Organic & Biomolecular Chemistry (v.14, #1)

Front cover (1-1).

Contents list (3-15).

The development of chemoselective reactions is a cornerstone of bioorganic chemistry and chemical ligation. Our contributions in this area include the development of two mechanistically distinct amide bond forming reactions, the α-ketoacid–hydroxylamine (KAHA) ligation for the chemical synthesis of proteins and the potassium acyltrifluoroborate (KAT) ligation for bioconjugation. The remarkable stability and unique reactivity of KATs with hydroxylamines prompted us to explore other acylborons as a ligation partner, which have been unappreciated in synthetic organic chemistry. A new convenient synthetic route was devised from KATs and suitable bidentate ligands, allowing for the preparation of a wide range of new acylboronates that retain one fluoride ligand on the boron. Our results established that a ligand on the boron is responsible for their reactivity and stability and provide a firm basis for further development of the acylboron–hydroxylamine amide bond forming ligation.

Metal catalyzed defunctionalization reactions by Atanu Modak; Debabrata Maiti (21-35).
Defunctionalization has a direct impact on the synthesis of value added products (e.g. biomass degradation). In synthetic chemistry it enables the functional group to act as a transient directing group. In this mini review, we have described the chronological development of metal assisted defunctionalization reactions from the stoichiometric to the catalytic stage with their application in synthetic organic chemistry. The proposed catalytic cycles of the transformations have been described to make this review comprehensible.

Solvent-induced emission of organogels based on tris(phenylisoxazolyl)benzene by Toshiaki Ikeda; Tetsuya Masuda; Midori Takayama; Hiroaki Adachi; Takeharu Haino (36-39).
Luminescent organogels based on tris(phenylisoxazolyl)benzene possessing perylenebisimide 1 were synthesized. The emission properties of the gels varied depending on the solvent properties: 1,4-dioxane gel was highly emissive, pyridine gel was moderately emissive, and benzene gel was non-emissive.

Photoswitchable anticancer activity via trans–cis isomerization of a combretastatin A-4 analog by Jonathon E. Sheldon; M. Michael Dcona; Charles E. Lyons; John C. Hackett; Matthew C. T. Hartman (40-49).
Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization. The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13–35 fold enhancement in potency upon illumination. EC50 values in the light were in the mid nM range. Due to its ability to thermally revert to less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Azo-CA4 is less potent than CA-4 because it degrades in the presence of glutathione as evidenced by UV-Vis spectroscopy and ESI-MS. Nevertheless, Azo-CA4 represents a promising strategy for switchable potency for treatment of cancer.

Trienamine catalyzed asymmetric synthesis and biological investigation of a cytochalasin B-inspired compound collection by Magnus Sellstedt; Melanie Schwalfenberg; Slava Ziegler; Andrey P. Antonchick; Herbert Waldmann (50-54).
Due to their enhanced metabolic needs many cancers need a sufficient supply of glucose, and novel inhibitors of glucose import are in high demand. Cytochalasin B (CB) is a potent natural glucose import inhibitor which also impairs the actin cytoskeleton leading to undesired toxicity. With a view to identifying selective glucose import inhibitors we have developed an enantioselective trienamine catalyzed synthesis of a CB-inspired compound collection. Biological analysis revealed that indeed actin impairment can be distinguished from glucose import inhibition and led to the identification of the first selective glucose import inhibitor based on the basic structural architecture of cytochalasin B.

With the aid of an axially chiral 2,2′-bipyridine ligand, we have successfully developed a palladium-catalyzed method for the enantioselective arylation of N-tosylarylimines, furnishing the chiral diarylmethamines with high yields and enantioselectivities under very mild conditions. An exogenous base was avoided and imine hydrolysis was inhibited in this transformation.

Accelerated cellular on- and off-target screening of bioactive compounds using microarrays by Jiaqi Fu; Zhenkun Na; Bo Peng; Mahesh Uttamchandani; Shao Q. Yao (59-64).
In situ proteome labeling was carried out with 9 drug-like probes in live mammalian cells, with the corresponding cellular targets captured on microarrays and simultaneously screened using a diverse set of antibodies, revealing potential on- and off-targets.

