Organic & Biomolecular Chemistry (v.9, #14)

Front cover (4989-4990).

Contents list (4991-5004).

Putting the ‘N’ in ACENE: Pyrazinacenes and their structural relatives by Gary J. Richards; Jonathan P. Hill; Toshiyuki Mori; Katsuhiko Ariga (5005-5017).
Acenes have emerged as an important class of organic electronic material. Related heteroatom-substituted compounds, or heteroacenes, introduce an important means for modulating properties and improving materials’ stability. In this perspective, we will review the historical origins of the heteroacenes and discuss recent progress in the field of acene and related compounds containing fused 1,4-diazabenzene units, i.e. pyrazine, also known as the ‘pyrazinacenes’. We focus not only on the types of materials that have been prepared but also on their chemical and physical properties, including synthetic procedures, electronic properties, self-assembly characteristics, and we also introduce some of the computational studies aimed at understanding the more unusual behaviours of this group of compounds, such as protic tautomerism and aromaticity/antiaromaticity.

Mild preparation of functionalized [2.2]paracyclophanes via the Pummerer rearrangement by Matteo Montanari; Alberto Bugana; Arvind K. Sharma; Dario Pasini (5018-5020).
[2.2]Paracyclophanes, incorporating functional groups in the aliphatic bridges, suitable for elimination to give [2.2]paracyclophanedienes, are synthesized through a novel approach. It relies on a double Pummerer rearrangement on dithiacyclophane precursors, followed by ring contraction through a photochemical sulfur extrusion, and it is compatible with aryl moieties possessing very different electronic properties.

Regioselective dibromination of methyl indole-3-carboxylate and application in the synthesis of 5,6-dibromoindoles by Thomas B. Parsons; Cédric Ghellamallah; Louise Male; Neil Spencer; Richard S. Grainger (5021-5023).
Treatment of methyl indole-3-carboxylate with bromine in acetic acid gives methyl 5,6-dibromoindole-3-carboxylate regioselectively, from which the parent 5,6-dibromoindole can be accessed via a one-pot, microwave-mediated ester hydrolysis and decarboxylation. Application of these building blocks in syntheses of natural and non-natural 5,6-dibromoindole derivatives, including meridianin F and 5,6-dibromo-2′-demethylaplysinopsin, is reported.

Fast and efficient microwave-assisted synthesis of functionalized peptoids via Ugi reactions by Angélica de Fátima S. Barreto; Otilie E. Vercillo; Mike A. Birkett; John C. Caulfield; Ludger A. Wessjohann; Carlos Kleber Z. Andrade (5024-5027).
A wide range of N-alkylglycines (peptoids) can be efficiently prepared via Ugi reactions using microwave irradiations. The results confirm the versatility and efficiency of the methodology for the preparation of functionalized peptoids. The products can be used in consecutive Ugi reactions to yield cyclic peptoids of potential biological interest.

FeCl3-Mediated synthesis of polysubstituted tetrahydroquinolines via domino Mannich/Friedel–Crafts reactions of aldehydes and amines by Yan-Fang Yang; Xing-Zhong Shu; Hai-Long Wei; Jian-Yi Luo; Shaukat Ali; Xue-Yuan Liu; Yong-Min Liang (5028-5033).
A useful method to construct highly substituted tetrahydroquinolines has been developed through an iron(iii) chloride-mediated domino Mannich and intramolecular Friedel–Crafts alkylation followed by intermolecular Friedel–Crafts alkylation reactions of aliphatic aldehydes with aromatic amines.

Stereoselective aza-Darzens reactions of tert-butanesulfinimines: convenient access to chiral aziridines by Toni Moragas Solá; Ian Churcher; William Lewis; Robert A. Stockman (5034-5035).
Stereoselective synthesis of 2,3-di- and 2,2′,3-tri-substituted aziridines in good yields and excellent diastereoselectivities are achieved through aza-Darzens reactions of a range of tert-butanesulfinyl aldimines and ketimines with ethyl bromoacetate.

Palladium-catalyzed three-component domino reaction for the preparation of benzo[b]thiophene and related compounds by Huanan Huang; Jing Li; Weining Zhao; Yanbo Mei; Zheng Duan (5036-5038).
A simple and efficient palladium-catalyzed three-component domino reaction of bromothiophenes with internal alkynes has been developed to produce benzo[b]thiophenes in moderate to good yields.

