination concept. 2′-Fluoro- and 3′-fluoro-biphenyl-4-carboxylic acid were also transformed, but more slowly than the non-fluorinated biphenyl carboxylic acid derivative. Thus, it is possible to design compounds in an iterative fashion with a longer metabolic half-life by identifying the sites that are most easily oxidised by in vitro methods and subsequent fluorination without recourse to extensive animal studies.

Highly selective azadipeptide nitrile inhibitors for cathepsin K: design, synthesis and activity assays by Xing-Feng Ren; Hong-Wei Li; Xuexun Fang; Yuqing Wu; Lincong Wang; Shuxue Zou (1143-1148).
We have developed a series of azadipeptide nitriles with different P3 groups. A triaryl meta-phenyl derivative, compound 13, was not only a potent inhibitor for cathepsin K (Ki = 0.0031 nM), but also highly selective over both cathepsins B and S (∼1000-fold). A protein–ligand docking study performed on the series provided a possible explanation why compound 13 could be significantly more potent than the others, especially compound 12 in the same series.

Understanding defence pathways of plants is crucial to develop disease-resistant agronomic crops, an important element of sustainable agriculture. For this reason, natural plant defenses such as phytoalexins, involved in protecting plants against microbial pathogens, have enormous biotechnological appeal. Crucifers are economically important plants, with worldwide impact as oilseeds, vegetables of great dietetic value and even nutraceuticals. Notably, the intermediates involved in the biosynthetic pathways of unique cruciferous phytoalexins such as rapalexin A and isocyalexin A remain unknown. Toward this end, using numerous perdeuterated compounds, we have established the potential precursors of these unique phytoalexins and propose for the first time their detailed biosynthetic pathway. This pathway involves a variety of intermediates and a novel amino acid as the central piece of this complex puzzle. This work has set the stage for the discovery of enzymes and genes of the biosynthetic pathway of cruciferous phytoalexins of unique scaffolds.

A general solid phase method for the synthesis of depsipeptides by Mary M. Nguyen; Nicole Ong; Laura Suggs (1167-1170).
Herein we describe the synthesis of depsipeptide sequences in which the backbone is composed of alternating esters and amides. Our methodology is based on the synthesis and protection of a depsidipeptide block, which is used as the growing unit for manual SPPS. We have explored Fmoc/OBzl and Fmoc/tBu SPPS strategies, and found the latter to be most compatible with our methodology.

A novel method for the synthesis of pyrazolo[1,5-a]quinolines under the transition-metal-free conditions has been developed. This method involves a novel combination of aromatic nucleophilic substitution and Knoevenagel condensation reactions to give pyrazolo[1,5-a]quinolines.

Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines by Hari Prasad Kokatla; Euna Yoo; Deepak B. Salunke; Diptesh Sil; Cameron F. Ng; Rajalakshmi Balakrishna; Subbalakshmi S. Malladi; Lauren M. Fox; Sunil A. David (1179-1198).
Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers.

Bis-vinyl selenides obtained via iron(iii) catalyzed addition of PhSeSePh to alkynes: synthesis and antinociceptive activity by Glaubia Sartori; José S. S. Neto; Ana Paula Pesarico; Davi F. Back; Cristina W. Nogueira; Gilson Zeni (1199-1208).
In the present study the synthesis and antinociceptive activity of bis-vinyl selenides, prepared via FeCl3 promoted reaction addition of diorganyl dichalcogenides to alkynes, is described. The pharmacological results demonstrated that bis-vinyl selenides 3a, 3d, 3h and 3t elicited antinociceptive effect in the mouse formalin test. The antinociceptive effects of bis-vinyl selenides are not sensitive to electronic effects of the substituents on the aromatic ring directly bonded to the selenium atom. Bis-vinyl selenides 3h and 3t were the most promising molecules for pharmacological purposes since these bis-vinyl selenides were effective in both phases of the formalin test and against edema. A single dose of bis-vinyl selenides 3a, 3d, 3h and 3t did not cause acute toxicity in mice.

The reduction of unprotected indoles and quinolines is described using water as a hydrogen source. The method is based on the application of a RANEY® type Ni–Al alloy in an aqueous medium. During the reaction the Al content of the alloy, used as reductants, reacts with water in situ providing hydrogen and a RANEY® Ni catalyst, thus the alloy serves as a hydrogen generator as well as a hydrogenation catalyst. The simplicity and efficacy of the method are illustrated by the selective reduction of a variety of substituted indoles and quinolines to indolines and tetrahydroquinolines, respectively.