Dual-responsive vesicles formed by an amphiphile containing two tetrathiafulvalene units in aqueous solution by Xiao-Jun Wang; Ling-Bao Xing; Bin Chen; Ying Quan; Chen-Ho Tung; Li-Zhu Wu (65-68).
The first example of tetrathiafulvalene (TTF)-based vesicle fabricated in water solution with 1 vol.% tetrahydrofuran that could be prevented by chemical oxidant Fe(ClO4)3 or electron-deficient cyclobis(paraquat-p-phenylene) tetracation cyclophane (CBPQT4+) is described.

The generation of cyclopent-2-enylzinc from cyclopentadiene based on a titanium-catalyzed hydroalumination/transmetallation sequence is described. Applied to the allylmetallation of phenylglycinol-derived imines, this sequence leads to homoallylic amines with moderate to good stereoselectivities. The synthesis of disubstituted azetidines and piperidines illustrates the potential of the method.

Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin by Vitaliy M. Sviripa; Ravshan Burikhanov; Josiah M. Obiero; Yaxia Yuan; Justin R. Nickell; Linda P. Dwoskin; Chang-Guo Zhan; Chunming Liu; Oleg V. Tsodikov; Vivek M. Rangnekar; David S. Watt (74-84).
Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or “arylquins” induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner. A structure–activity study identified arylquins that promote Par-4 secretion, and an evaluation of arylquin binding to the hERG potassium ion channel using a [3H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par-4 secretory activity. A binding study that relied on the natural fluorescence of arylquins and that used the purified rod domain of vimentin (residues 99-411) suggested that the mechanism behind Par-4 release involved arylquin binding to multiple sites in the rod domain.

Synthesis of 3-substituted isoindolin-1-ones via a tandem desilylation, cross-coupling, hydroamidation sequence under aqueous phase-transfer conditions by Socrates B. Munoz; Alexandra N. Aloia; Alexander K. Moore; Attila Papp; Thomas Mathew; Santos Fustero; George A. Olah; G. K. Surya Prakash (85-92).
A simple and expedient method for the synthesis of 3-methylene-isoindolin-1-ones 4 under aqueous phase-transfer conditions has been developed. Starting from 2-iodobenzamides 1 and (silyl)alkynes, the products are obtained in high yields and short reaction times (30 min) with the use of inexpensive CuCl/PPh3 catalyst system in the presence of n-Bu4NBr (TBAB) as a phase-transfer agent. Terminal alkynes are conveniently “unmasked” upon in situ desilylation under the reaction conditions. Alkynes possessing heterocyclic moieties were also found as amenable substrates. Furthermore, a one-pot process starting from 2-iodobenzamides 1, aryl halides (bromides or iodides) and trimethylsilylacetylene (TMSA) as a convenient acetylene surrogate was also shown to be feasible under Pd/Cu catalysis.

The highly enantio- and diastereoselective aldol reaction of isocyanoacetates catalysed by Ag2O and cinchona-derived amino phosphines applied to the synthesis of (−)- and (+)-chloramphenicol is described. The concise synthesis showcases the utility of this catalytic asymmetric methodology for the preparation of bioactive compounds possessing α-amino-β-hydroxy motifs.

Investigation of benzoyloximes as benzoylating reagents: benzoyl-Oxyma as a selective benzoylating reagent by Satvika Burugupalli; Sayali Shah; Phillip L. van der Peet; Seep Arora; Jonathan M. White; Spencer J. Williams (97-104).
Hydroxybenzotriazole (HOBt) and HOBt-derived reagents have been classified as Class I explosives, with restrictions on their transportation and storage. We explored a range of benzoylated oxime-based reagents as alternatives to benzoyloxybenzotriazole (BBTZ) for the selective benzoylation of carbohydrate polyols. Benzoylated oximes derived from 2-hydroximino-malononitrile, ethyl 2-hydroximino-2-cyanoacetate (Oxyma), and tert-butyl 2-hydroximino-2-cyanoacetate were most effective for benzoylation of a simple primary alcohol, with yields approaching that obtained for BBTZ. When applied to carbohydrate diols, the most effective reagent was identified as benzoyl-Oxyma. Benzoyl-Oxyma is a highly crystalline, readily prepared alternative to BBTZ, useful in the selective benzoylation of carbohydrate polyols.