CuBr Catalyzed C–N cross coupling reaction of purines and diaryliodonium salts to 9-arylpurines by Hong-Ying Niu; Chao Xia; Gui-Rong Qu; Qian Zhang; Yi Jiang; Run-Ze Mao; De-Yang Li; Hai-Ming Guo (5039-5042).
CuBr was found to be an efficient catalyst for the C–N cross coupling reaction of purine and diaryliodonium salts. 9-Arylpurines were synthesized in excellent yields with short reaction times (2.5 h). The method represents an alternative to the synthesis of 9-arylpurines via Cu(ii) catalyzed C–N coupling reaction with arylboronic acids as arylating agents.

Ligand-free highly effective iron/copper co-catalyzed formation of dimeric aryl ethers or sulfides by Xiaoming Qu; Tingyi Li; Yan Zhu; Peng Sun; Hailong Yang; Jincheng Mao (5043-5046).
Highly selective coupling of diiodoarenes with phenols or phenthiols can be performed by using a low-cost, benign character and readily available Fe/Cu catalytic system in the absence of ligands. It is noteworthy that the desired dimeric aryl ethers or sulfides could be obtained in high yields by coupling between diiodoarenes and phenols, or diphenols with aryl iodides.

Enantioselective binding of a lanthanide(iii) complex to human serum albumin studied by 1H STD NMR techniques by David M. Dias; João M. C. Teixeira; Ilya Kuprov; Elizabeth J. New; David Parker; Carlos F. G. C. Geraldes (5047-5050).
The enantioselective binding of the (SSS)-Δ isomer of an yttrium(iii) tetraazatriphenylene complex to ‘drug-site II’ of human serum albumin (HSA) was detected by the intensity differences of its STD 1H NMR spectrum relative to the (RRR)-Λ isomer, by the effect of the competitive binder to that site, N-dansyl sarcosine, upon the STD spectrum of each isomer, in the presence of HSA and by 3D docking simulations.

Intramolecular charge transfer (ICT) based fluorescent reagents containing a dansyl fluorophore have been synthesized and characterized. The reagent 1 and its complex, 1+Hg2+ in sodium acetate buffer (pH 6.7) revealed considerable fluorescence enhancement (switched-on) in the presence of bovine serum albumin (BSA) with 10 ppb detection sensitivity. 1H NMR spectral analysis suggests complexation between 1 and Hg2+ ion involving the N,N-dimethylamino and carboxylic functions.

A programmable “build–couple” approach to the synthesis of heterofunctionalized polyvalent molecules by Ritwik Burai; Jaruwan Chatwichien; Brian R. McNaughton (5056-5058).
A maximally divergent “build–couple” synthesis of heterofunctionalized polyvalent molecules is described. This strategic approach enables the synthesis of highly diverse polyvalent structures from a pre-programmed combinatorial set of modules.

Designing neutral metallophilic hydrogels from di- and tripeptides by Ibon Odriozola; Pablo Casuso; Iraida Loinaz; Germán Cabañero; Hans. J. Grande (5059-5061).
Here we report the metallophilic attraction driven gel-forming capability of four cysteine-containing short peptides at neutral pH. Such peptides were designed to have an isoelectric point (pI) close to 7, aided by the introduction of an arginine unit with its highly basic guanidinium group.

Studies on transannulation reactions across a nine-membered ring: the synthesis of natural product-like structures by Mudassar Iqbal; Richard J. G. Black; Joby Winn; Andrew T. Reeder; Alexander J. Blake; Paul A. Clarke (5062-5078).
A series of diverse natural product-like structures have been synthesised by the use of a number of novel transannulation reactions across a cyclononene ring. Transannular cyclisations through oxygen functionality have generated a number of bicyclo[5.3.1]systems containing bridged cyclic ethers and bicyclo[5.2.2]lactones, as well as a tetrahydrofuran-containing bridged analogue of hexacyclinic acid. An unprecedented Brønsted acid mediated transannular cyclisation between proximal carbons generated bicyclo[4.3.0]nonanes which form the core of the pinguisane and austrodorane families of sesquiterpenoids. In all cases the key factor that determined the mode of reactivity was the conformation of the nine-membered ring and the distance between the reacting centres.