Metal-catalyzed rearrangements of 3-allenyl 3-hydroxyindolin-2-ones in the presence of halogenated reagents by Benito Alcaide; Pedro Almendros; Amparo Luna; Natividad Prieto (1216-1225).
The reactions of 3-allenyl 3-hydroxyoxindoles with a variety of halogenated reagents in the presence of catalytic amounts of precious metal salts were explored. Both, rearrangement and oxycyclization reactions to give 4-(1-halovinyl)-quinolinediones or spirocyclic halooxindoles, respectively, are competitive pathways. The kind of functionalization is substrate and reaction conditions dependent.

Synthesis of α-iodoketals from methyl ketones via sustainable and orthogonal tandem catalysis by Yan Yang; Meng Gao; Wen-Ming Shu; Liu-Ming Wu; Dong-Xue Zhang; An-Xin Wu (1226-1233).
A highly efficient method for the direct synthesis of α-iodoketals from methyl ketones has been developed via sustainable integration of orthogonal tandem catalytic reactions: copper(ii) oxide catalyzed iodination reaction and the subsequent excess or regenerated iodine catalyzed regioselective ketalization reaction.

The formations of host–guest complexes between cucurbit[7]uril and a series of N-substituted N-methylpiperidinium, N-methylpyrrolidinium, and N-methylmorpholinium cations in aqueous solution have been investigated using 1H NMR spectroscopy and electrospray ionization mass spectrometry. Dications comprising the N-methylheterocyclic head groups, bridged by a decamethylene chain, form sequential 1 : 1 ([2]pseudorotaxanes) and 2 : 1 host–guest complexes with cucurbit[7]uril. The cucurbituril initially resides over the decamethylene chain, however with further additions of the host molecule a translocation of the hosts to the cationic N-heterocyclic head groups occurs. The order of the magnitude of the cucurbituril host–guest stability constants, determined by competitive 1H NMR binding experiments, follows the trend in the hydrophobicity of the quaternary ammonium cations.

Low molecular weight PEI-based biodegradable lipopolymers as gene delivery vectors by Miao-Miao Xun; Xue-Chao Zhang; Ji Zhang; Qian-Qian Jiang; Wen-Jing Yi; Wen Zhu; Xiao-Qi Yu (1242-1250).
Non-viral gene vectors play an important role in the development of gene therapy. In this report, different hydrophobic chains were introduced into low molecular weight (LMW) PEI-based biodegradable oligomers to form a series of lipopolymers (LPs), and their structure–activity relationships were studied. Results revealed that the nine polymers can condense plasmid DNA well to form nanoparticles with appropriate sizes (120–250 nm) and positive zeta-potentials (+25–40 V). In vitro experiments were carried out and it was found that LP2 showed much higher transfection efficiency both in the presence and in the absence of serum under the polymer/DNA weight ratio of 0.8 in A549 cells.

Eleven new highly oxygenated triterpenoids from the leaves and stems of Schisandra chinensis by Qiu-Yan Song; Kan Jiang; Qian-Qian Zhao; Kun Gao; Xiao-Jie Jin; Xiao-Jun Yao (1251-1258).
Eleven new triterpenoids, schinchinenins A–H (1–8) and schinchinenlactones A–C (9–11) together with three known triterpenoids, henrischinins A–C (12–14), were isolated from the leaves and stems of Schisandra chinensis by bioassay-guided fractionation. Schinchinenin A (1) is the first example of a highly oxygenated triterpenoid characterized by a 5/5/7/6/5-fused pentacyclic ring and a 3-one-2-oxabicyclo[3.2.1]-octane moiety. Schinchinenins E and F (5 and 6) are highly oxygenated triterpenoids that contain a hydroperoxyl moiety, which is rare in compounds from the Schisandra genus. The structures and stereochemistry of 1–11 were elucidated using spectroscopic analysis, single-crystal X-ray diffraction, computational optical rotation, chemical transformation, and CD exciton chirality methods. The activities of compounds 1, 2, 7, and 12–14 against HSV-2 and adenovirus were evaluated for the first time, and of these compounds, 13 was the most active inhibitor of HSV-2, with a selectivity index value as high as 29.95.

Back cover (1259-1260).