Evaluation of fluoropyruvate as nucleophile in reactions catalysed by N-acetyl neuraminic acid lyase variants: scope, limitations and stereoselectivity by Jennifer Stockwell; Adam D. Daniels; Claire L. Windle; Thomas A. Harman; Thomas Woodhall; Tomas Lebl; Chi H. Trinh; Keith Mulholland; Arwen R. Pearson; Alan Berry; Adam Nelson (105-112).
The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3-dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C–C bond formation.

Staphylococcus aureus uses short macrocyclic peptides (i.e., autoinducing peptides, or AIPs) to assess its local population density in a cell–cell signaling mechanism called quorum sensing (QS). At high cell numbers, this pathogen can initiate many virulent behaviors that allow for the establishment of infection. Binding of the AIP signal to its cognate transmembrane AgrC-type receptor is a critical event in the QS signaling cascade; consequently, interference of AIP:receptor interactions may have the potential to prevent and eradicate certain S. aureus infections. To date, four pairs of AIP:AgrC receptors have been identified in S. aureus, each pair being utilized by a specific S. aureus group (I–IV). Other staphylococcal species also use closely related, but distinct, AIP:AgrC pairs to control QS. We seek to develop non-native ligands capable of intercepting AIP:AgrC binding in each S. aureus group and in related species. As these bacteria may use their respective AIP signal to attenuate the QS systems of other groups/species, such ligands would provide valuable chemical tools to probe possible interference mechanisms in a range of contexts. In the current study, we used solution-phase NMR techniques to characterize the 3-D structures of a set of known native and non-native peptides that have differential modulatory activity in certain AgrC receptors. Analysis of these structures revealed several distinct structural motifs that belay differential activity in selected S. aureus AgrC receptors (i.e., AgrC-I, AgrC-II, and AgrC-III). The results of this study can be leveraged for the design of new synthetic ligands with enhanced selectivities and potencies for these AgrC receptors.

We have developed a highly efficient synthetic route to carbazoles that employs sequential C–C/C–N bond formation via Suzuki cross-coupling and Cadogan cyclization using commercially available or easily preparable starting materials. The developed method is compatible with electron neutral, rich or deficient substrates. The synthetic utility of this method was demonstrated by the concise syntheses of four natural products (glycozoline, glycozolicine, glycozolidine and clausenalene).

An efficient stereoselective synthesis of the nuphar alkaloid, (−)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C–C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.

Multivalency effects on Pseudomonas aeruginosa biofilm inhibition and dispersal by glycopeptide dendrimers targeting lectin LecA by Myriam Bergmann; Gaëlle Michaud; Ricardo Visini; Xian Jin; Emilie Gillon; Achim Stocker; Anne Imberty; Tamis Darbre; Jean-Louis Reymond (138-148).
The galactose specific lectin LecA partly mediates the formation of antibiotic resistant biofilms by Pseudomonas aeruginosa, an opportunistic pathogen causing lethal airways infections in immunocompromised and cystic fibrosis patients, suggesting that preventing LecA binding to natural saccharides might provide new opportunities for treatment. Here 8-fold (G3) and 16-fold (G4) galactosylated analogs of GalAG2, a tetravalent G2 glycopeptide dendrimer LecA ligand and P. aeruginosa biofilm inhibitor, were obtained by convergent chloroacetyl thioether (ClAc) ligation between 4-fold or 8-fold chloroacetylated dendrimer cores and digalactosylated dendritic arms. Hemagglutination inhibition, isothermal titration calorimetry and biofilm inhibition assays showed that G3 dendrimers bind LecA slightly better than their parent G2 dendrimers and induce complete biofilm inhibition and dispersal of P. aeruginosa biofilms, while G4 dendrimers show reduced binding and no biofilm inhibition. A binding model accounting for the observed saturation of glycopeptide dendrimer galactosyl groups and LecA binding sites is proposed based on the crystal structure of a G3 dendrimer LecA complex.