First asymmetric cascade reaction catalysed by chiral primary aminoalcohols by Carlos Arróniz; Carmen Escolano; F. Javier Luque; Joan Bosch; Mercedes Amat (5079-5085).
Readily available chiral primary 1,2-aminoalcohols and diamines have been explored as organocatalysts for a domino Michael–aldol reaction. Their application in this organocascade process afforded cyclohexanone A with high levels of reactivity (up to 91% yield) and stereoselectivity (>97 : 3 d.r., up to 93% ee). Depending on the acid cocatalyst different chiral species (cyclic secondary amines vs. acyclic primary amines) might catalyse the process. In order to shed light on the catalytic activation, several experiments were carried out and a detailed possible reaction mechanism is proposed. Theoretical studies support the stereochemical outcome of the process.

Inherently chiral phosphonatocavitands as artificial chemo- and enantio-selective receptors of natural ammoniums by Jérôme Vachon; Steven Harthong; Erwann Jeanneau; Christophe Aronica; Nicolas Vanthuyne; Christian Roussel; Jean-Pierre Dutasta (5086-5091).
Inherently chiral phosphonatocavitands with various bridging moieties at their wide rim were synthesized. Optical resolution by chiral HPLC was performed with cavitand 8 to afford enantiopure compounds (+)-8 and (−)-8. The molecular structures of hosts 8 and 12 were determined by X-ray diffraction. The host properties were investigated by 1H and 31P NMR spectroscopy. The phosphonatocavitands form inclusion complexes with chiral ammonium neurotransmitters, some presenting enantioselectivity towards the right or left-handed host enantiomers.

Chemiluminescent acridinium dimethylphenyl esters, containing two methyl groups flanking the phenolic ester bond, display excellent chemiluminescence stability and are used as labels in automated immunoassays for clinical diagnostics. Light emission from these labels is triggered with alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride. Under these conditions, light emission is rapid and is complete in <5 s. In the present study we examined the effect of various surfactants on light emission from acridinium dimethylphenyl ester labels and their conjugates containing hydrophilic linkers derived either from hexa(ethylene)glycol or a sulfobetaine zwitterion. Sulfobetaine zwitterions are very polar and incorporation of these functional groups in acridinium dimethyphenyl esters and their conjugates represents a new approach to improving the aqueous solubility of these chemiluminescent labels. Our results indicate that in general, surfactants affect light emission from these labels and their conjugates by two discrete mechanisms. Cationic surfactants, but not anionic or non-ionic surfactants, accelerate overall light emission kinetics and a more modest effect is observed with zwitterionic surfactants. Surfactants also enhance total light output and the magnitude of this enhancement is maximal for cationic surfactants and a sulfobetaine zwitterionic surfactant. These observations are the first to clearly delineate the role of the surfactant on the chemiluminescence reaction pathway of acridinium esters and can be rationalized based on known effects of surfactant aggregates on bimolecular and unimolecular reactions.

A tag removal–cyclisation sequence is described that is initiated by reduction using a Sm(ii) species and completed by a Sm(iii) Lewis acid that is formed in an earlier stage. Therefore, the reaction cascade utilises both oxidation states of a samarium reagent in discrete steps and allows access to privileged, pyrrolidinyl-spirooxindole scaffolds and analogues inspired by the anti-cancer natural product spirotryprostatin A.

A significant role of alkaline cations on the Reimer–Tiemann reaction by Shinichi Yamabe; Takeshi Fukuda (5109-5114).
The Reimer–Tiemann (R–T) reaction was investigated by DFT calculations. A model composed of CHCl3, PhO(Na+)H2O and [NaOH(H2O)2]2 was employed for geometry optimizations. A K+-containing model was also investigated. The dichlorocarbene reagent, which has been thought of for a long time, was found to intervene only transiently in the carbenoid form. In this form, the Na+ (or K+) coordination to CCl2 enhances its electrophilicity toward C6H5O. The counter ion also works to stabilize the precursor phenoxide ion and intermediates of the substituted phenoxides in the hexagonal pyramidal coordination. The Na+-containing reaction consists of seven elementary processes, (K+, six ones) with extremely high exothermicity and spontaneity.

