Organic & Biomolecular Chemistry (v.13, #20)
Front cover (5559-5559).
Inside front cover (5560-5560).
Contents list (5561-5569).
The tale of RNA G-quadruplex by Prachi Agarwala; Satyaprakash Pandey; Souvik Maiti (5570-5585).
G-quadruplexes are non-canonical secondary structures found in guanine rich regions of DNA and RNA. Reports have indicated the wide occurrence of RNA G-quadruplexes across the transcriptome in various regions of mRNAs and non-coding RNAs. RNA G-quadruplexes have been implicated in playing an important role in translational regulation, mRNA processing events and maintenance of chromosomal end integrity. In this review, we summarize the structural and functional aspects of RNA G-quadruplexes with emphasis on recent progress to understand the protein/trans factors binding these motifs. With the revelation of the importance of these secondary structures as regulatory modules in biology, we have also evaluated the various advancements towards targeting these structures and the challenges associated with them. Apart from this, numerous potential applications of this secondary motif have also been discussed.
An interactive database to explore herbicide physicochemical properties by Michael N. Gandy; Maxime G. Corral; Joshua S. Mylne; Keith A. Stubbs (5586-5590).
Herbicides are an essential tool not only in weed management, but also in conservation tillage approaches to cropping. The first commercial herbicides were released in the 1940s and hundreds more since then, although genetic resistance to them is an issue. Here, we review the experimental and estimated physicochemical properties of 334 successful herbicidal compounds and make available a dynamic electronic database containing detailed analyses of the main chemical properties for herbicides and which adopts the Simplified Molecular-Input Line-Entry System (SMILES) for describing the structure of chemical molecules. This fully available resource allows for the rapid comparison of potential new herbicidal compounds to the chemical properties of known herbicides.
Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: an organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent by Elisabetta Massolo; Maurizio Benaglia; Andrea Genoni; Rita Annunziata; Giuseppe Celentano; Nicoletta Gaggero (5591-5596).
An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-β-aryl-α-keto esters with up to 92% ee were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of a GABAB receptor agonist baclofen.
Stereoselective construction of functionalized tetracyclic and pentacyclic coumarinopyranpyrazole/pyrimidinedione/coumarin scaffolds using a solid-state melt reaction by Manickam Bakthadoss; Damodharan Kannan; Nagappan Sivakumar; Palani Malathi; Vasudevan Manikandan (5597-5601).
An assembly of tetra / pentacyclic hybrid scaffolds have been synthesized for the first time using a solid-state melt reaction in a stereoselective fashion with excellent yields.
Copper-catalyzed aerobic oxidative amination of C(sp3)–H bonds: synthesis of imidazo[1,5-a]pyridines by Darapaneni Chandra Mohan; Sadu Nageswara Rao; Chitrakar Ravi; Subbarayappa Adimurthy (5602-5607).
Copper-catalyzed synthesis of imidazo[1,5-a]pyridine-1-carboxylates through oxidative amination of C(sp3)–H bonds under mild aerobic conditions with broad substrate scope is described. Use of naturally abundant air as the sole oxidant was found to be efficient and selective. The present protocol is also applicable for direct synthesis of functionalized imidazo[1,5-a]pyridines from amino acid derivatives.
Heteroatom-substituted tetra(3,4-pyrido)porphyrazines: a stride toward near-infrared-absorbing macrocycles by Lenka Vachova; Miloslav Machacek; Radim Kučera; Jiri Demuth; Pavel Cermak; Kamil Kopecky; Miroslav Miletin; Adela Jedlickova; Tomas Simunek; Veronika Novakova; Petr Zimcik (5608-5612).
A synthesis procedure for heteroatom-substituted tetra(3,4-pyrido)porphyrazines that absorb light near 800 nm was developed. Based on the observed relationships between the structure and photophysical parameters, a novel highly photodynamically active (IC50 = 0.26 μM) compound was synthesized and biologically characterized.
Direct conversion of allyl arenes to aryl ethylketones via a TBHP-mediated palladium-catalyzed tandem isomerization–Wacker oxidation of terminal alkenes by JinWu Zhao; Li Liu; ShiJian Xiang; Qiang Liu; HuoJi Chen (5613-5616).
A TBHP-mediated palladium-catalyzed tandem isomerization–Wacker oxidation of terminal alkenes was developed. This methodology provides a new efficient and simple route for conversion of a range of allyl arenes directly into aryl ethylketones in good yields with high chemoselectivity.