Increased duplex stabilization in porphyrin-LNA zipper arrays with structure dependent exciton coupling by Daniel G. Singleton; Rohanah Hussain; Giuliano Siligardi; Pawan Kumar; Patrick J. Hrdlicka; Nina Berova; Eugen Stulz (149-157).
Porphyrins were attached to LNA uridine building blocks via rigid 5-acetylene or more flexible propargyl-amide linkers and incorporated into DNA strands. The systems show a greatly increased thermodynamic stability when using as little as three porphyrins in a zipper arrangement. Thermodynamic analysis reveals clustering of the strands into more ordered duplexes with both greater negative ΔΔS and ΔΔH values, and less ordered duplexes with small positive ΔΔS differences, depending on the combination of linkers used. The exciton coupling between the porphyrins is dependent on the flanking DNA sequence in the single stranded form, and on the nature of the linker between the nucleobase and the porphyrin in the double stranded form; it is, however, also strongly influenced by intermolecular interactions. This system is suitable for the formation of stable helical chromophore arrays with sequence and structure dependent exciton coupling.

A method for investigating the stereochemical course of terpene cyclisations by Patrick Rabe; Jan Rinkel; Tim A. Klapschinski; Lena Barra; Jeroen S. Dickschat (158-164).
Three sesquiterpene cyclases from Streptomyces scabei 87.22, Streptomyces venezuelae ATCC 10712 and Streptomyces clavuligerus ATCC 27064 were characterised and their products were identified as (−)-neomeranol B, (+)-isodauc-8-en-11-ol and (+)-intermedeol, respectively. The stereochemical courses of the terpene cyclisations were investigated by use of various 13C-labelled FPP isotopomers. A quick and easy test was developed that allows to distinguish reprotonations of olefinic double bonds in neutral intermediates from the two stereoheterotopic faces. The method makes use of incubating 13C-FPP isotopomers labelled at the reprotonated carbon in deuterium oxide and subsequent HSQC analysis of the product. A 1,7-cyclisation towards (+)-isodauc-8-en-11-ol was followed by use of (1,7-13C2)FPP. Surprisingly, the (+)-isodauc-8-en-11-ol also accepted (2Z,6E)-FPP resulting in the same product profile as obtained from (2E,6E)-FPP.

DBU-mediated metal-free oxidative cyanation of α-amino carbonyl compounds: using molecular oxygen as the oxidant by Lei Li; Qian Wang; Pei Liu; Hua Meng; Xing-Lan Kan; Qun Liu; Yu-Long Zhao (165-171).
A novel DBU-mediated oxidative cyanation of α-amino carbonyl compounds by using air as the sole oxidant was developed under mild metal-free conditions for the first time. The reaction involves a tandem oxidation/Strecker reaction/oxidation process and provides a new and efficient method for the construction of α-iminonitriles in good to high yields in a single step.

Synthesis of dibenzylamino-1-methylcyclohexanol and dibenzylamino-1-trifluoromethylcyclohexanol isomers by D. Heulyn Jones; Stefano Bresciani; James P. Tellam; Justyna Wojno; Anthony W. J. Cooper; Alan R. Kennedy; Nicholas C. O. Tomkinson (172-182).
The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethylcyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally assigned through a combination of NMR spectroscopy and single crystal X-ray analysis. The cis-isomer of 3-N,N-dibenzylamino-1-trifluoromethylcyclohexanol and its derivatives display an unusual conformational behaviour in both solution-phase and the solid-state, where the amino group usually adopts an axial conformation.

Flexible synthesis of polyfunctionalised 3-fluoropyrroles by Thomas J. Cogswell; Craig S. Donald; Rodolfo Marquez (183-190).
An efficient and selective approach for the synthesis of polyfunctionalised 3-fluoropyrroles has been developed starting from commercial aldehydes. The methodology is concise, efficient and allows for the modular and systematic assembly of polysubstituted 3-fluoropyrroles. This synthesis provides an alternative and highly convergent strategy for the generation of these chemically and biologically important units.

Highly selective, sensitive and fluorescent sensing of dimeric G-quadruplexes by a dimeric berberine by Chun-Qiong Zhou; Jian-Wei Yang; Cheng Dong; Yong-Min Wang; Bin Sun; Jin-Xiang Chen; Ya-Shi Xu; Wen-Hua Chen (191-197).
This paper describes the highly selective, sensitive and topology-specific fluorescent sensing of dimeric G-quadruplexes by a polyether-tethered dimeric berberine 1. Compound 1 displays high selectivity for dimeric G-quadruplexes over monomeric ones, and can be lit up by dimeric G-quadruplexes, in particular by the one linked with one TTA subunit. In addition, it shows no effect on the topology or thermal stability of the G-quadruplexes.