Mechanism of epoxide hydrolysis in microsolvated nucleotide bases adenine, guanine and cytosine: A DFT study by Kunduchi P. Vijayalakshmi; Neetha Mohan; Manjaly J. Ajitha; Cherumuttathu H. Suresh (5115-5122).
Six water molecules have been used for microsolvation to outline a hydrogen bonded network around complexes of ethylene epoxide with nucleotide bases adenine (EAw), guanine (EGw) and cytosine (ECw). These models have been developed with the MPWB1K-PCM/6-311++G(3df,2p)//MPWB1K/6-31+G(d,p) level of DFT method and calculated SN2 type ring opening of the epoxide due to amino group of the nucleotide bases, viz. the N6 position of adenine, N2 position of guanine and N4 position of cytosine. Activation energy (Eact) for the ring opening was found to be 28.06, 28.64, and 28.37 kcal mol−1 respectively for EAw, EGw and ECw. If water molecules were not used, the reactions occurred at considerably high value of Eact, viz. 53.51 kcal mol−1 for EA, 55.76 kcal mol−1 for EG and 56.93 kcal mol−1 for EC. The ring opening led to accumulation of negative charge on the developing alkoxide moiety and the water molecules around the charge localized regions showed strong hydrogen bond interactions to provide stability to the intermediate systems EAw-1, EGw-1 and ECw-1. This led to an easy migration of a proton from an activated water molecule to the alkoxide moiety to generate a hydroxide. Almost simultaneously, a proton transfer chain reaction occurred through the hydrogen bonded network of water molecules and resulted in the rupture of one of the N–H bonds of the quaternized amino group. The highest value of Eact for the proton transfer step of the reaction was 2.17 kcal mol−1 for EAw, 2.93 kcal mol−1 for EGw and 0.02 kcal mol−1 for ECw. Further, the overall reaction was exothermic by 17.99, 22.49 and 13.18 kcal mol−1 for EAw, EGw and ECw, respectively, suggesting that the reaction is irreversible. Based on geometric features of the epoxide–nucleotide base complexes and the energetics, the highest reactivity is assigned for adenine followed by cytosine and guanine. Epoxide-mediated damage of DNA is reported in the literature and the present results suggest that hydrated DNA bases become highly SN2 active on epoxide systems and the occurrence of such reactions can inflict permanent damage to the DNA.

Covalent immobilization of active lysozyme on Si/glass surface using alkoxy Fischer carbene complex on SAM by Piyali Dutta; Namrata Ray; Sarita Roy; Anjan Kr. Dasgupta; Othman Bouloussa; Amitabha Sarkar (5123-5128).
A cross-metathesis reaction between an alkene terminated self-assembled monolayer (SAM) on glass/Si wafer and an alkene tethered Fischer carbene complex yielded a functionalized surface. Rapid aminolysis of the Fischer carbene moieties permit efficient anchoring of amine containing molecules on such a surface. Attachment of 1-pyrenemethylamine was thus monitored by ATR-IR spectroscopy and fluorescence microscopy. Similarly, BSA and lysozyme were individually grafted to such Fischer carbene modified surfaces using their pendant lysine residues. It has been demonstrated that the anchored lysozyme retains its bactericidal property.

Rapid preparation of triazolyl substituted NH-heterocyclic kinase inhibitors via one-pot Sonogashira coupling–TMS-deprotection–CuAAC sequence by Eugen Merkul; Fabian Klukas; Dieter Dorsch; Ulrich Grädler; Hartmut E. Greiner; Thomas J. J. Müller (5129-5136).
The one-pot, three-component Sonogashira coupling–TMS-deprotection–CuAAC (“click”) sequence is the key reaction for the rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, and imidazole. Subsequently, the protective group was readily removed to give the corresponding triazolyl derivatives of these tremendously important NH-heterocycles. All compounds have been tested in a broad panel of kinase assays. Several compounds, 8f, 8h, 8k, and 8l, have been shown to inhibit the kinase PDK1, a target with high oncology relevance, and thus they are promising lead structures for the development of more active derivatives. The X-ray structure analysis of compound 8f in complex with PDK1 has revealed the detailed binding mode of the molecule in the kinase.