A preorganized β-amino acid bearing a guanidinium side chain and its use in cell-penetrating peptides by Yosuke Demizu; Makoto Oba; Koyo Okitsu; Hiroko Yamashita; Takashi Misawa; Masakazu Tanaka; Masaaki Kurihara; Samuel H. Gellman (5617-5620).
A cyclic β-amino acid (APCGu) bearing a side-chain guanidinium group has been developed. The APCGu residue was incorporated into an α/β-peptide based on the Tat(47–57) fragment, leading to an oligomer with substantial helicity in methanol that enters HeLa cells much more readily than does the corresponding Tat α-peptide.
Fluorine containing amino acids: synthesis and peptide coupling of amino acids containing the all-cis tetrafluorocyclohexyl motif by Mohammed Salah Ayoup; David B. Cordes; Alexandra M. Z. Slawin; David O'Hagan (5621-5624).
A synthesis of two (S)-phenylalanine derivatives is described which have the all-cis, 2,3,5,6-tetrafluorocyclohexyl motif attached to the aromatic ring at the meta and para positions; the para substituted isomer is elaborated into illustrative dipeptides via the free amine and carboxylate respectively demonstrating its utility as a novel amino acid for peptide synthesis and offering a vehicle for incorporation of this unique and facially polarized ring system into bioactive compounds.
Simultaneous introduction of trifluoromethyl and λ6-pentafluorosulfanyl substituents using F5S–CC–CF3 as a dienophile by Blazej Duda; Dieter Lentz (5625-5628).
F5S–CC–CF3 can be easily prepared in high yields in two steps from 3,3,3-trifluoropropyne. It is a powerful, versatile dienophile in Diels–Alder reactions. Reactions at room temperature provide the corresponding products in up to quantitative yields allowing the introduction of the pentafluorosulfanyl group and trifluoromethyl group at the 1,2 position.
Maleimide as an efficient nucleophilic partner in the aza-Morita–Baylis–Hillman reaction: synthesis of chiral 3-substituted-3-aminooxindoles by Akshay Kumar; Vivek Sharma; Jasneet Kaur; Naveen Kumar; Swapandeep Singh Chimni (5629-5635).
A highly enantioselective Morita–Baylis–Hillman reaction of maleimides with isatin derived ketimines has been developed to obtain enantiomerically enriched 3-substituted-3-aminooxindoles using β-isocupreidine as an organocatalyst. Maleimide acting as a nucleophile provides products with up to 99% ee.
Enantioselective synthesis of chiral heterocycles containing both chroman and pyrazolone derivatives catalysed by a chiral squaramide by Jun-Hua Li; Da-Ming Du (5636-5645).
An efficient chiral squaramide-catalysed enantioselective Michael addition of pyrazolin-5-ones to 3-nitro-2H-chromenes for the synthesis of chiral heterocyclic systems containing both chroman and pyrazolone derivatives has been developed. This reaction afforded the desired products in high to excellent yields (up to 98%) with high enantioselectivities (up to 96%) and excellent diastereoselectivities (up to 99 : 1) under very low catalyst loading (0.2 mol%). This catalytic asymmetric reaction provides an efficient route toward the synthesis of chiral heterocyclic systems containing both chroman and pyrazolone derivatives, which possess potential pharmaceutical activities.
Regulation of telomeric i-motif stability by 5-methylcytosine and 5-hydroxymethylcytosine modification by Baochang Xu; Gitali Devi; Fangwei Shao (5646-5651).
The two important epigenetic markers in the human genome, 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC), are involved in gene regulation processes. As a major epigenetic target, cytosines in a C-rich DNA sequence were substituted with mC and hmC to investigate the thermal stability and pH sensitivity of the corresponding i-motifs. Circular Dichroism (CD) studies indicate the formation of i-motifs at acidic pH (<6.5) for mC- and hmC-modified DNA sequences. Thermal denaturation results suggest that DNA i-motifs are stabilized when modified with one or two mCs. However, hypermethylation with mC and single modification with hmC cause destabilization of the structure. A biomimetic crowding agent does not alter the stability effect trends resulting from mC and hmC modifications, though the corresponding i-motifs show elevated melting temperatures without significant changes in pKa values.