Total synthesis and preliminary SAR study of (±)-merochlorins A and B by Hongzhi Yang; Xue Liu; Qingong Li; Longbo Li; Jing-Ren Zhang; Yefeng Tang (198-205).
A modular synthesis of merochlorins A and B, two naturally occurring antibiotics, has been achieved concisely from readily available building blocks in 4–6 steps. The key steps include the bio-inspired tandem phenol oxidative dearomatization/[5 + 2] and [3 + 2] cycloadditions to construct the tricyclic cores of the targets, and the intermolecular Diels–Alder reaction followed by dehydrogenative aromatization to assemble the remaining aromatic units. The antibacterial activities of merochlorins A, B and some advanced synthetic intermediates were also evaluated, which provided valuable information on the structure–activity relationship (SAR) of this class of new antibiotics.

A simple and practical method for the determination of rate constants for trifluoromethyl radical addition to various alkenes by applying competition kinetics is introduced. In the kinetic experiments the trifluoromethyl radicals are generated in situ from a commercially available hypervalent-iodine-CF3 reagent (Togni-reagent) by SET-reduction with TEMPONa in the presence of TEMPO and a π-acceptor. From the relative ratio of TEMPOCF3 and CF3-addition product formed, which is readily determined by 19F-NMR spectroscopy, rate constants for trifluoromethyl radical addition to the π-acceptor can be calculated. The practical method is also applicable to measure rate constants for the addition of other perfluoroalkyl radicals to alkenes as documented for CF3CF2-radical addition reactions.

Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones by Michael J. Corr; Rodrigo A. Cormanich; Cortney N. von Hahmann; Michael Bühl; David B. Cordes; Alexandra M. Z. Slawin; David O'Hagan (211-219).
The CF2 group is incorporated into specific positions within the lactone ring of the natural musk lactone, (12R)-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The approach is taken as it was anticipated that CF2 groups would dictate corner locations in the macrocycle and limit the conformational space available to the lactone. Three fluorine containing lactones are prepared by organic synthesis. One (8) has CF2 groups located at the C-6 and C-9 positions, another (9) with CF2 groups at the C-5 and C-9 positions, and a third (10) with a CF2 group at C-8. Two of the fluorine containing lactones (8 and 10) were sufficiently crystalline to obtain X-ray crystal structures which revealed that the CF2 groups do adopt corner locations. All three lactones were subject to computational analysis at the B3LYP-D3/6-311+G** level to assess the relative energies of different conformers. In all cases, the global minima and most of the lowest energy minima have squared/rectangular geometries and located the CF2 groups at the corners. The lowest energy structures for 8 and 10 closely approximated the observed X-ray structures, suggesting good convergence of theory and experiment in determining relevant low energy conformations. All three compounds retained a pleasant odour suggesting the rings retained sufficient conformational flexibility to access relevant olfactory conformations.

Synthesis of (E)-oxindolylidene acetate using tandem palladium-catalyzed Heck and alkoxycarbonylation reactions by Wei-Jen Lin; Kak-Shan Shia; Jen-Shin Song; Ming-Hsien Wu; Wen-Tai Li (220-228).
Tandem reactions use consecutive reaction steps to efficiently synthesize compounds of high molecular complexity. This paper presents a tandem Pd-catalyzed Heck and alkoxycarbonylation reaction for the stereoselective synthesis of (E)-oxindolylidene acetates. The mechanism underlying the Pd-catalyzed tandem reaction involves the syn-carbopalladation of ynamides followed by alkoxycarbonylation with CO and alcohol. This method makes it possible to obtain the desired (E)-configuration of oxindolylidene acetates exclusively. We evaluated the scope of the reaction by applying optimal reaction conditions to the facile synthesis of a library of (E)-oxindolylidene acetates. The resulting (E)-oxindolylidene acetates exhibited potent anticancer activities against a variety of human cancer cell lines. The anticancer activities of some (E)-oxindolylidene acetates were even superior to those of known CDK inhibitors indirubin-3′-oxime and roscovitine.