Pyrroloquinoxaline hydrazones as fluorescent probes for amyloid fibrils by Sandra Gemma; Laura Colombo; Gianluigi Forloni; Luisa Savini; Claudia Fracasso; Silvio Caccia; Mario Salmona; Margherita Brindisi; Bhupendra P. Joshi; Pierangela Tripaldi; Gianluca Giorgi; Orazio Taglialatela-Scafati; Ettore Novellino; Isabella Fiorini; Giuseppe Campiani; Stefania Butini (5137-5148).
Here we describe the identification and preliminary characterization of a new class of pyrrolo(imidazo)quinoxaline hydrazones as flurescent probes for Aβ1-42 fibrils. All the newly developed compounds were able to bind amyloid fibrils formed in vitro and some of them displayed an increase of their fluorescence upon binding. When tested on brain tissue preparations presenting Aβ deposits, the described hydrazones selectively stained amyloid structures and did not display aspecific binding. The hydrazones did not show antifibrillogenic activity and electron microscopy analysis revealed that they do not interfere with fibrils structure. The described pyrrolo(imidazo)quinoxalines could be useful for studying amyloid structures in vitro. Moreover, their experimentally proven ability to cross the blood–brain barrier in mouse opens the possibility of developing these compounds as potential amyloid imaging agents for in vivo applications.

The enzymatic oxidation of urate leads to the sequential formation of optically active intermediates with unknown stereochemistry: (−)-5-hydroxyisourate (HIU) and (−)-2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU). In accordance with the observation that a defect in HIU hydrolase causes hepatocarcinoma in mouse, a detoxification role has been proposed for the enzymes accelerating the conversion of HIU and OHCU into optically active (+)-allantoin. The enzymatic products of urate oxidation are normally not present in humans, but are formed in patients treated with urate oxidase. We used time-dependent density functional theory (TDDFT) to compute the electronic circular dichroism (ECD) spectra of the chiral compounds of urate degradation (HIU, OHCU, allantoin) and we compared the results with experimentally measured ECD spectra. The calculated ECD spectra for (S)-HIU and (S)-OHCU reproduced well the experimental spectra obtained through the enzymatic degradation of urate. Less conclusive results were obtained with allantoin, although the computed optical rotations in the transparent region supported the original assignment of the (+)-S configuration. These absolute configuration assignments can facilitate the study of the enzymes involved in urate metabolism and help us to understand the mechanism leading to the toxicity of urate oxidation products.

Domino synthesis of 1,3,5-trisubstituted hydantoins: a DFT study by Tommaso Marcelli; Francesca Olimpieri; Alessandro Volonterio (5156-5161).
The mechanism of the reaction between carbodiimides and activated α,β-unsaturated carboxylic acids yielding fully substituted hydantoins and variable amounts of N-acyl urea by-products was studied using density functional theory calculations. Two alternative pathways featuring N-acyl ureas and imino-oxazolidinones as intermediates for the formation of the hydantoin product were taken into account. The results obtained using two different computational models indicate that the overall barriers are similar for the two pathways considered. In all cases, inclusion of a second molecule of carboxylic acid was required to mediate tautomerizations and rearrangement steps. The calculations successfully reproduce the experimentally observed regioselectivity with respect to both N-acyl urea and hydantoin products.

Theoretical studies on the inactivation mechanism of γ-aminobutyric acid aminotransferase by A. T. Durak; H. Gökcan; F. A. S. Konuklar (5162-5171).
The inactivation mechanism of γ-aminobutyric acid aminotransferase (GABA-AT) in the presence of γ-vinyl-aminobutyric acid, an anti-epilepsy drug, has been studied by means of theoretical calculations. Density functional theory methods have been applied to compare the three experimentally proposed inactivation mechanisms (Silverman et al., J. Biol. Chem., 2004, 279, 363). All the calculations were performed at the B3LYP/6-31+G(d,p) level of theory. Single point solvent calculations were carried out in water, by means of an integral equation formalism-polarizable continuum model (IEFPCM) at the B3LYP/6-31+G(d,p) level of theory. The present calculations provide an insight into the mechanistic preferences of the inactivation reaction of GABA-AT. The results also allow us to elucidate the key factors behind the mechanistic preferences. The computations also confirm the importance of explicit water molecules around the reacting center in the proton transfer steps.