Carbonic anhydrase II as host protein for the creation of a biocompatible artificial metathesase by Jingming Zhao; Anna Kajetanowicz; Thomas R. Ward (5652-5655).
An artificial metathesase results from incorporation of an Hoveyda-Grubbs catalyst bearing an arylsulfonamide anchor within human carbonic anhydrase II. The optimization of the catalytic performance is achieved upon combining both chemical and genetic means. Up to 28 TONs were obtained within four hours under aerobic physiological conditions.
Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists by Zong-Jie Gan; Yu-Hua Wang; Yun-Gen Xu; Ting Guo; Jun Wang; Qiao Song; Xue-Jun Xu; Shi-Yuan Hu; Yu-Jun Wang; De-Chuan Wang; De-Zhu Sun; Di Zhang; Tao Xi; Hao-Dong Li; Hai-Bo Zhang; Tai-Jun Hang; Hong-Guo Lu; Jing-Gen Liu (5656-5673).
A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a–maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg−1) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg−1) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg−1) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg−1), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.
Colchicine derivatives with potent anticancer activity and reduced P-glycoprotein induction liability by Baljinder Singh; Ashok Kumar; Prashant Joshi; Santosh K. Guru; Suresh Kumar; Zahoor A. Wani; Girish Mahajan; Aashiq Hussain; Asif Khurshid Qazi; Ajay Kumar; Sonali S. Bharate; Bishan D. Gupta; Parduman R. Sharma; Abid Hamid; Ajit K. Saxena; Dilip M. Mondhe; Shashi Bhushan; Sandip B. Bharate; Ram A. Vishwakarma (5674-5689).
Colchicine (1), a nature-derived microtubule polymerization inhibitor, develops multi-drug resistance in tumor cells due to its P-gp substrate and induction activity, which in turn leads to its rapid efflux from tumor cells. This auto-induction of the efflux of colchicine remains a major challenge to medicinal chemists. Based on structure-based molecular modeling, a series of new colchicine derivatives were designed and synthesized with a potential for reduced P-gp induction liability. Screening of the prepared derivatives for P-gp induction activity revealed that a number of derivatives possess remarkably lower P-gp-induction activity (>90% intracellular accumulation of rhodamine 123 in LS-180 cells) compared to the parent natural product colchicine (62% Rh123 accumulation in LS-180 cells). The reduced P-gp-induction activity of new derivatives may be due to their reduced ability to interact and change the conformation of P-gp. The synthesized derivatives were then screened for antiproliferative activity against two colon cancer cell lines including HCT-116 and Colo-205. The derivative 4o showed potent cytotoxicity in HCT-116 cells with IC50 of 0.04 μM with significantly reduced P-gp induction liability. Compound 4o also inhibited microtubule assembly and induced expression of pro-apoptotic protein p21. In an Ehrlich solid tumor mice model, compound 4o showed 38% TGI with no mortality at 2 mg kg−1 dose (oral). Compound 4o, with potent in vitro and in vivo anticancer activity, significantly reduced P-gp induction activity and its excellent physicochemical and pharmacokinetic properties open up new opportunities for the colchicine scaffold.
Galacto configured N-aminoaziridines: a new type of irreversible inhibitor of β-galactosidases by Anna Alcaide; Ana Trapero; Yolanda Pérez; Amadeu Llebaria (5690-5697).
A new type of galactose mimetics has been synthesized following a straightforward synthetic approach based on cyclohexene olefin aziridination reactions directed by hydroxyl substituents. These enantiomerically pure galacto-configured N-aminoaziridines are potent irreversible inhibitors of Aspergillus oryzae and Escherichia coliβ-galactosidases.
Organocatalytic regioselective asymmetric Michael addition of azlactones to o-hydroxy chalcone derivatives by Shao-Yun Zhang; Gui-Yu Ruan; Zhi-Cong Geng; Nai-Kai Li; Ming Lv; Yong Wang; Xing-Wang Wang (5698-5709).
The regioselective and enantioselective Michael addition between azlactones and o-hydroxy chalcone derivatives is reported. Enantiomerically enriched N,O-aminals with two continuous stereogenic centers are exclusively obtained in moderate to good yields with excellent diastereoselectivities and good to excellent enantioselectivities. The experimental results show that an o-hydroxy group on the cinnamenyl motif of chalcone derivatives plays a crucial role at the reaction sites for the regioselective Michael addition. In addition, circular dichroism (CD) spectroscopy and density functional theory (DFT) are used to investigate the absolute configuration of N,O-aminals and the corresponding transition-state structures.