Rhodium(iii)-catalyzed C–C coupling of 7-azaindoles with vinyl acetates and allyl acetates by Shuai-Shuai Li; Cheng-Qi Wang; Hui Lin; Xiao-Mei Zhang; Lin Dong (229-237).
The behaviour of electron-rich alkenes with 7-azaindoles in rhodium(iii)-catalyzed C–H activation is investigated. Various substituted vinyl acetates and allyl acetates as coupling partners reacted smoothly providing a wide variety of 7-azaindole derivatives, and the selectivity of the coupling reaction is alkene-dependent. In addition, the approaches of rhodium(iii)-catalyzed dehydrogenative Heck-type reaction (DHR) and carbonylation reaction were quite novel and simple.

The structure of tagetitoxin by Abil E. Aliev; Kersti Karu; Robin E. Mitchell; Michael J. Porter (238-245).
Based on detailed analysis of newly acquired NMR data, we show that the previously revised structure of tagetitoxin is incorrect. A new structure of tagetitoxin is proposed which is consistent with the NMR and MS data.

An efficient and practical protocol for palladium-catalyzed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids with aryl chlorides has been developed. Note that the reaction could proceed smoothly without an additive in aqueous medium under an ambient atmosphere, and the addition of H2O could effectively promote the decarboxylative arylation. Particularly noteworthy is that these results represent the first examples of Pd-catalyzed decarboxylative coupling reactions of (hetero) aromatic carboxylic acids in aqueous medium under air, and the first successful examples of the synthesis of 3-aryl-imidazo[1,2-a]pyridines using cheap, diverse aryl chlorides and heteroaryl chlorides as the starting materials.

Total synthesis of a piperidine alkaloid, microcosamine A by Chada Raji Reddy; Bellamkonda Latha; Kamalkishor Warudikar; Kiran Kumar Singarapu (251-258).
The first asymmetric total synthesis of a new natural piperidine alkaloid, microcosamine A, has been accomplished from d-serine and d-methyl lactate as chiral pool starting materials. Key features of the strategy include the utility of Horner–Wadsworth–Emmons reaction, Luche reduction, intramolecular carbamate N-alkylation to form the piperidine framework and Julia–Kocienski olefination to install the triene side-chain.

C-glycosides are important compounds as they are used as bioactive molecules and building blocks. We have developed methods to concisely synthesize C-glycosides from unprotected 2-N-acyl-aldohexoses and unactivated ketones; we designed aldol-condensation–oxa-Michael addition reactions catalyzed by amine-based catalysts using additives. Depending on the conditions used, C-glycosides were stereoselectively obtained. Our methods allowed the C–C bond formations at the anomeric centers of unprotected carbohydrates under mild conditions to lead the C-glycosides in atom- and step-economical ways.

Synthesis of two distinct pyrrole moiety-containing arenes from nitroanilines using Paal–Knorr followed by an indium-mediated reaction by Byeong Hyo Kim; Seolhee Bae; Ahra Go; Hyunseung Lee; Cheoloh Gong; Byung Min Lee (265-276).
Synthesis of arenes substituted with two differently substituted-pyrrole moieties was investigated. A Paal–Knorr condensation reaction of nitroanilines with 1,4-diketone to nitrophenyl-1H-pyrroles followed by an indium-mediated reduction-triggered coupling reaction with another kind of 1,4-diketone resulted in two distinct pyrrole-containing arenes, variously substituted 1-((1H-pyrrol-1-yl)phenyl)-1H-pyrroles, in reasonable yield.