Synthesis and characterization of bis-cyclopropanated 1,3,5-tricarbonyl compounds. A combined synthetic, spectroscopic and theoretical study by Thomas Rahn; Franziska Bendrath; Martin Hein; Wolfgang Baumann; Haijun Jiao; Armin Börner; Alexander Villinger; Peter Langer (5172-5184).
Bis-cyclopropanated 1,3,5-tricarbonyl compounds were prepared by a sequence of Claisen condensations and cyclopropanations. The optimization of the conditions proved to be very important to suppress retro-Claisen reactions. The conformation of these molecules was studied by experimental and computational methods. The syn/syn;syn/syn conformation is present for all derivatives. It is exclusively present in the case of the derivative containing a phenyl group located at the terminal carbon atom. In most cases, equilibria with other conformers are found.

Angiotensin converting enzyme (ACE) regulates the blood pressure by converting angiotensin I to angiotensin II and bradykinin to bradykinin 1–7. These two reactions elevate the blood pressure as angiotensin II and bradykinin are vasoconstrictory and vasodilatory hormones, respectively. Therefore, inhibition of ACE is an important strategy for the treatment of hypertension. The natural substrates of ACE, i.e., angiotensin II and bradykinin, contain a Pro-Phe motif near the site of hydrolysis. Therefore, there may be a Pro-Phe binding pocket at the active site of ACE, which may facilitate the substrate binding. In view of this, we have synthesized a series of thiol- and selenol-containing dipeptides and captopril analogues and studied their ACE inhibition activities. This study reveals that both the selenol or thiol moiety and proline residues are essential for ACE inhibition. Although the introduction of a Phe residue to captopril and its selenium analogue considerably reduces the inhibitory effect, there appears to be a Phe binding pocket at the active site of ACE.

Mechanistic investigations on the efficient catalytic decomposition of peroxynitrite by ebselen analogues by Krishna P. Bhabak; Amit A. Vernekar; Surendar R. Jakka; Gouriprasanna Roy; Govindasamy Mugesh (5193-5200).
In this study, ebselen and its analogues are shown to be catalysts for the decomposition of peroxynitrite (PN). This study suggests that the PN-scavenging ability of selenenyl amides can be enhanced by a suitable substitution at the phenyl ring in ebselen. Detailed mechanistic studies on the reactivity of ebselen and its analogues towards PN reveal that these compounds react directly with PN to generate highly unstable selenoxides that undergo a rapid hydrolysis to produce the corresponding seleninic acids. The selenoxides interact with nitrite more effectively than the corresponding seleninic acids to produce nitrate with the regeneration of the selenenyl amides. Therefore, the amount of nitrate formed in the reactions mainly depends on the stability of the selenoxides. Interestingly, substitution of an oxazoline moiety on the phenyl ring stabilizes the selenoxide, and therefore, enhances the isomerization of PN to nitrate.

Electron-rich aryl ethers and phenols react with isoprene (2-methylbuta-1,3-diene) in the presence of catalytic Bi(OTf)3 at 40 °C to afford the corresponding prenylated or 2,2-dimethylchroman products, respectively, in moderate to good yields. This transformation offers a convenient and expedient entry to prenylated derivatives of electron-rich aromatics that often display enhanced biological activities. The methodology has been employed in the efficient synthesis of a biologically active natural product and related compounds.

Tandem allylic oxidation–condensation/esterification catalyzed by silica gel: an expeditious approach towards antimalarial diaryldienones and enones from natural methoxylated phenylpropenes by Abhishek Sharma; Naina Sharma; Amit Shard; Rakesh Kumar; Dinesh Mohanakrishnan; Saima; Arun K. Sinha; Dinkar Sahal (5211-5219).
A new one-pot strategy has been developed, wherein abundantly available methoxylated phenylpropenes are directly transformed into corresponding dienones (1,5-diarylpenta-2,4-dien-1-ones) and enones (chalcones and cinnamic esters) via allylic oxidation–condensation or allylic oxidation–esterification sequences. Preliminary antimalarial activity studies of the above synthesized diaryldienones and enones against Plasmodium falciparum (Pf3D7) have shown them to be promising lead candidates for developing newer and economical antimalarial agents. In particular, two enones (12b and 13b) were found to possess comparatively better activity (IC50 = 4.0 and 3.4 μM, respectively) than licochalcone (IC50 = 4.1 μM), a well known natural antimalarial compound.