Design, synthesis and anticancer activities of novel otobain derivatives by Zhongzhou Li; Hui Su; Weiwei Yu; Xinjun Li; Hao Cheng; Mingyao Liu; Xiufeng Pang; Xinzhuo Zou (277-287).
A series of novel racemic otobain derivatives was designed and synthesised using 2-piperonyl-1,3-dithianes in the conjugate addition–alkylation to 5H-furan-2-one, followed by cationic cyclisation. All the synthesised compounds were consequently evaluated for their anticancer activity against several human cancers in vitro. The efficacy of the most active compound 27g was comparable with etoposide, with IC50 values ranging from 1.06 μM to 4.16 μM in different cancer cell lines. Notably, compound 27g strongly induced cell cycle arrest and increased the expression of mitosis-specific markers MPM-2 and phosphorylated histone H3, but it did not trigger cell apoptosis. Further a colony formation assay showed that compound 27g effectively inhibited the anchor growth of lung cancer cells in a dose-dependent manner. More importantly, compound 27g at 40 mg kg−1 significantly suppressed tumour volume (P < 0.01) and tumour weight (P < 0.05) in a human lung cancer cell xenograft mouse model without causing systematic toxicity in mice. Our findings indicated that compound 27g has significant potential for further drug development.

Electronically modified amine substituted alkynols for regio-selective synthesis of dihydrofuran derivatives by Vijay V; Manjusha V. Karkhelikar; B. Sridhar; Nedaossadat Mirzadeh; Suresh Bhargava; Pravin R. Likhar (288-295).
An efficient and simple approach has been developed for the regio-selective synthesis of iodo-substituted dihydrofurans from amine substituted alkynols. The resulting iodo-substituted dihydrofurans have been further diversified by C–C couplings and C–N coupling reactions to afford a diverse range of substituted dihydrofuran derivatives.

Photocontrol of ion permeation in lipid vesicles with (bola)amphiphilic spirooxazines by Yamuna S. Kandasamy; Jianxin Cai; John G. Ottaviano; Kelti A. Smith; Ashley N. Williams; Jarod Moore; Kristen M. Louis; Lindsay Selzler; Alisha Beler; Tobechi Okwuonu; R. Scott Murphy (296-308).
Three (bola)amphiphilic spirooxazines have been synthesized and their photochromism has been characterized. The large biphotochromic structure of 2 significantly affects its conformational flexibility and the rate constants for thermal ring closure are particularly dependent on the lipid phase state. Two comprehensive ion permeation studies were performed to examine the effect of spirooxazine inclusion and isomerization on membrane permeability. In all cases, the open-ring isomers of these spirooxazines are more disruptive in bilayer membranes than their closed-ring isomers. Further, the rate of ion permeation and net release are highly dependent on the lipid bilayer phase state and the relative position of the photochromic moiety in the bilayer membrane. Moreover, the difference in potassium ion permeability under UV and visible irradiation is more pronounced than previously reported photoresponsive membrane disruptors with reversible photocontrols.

Automated glycan assembly of xyloglucan oligosaccharides by Pietro Dallabernardina; Frank Schuhmacher; Peter H. Seeberger; Fabian Pfrengle (309-313).
We report the automated glycan assembly of oligosaccharide fragments related to the hemicellulose xyloglucan (XG). Iterative addition of monosaccharide and disaccharide building blocks to a solid support provided seven cellulose and xyloglucan fragments including XXGG- and XXXG-type oligosaccharides.

NMR analysis of the binding mode of two fungal endo-β-1,4-mannanases from GH5 and GH26 families by Roberta Marchetti; Jean-Guy Berrin; Marie Couturier; Shah Ali Ul Qader; Antonio Molinaro; Alba Silipo (314-322).
The enzymatic digestion of the main components of lignocellulosic biomass, including plant cell wall mannans, constitutes a fundamental step in the renewable biofuel production, with great potential benefit in the industrial field. Despite several reports of X-ray structures of glycoside hydrolases, how polysaccharides are specifically recognized and accommodated in the enzymes binding site still remains a pivotal matter of research. Within this frame, NMR spectroscopic techniques provide key binding information, complementing and/or enhancing the structural view by X-ray crystallography. Here we provide deep insights into the binding mode of two endo-β-1,4 mannanases from the coprophilous ascomycete Podospora anserina, PaMan26A and PaMan5A, involved in the hydrolysis of plant cell wall mannans and heteromannans. The investigation at a molecular level of the interaction between the wild-type enzymes and inactive mutants with manno-oligosaccharides, revealed a different mode of action among the two glycoside hydrolases most likely due to the presence of the additional and peculiar −4 subsite in the PaMan26A binding pocket.

Efficient, versatile and practical palladium-catalyzed highly regioselective ortho-halogenation of azoxybenzenes by Meng Sun; Xiangxiang Chen; Liang Zhang; Wei Sun; Zhe Wang; Peiyu Guo; Ya-Min Li; Xiao-Juan Yang (323-329).
A highly efficient and practical strategy for regio-selective ortho-halogenation (I, Br, Cl) of azoxybenzenes with NXS in the presence of palladium catalysts has been developed in good to excellent yields. The reaction proceeds smoothly and can tolerate a variety of functional groups. Moreover, this chemistry can be applied to substrates in at least a gram scale.

Oxacalix[2]arene[2]triazine based ion-pair transporters by Xu-Dong Wang; Sen Li; Yu-Fei Ao; Qi-Qiang Wang; Zhi-Tang Huang; De-Xian Wang (330-334).
Heteracalixaromatics are a new generation of macrocyclic hosts showing a unique structure and versatile recognition properties towards various guests. Amazingly, the application of heteracalixaromatics as membrane transporters or ion channels has never been explored. We reported herein the elaborated design of a series of oxacalix[2]arene[2]triazine-based derivatives 1–10 and their ion transport properties. Among these compounds, 3, 8–10 can mediate the transport of chloride across the lipid bilayer of EYPC with activity (EC50) ranging from 0.43 to 8.23 μM. These compounds serve as ion carriers during the transport process, and the transport activity is both anion- and cation-dependent, suggesting a Cl/M+ ion-pair transport model. Structure–activity studies indicate that hydrogen bonding, electron deficiency of the triazine rings, lipophilicity and macrocyclic frameworks are essential for ion transport.

Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering by C. Guzzi; P. Alfarano; I. Sutkeviciute; S. Sattin; R. Ribeiro-Viana; F. Fieschi; A. Bernardi; J. Weiser; J. Rojo; J. Angulo; P. M. Nieto (335-344).
DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLR) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose-containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN-dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand 2.

A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization by Shao-Rong Wang; Pedro A. Sánchez-Murcia; Federico Gago; Wei-Shuo Fang (345-352).
A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D-spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids.

Copper-catalyzed direct C–H fluoroalkenylation of heteroarenes by Kevin Rousée; Cédric Schneider; Jean-Philippe Bouillon; Vincent Levacher; Christophe Hoarau; Samuel Couve-Bonnaire; Xavier Pannecoucke (353-357).
Copper-catalyzed direct C–H fluoroalkenylation of heterocycles using various gem-bromofluoroalkenes as electrophiles is reported. This efficient method offers step-economical, low-cost and stereocontrolled access to relevant heteroarylated monofluoroalkenes. The synthesis of fluorinated analogues of biomolecules and therapeutic agents for the treatment of Duchenne muscular dystrophy as application is reported.

Influence of the oxazole ring connection on the fluorescence of oxazoyl-triphenylamine biphotonic DNA probes by Blaise Dumat; Elodie Faurel-Paul; Pauline Fornarelli; Nicolas Saettel; Germain Metgé; Céline Fiorini-Debuisschert; Fabrice Charra; Florence Mahuteau-Betzer; Marie-Paule Teulade-Fichou (358-370).
On the basis of our previous work on DNA fluorophores derived from vinylpyridinium-triphenylamine, we explored the structure space around the electron-rich triphenylamine (TP) core by changing the vinyl bond to an oxazole ring. As 2,5-diaryloxazoles are known to be highly fluorescent and efficient two photon absorbers, we synthesized analogues with two different connections of the oxazole to the triphenylamine core: TP-Ox2Py and TP-Ox5Py sets. Since the benzimidazolium group was proven to be more effective in the TP series than the pyridinium, we also synthesized a TP-Ox5Bzim set. The TP-Ox5Py series retains the TP-Py properties: on/off behavior on DNA, good two-photon cross-section and bright staining of nuclear DNA by microscopy under both one or two-photon excitation. On the other hand, the TP-Ox2Py series does not display fluorescence upon binding to DNA. The TP-Ox5Bzim set is fluorescent even in the absence of DNA and displays lower affinity than the corresponding TP-Ox5Py. CD experiments and docking were performed to understand these different behaviors.

Back cover (371-372).