S-Alkyl O,O-dialkyl thiophosphates are prepared by alkylation of the triethylammonium salt of O,O-diisopropyl thiophosphoric acid. S-Benzyl thiophosphate was metallated at temperatures of ≥−45 °C by trityllithium and LiTMP (lithium 2,2,6,6-tetramethylpiperidide) and S-alkyl thiophosphates only by LiTMP to give dipole-stabilised carbanions which rearrange to α-mercaptophosphonates in yields of up to 45%. Metallation occurs with a high primary kinetic isotope effect (kH/kD up to ≈50). When the lithium (R)-N-isopropyl-1-phenylethylamide was used to induce the isomerisation of S-pentyl thiophosphate an α-mercaptophosphonate with an ee of 22% was isolated. (R)-S-[1-D1]hexyl O,O-diisopropyl thiophosphate was rearranged to a dextrorotary α-mercapto-[1-D1]hexylphosphonate, whose (R)-configuration was determined by chemical correlation. The thiophosphate–mercaptophosphonate rearrangement proceeds with retention of configuration.

1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one: Selected Chemistry at the C-6, C-7 and C-8 Positions by Panayiotis A. Koutentis; Harry Krassos; Daniele Lo Re (5228-5237).
1,3-Diphenylbenzo[e][1,2,4]triazin-7(1H)-one (6) reacts with tetracyanoethylene (TCNE) or tetracyanoethylene oxide (TCNEO) to give the deep green 2-[1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-ylidene]propanedinitrile (11) in 17 and 15% yields, respectively. Nucleophiles such as amines, alkoxides, thiols and Grignard reagents all reacted with the 1,3-diphenylbenzotriazinone 6 regioselectively at C-6, while halogenating agents reacted exclusively at C-8. Furthermore, 8-iodo-1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (32) undergoes palladium-catalysed Suzuki–Miyaura and Stille coupling reactions to give 8-aryl- or heteroaryl-substituted benzotriazinones. By combining both the C-6 and C-8 chemistries 1,3,6,8-tetraphenylbenzo[e][1,2,4]triazin-7(1H)-one (42) and 1,3-diphenyl-6,8-di(thien-2-yl)-benzo[e][1,2,4]triazin-7(1H)-one (43) can be prepared. All new compounds are fully characterized.

Hyperbranched polymers versus dendrimers containing a carbosilane framework and terminal ammonium groups as antimicrobial agents by Paula Ortega; Beatriz Macarena Cobaleda; Jose Manuel Hernández-Ros; Elena Fuentes-Paniagua; Javier Sánchez-Nieves; M<sup>a</sup> Pilar Tarazona; Jose Luis Copa-Patiño; Juan Soliveri; Fco. Javier de la Mata; Rafael Gómez (5238-5248).
A new family of amine- and ammonium-terminated hyperbranched polycarbosilanes (PCS) and dendrimers has been synthesized. The functionalization of a polycarbosilane matrix was carried out with peripheral allyl groups by two strategies in the case of PCS: 1) hydrosilylation of allyl amines with PCS containing terminal Si–H bonds, or 2) hydrosilylation of PCS–allyl with an aminosilane. Dendrimers with terminal amine groups were synthesized by hydrosilylation of allydimethylamine. Quaternized systems with MeI are soluble and stable in water or other protic solvent. The antibacterial properties of the ammonium-terminated hyperbranched polycarbosilanes and dendrimers have been evaluated showing that they act as potent biocides against Gram-positive and Gram-negative bacterial strains.

Prodrug design for the potent cardiovascular agent Nω-hydroxy-l-arginine (NOHA): Synthetic approaches and physicochemical characterization by Dennis Schade; Jürke Kotthaus; Nikola Klein; Joscha Kotthaus; Bernd Clement (5249-5259).
Nω-Hydroxy-l-arginine (NOHA)—the physiological nitric oxide precursor—is the intermediate of NO synthase (NOS) catalysis. Besides the important fact of releasing NO mainly at the NOS-side of action, NOHA also represents a potent inhibitor of arginases, making it an ideal therapeutic tool to treat cardiovascular diseases that are associated with endothelial dysfunction. Here, we describe an approach to impart NOHA drug-like properties, particularly by wrapping up the chemically and metabolically instable N-hydroxyguanidine moiety with different prodrug groups. We present synthetic routes that deliver several more or less highly substituted NOHA derivatives in excellent yields. Versatile prodrug strategies were realized, including novel concepts of bioactivation. Prodrug candidates were primarily investigated regarding their hydrolytic and oxidative stabilities. Within the scope of this work, we essentially present the first prodrug approaches for an interesting pharmacophoric moiety, i.e., N-hydroxyguanidine.

The triphenylphosphine-catalyzed formal [3 + 2] cycloaddition of allenoates and trifluoromethylketones was realized to give the corresponding dihydrofurans in good yields with excellent γ-regioselectivities. Hydrogenation of the dihydrofurans gave 2,4,4-trisubstituted tetrahydrofurans in good yields with exclusive cis-selectivities.

Profiling the tuneable R-SMS-Phos structure in the rhodium(i)-catalyzed hydrogenation of olefins: the last stand? by Michel Stephan; Damjan Šterk; Borut Zupančič; Barbara Mohar (5266-5271).
A diversified family of enantiopure P-stereogenic “R-SMS-Phos” {R-SMS-Phos = 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane} ligands wherein R = branched or heteroatom-substituted alkyl, aralkyl, silyl, acyl, sulfonyl, etc. was screened for the Rh(i)-catalyzed hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to Knowles' ultimate DiPAMP {DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane} design. Mutant ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure is found embedded were identified.

Bridged nucleic acid conjugates at 6′-thiol: synthesis, hybridization properties and nuclease resistances by Kazuto Mori; Tetsuya Kodama; Takeshi Baba; Satoshi Obika (5272-5279).
The bridged nucleic acid (BNA) containing a thiol at the 6′-position in the bridged structure was synthesized from the disulfide-type BNA and conjugated with various functional molecules via the thioether or the disulfide linkage post-synthetically and efficiently in solution phase. The disulfide-linked conjugate was cleaved under reductive conditions derived from glutathione and an oligonucleotide bearing a free thiol was released smoothly. Conjugated functional molecules had great effects on duplex stability with the DNA complement. In contrast, the molecules little influenced the stability with the RNA complement. Moreover, the oligonucleotides with functional groups at the 6′-position had as high or higher resistances against 3′-exonuclease than phosphorothioate oligonucleotide (S-oligo).

A series of chiral pyrrolidinyl-sulfamide derivatives have been identified as efficient bifunctional organocatalysts for the direct Michael addition of cyclohexanone to a wide range of nitroalkenes. The desired Michael adducts were obtained in high chemical yields and excellent stereoselectivities (up to 99/1 dr and 95% ee).

Chlorination and ortho-acetoxylation of 2-arylbenzoxazoles by Yuting Leng; Fan Yang; Weiguo Zhu; Yangjie Wu; Xiang Li (5288-5296).
Efficient and facile catalytic protocols for chlorination and ligand-directed ortho-acetoxylation of 2-arylbenzoxazoles have been developed. The chlorination is not a ligand-directed ortho-functionalization, but an electrophilic substitution process in the benzo ring of the benzoxazole moiety. Meanwhile, the acetoxylation exhibited high regioselectivity for the substrates containing a meta-substituent and occurred at the less sterically hindered ortho-C–H bond of the directing group.

An efficient asymmetric cascade reaction catalyzed by a chiral bifunctional indane amine–thiourea catalyst has been developed. From a broad substrate scope, chiral dihydro-2H-pyran complexes that contained two stereogenic centers were obtained in a one-pot manner in good to excellent yields (72–97%) and high to excellent stereoselectivities (92–97% ee).

Back cover (5303-5304).