Indium-catalyzed oxidative cross-dehydrogenative coupling of chromenes with 1,3-dicarbonyls and aryl rings by Fanmei Li; Zhilin Meng; Jing Hua; Wei Li; Hongxiang Lou; Lei Liu (5710-5715).
An effective indium-catalyzed oxidative cross-dehydrogenative coupling of electronically varied chromenes with 1,3-dicarbonyl compounds and aryl rings has been established. Both the C–H alkylation and arylation proceed smoothly at room temperature to afford diverse α-substituted chromene compounds in up to 91% yields. Besides these two types of C–H components, simple ketones like cyclohexanones also prove to be well tolerated.
Synthetic studies toward the brasilinolides: controlled assembly of a protected C1–C38 polyol based on fragment union by complex aldol reactions by Ian Paterson; Michael P. Housden; Christopher J. Cordier; Paul M. Burton; Friedrich A. Mühlthau; Olivier Loiseleur (5716-5733).
The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1–C19 and C20–C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19–C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1–C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.
Effect of preorganization on the affinity of synthetic DNA binding motifs for nucleotide ligands by S. Vollmer; C. Richert (5734-5742).
Triplexes with a gap in the purine strand have been shown to bind adenosine or guanosine derivatives through a combination of Watson–Crick and Hoogsteen base pairing. Rigidifying the binding site should be advantageous for affinity. Here we report that clamps delimiting the binding site have a modest effect on affinity, while bridging the gap of the purine strand can strongly increase affinity for ATP, cAMP, and FAD. The lowest dissociation constants were measured for two-strand triple helical motifs with a propylene bridge or an abasic nucleoside analog, with Kd values as low as 30 nM for cAMP in the latter case. Taken together, our data suggest that improving preorganization through covalent bridges increases the affinity for nucleotide ligands. But, a bulky bridge may also block one of two alternative binding modes for the adenine base. The results may help to design new receptors, switches, or storage motifs for purine-containing ligands.
Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria by Steven M. Wales; Katherine A. Hammer; Amy M. King; Andrew J. Tague; Dena Lyras; Thomas V. Riley; Paul A. Keller; Stephen G. Pyne (5743-5756).
Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure–activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 μg mL−1 against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs ≥2 μg mL−1), S. pneumoniae (MICs ≥1 μg mL−1), E. coli (MICs ≥4 μg mL−1), A. baumannii (MICs ≥4 μg mL−1) and vancomycin-resistant E. faecalis (MICs ≥4 μg mL−1).
Resveratrol-based benzoselenophenes with an enhanced antioxidant and chain breaking capacity by Damiano Tanini; Lucia Panzella; Riccardo Amorati; Antonella Capperucci; Elio Pizzo; Alessandra Napolitano; Stefano Menichetti; Marco d'Ischia (5757-5764).
The structural modification of the resveratrol scaffold is currently an active issue in the quest for more potent and versatile antioxidant derivatives for biomedical applications. Disclosed herein is an expedient and efficient entry to a novel class of resveratrol derivatives featuring an unprecedented 2-phenylbenzoselenophene skeleton. The new compounds were obtained in good yields by direct selenenylation of resveratrol with Se(0) and SO2Cl2 in dry THF. Varying the [Se : SO2Cl2 : resveratrol] ratio resulted in the formation of the parent benzoselenophene (1) and/or mono (2) and/or dichloro (3) benzoselenophene derivatives. All the benzoselenophene derivatives proved to be more efficient than resveratrol in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assays, with 1 showing an activity nearly comparable to that of Trolox. 1–3 also proved to be more efficient inhibitors than the parent resveratrol in kinetic experiments of styrene autoxidation. DFT calculations of the O–H bond dissociation enthalpy (BDE) revealed that the introduction of the Se-atom causes a significant decrease of the BDE of 3-OH and 5-OH, with just a small increase of the 4′-OH BDE. Compounds 1–3 showed no cytotoxicity at 5 μM concentrations on human keratinocyte (HaCaT) and intestinal (CaCo-2) cell lines.
Synthesis of new carolacton derivatives and their activity against biofilms of oral bacteria by N. Stumpp; P. Premnath; T. Schmidt; J. Ammermann; G. Dräger; M. Reck; R. Jansen; M. Stiesch; I. Wagner-Döbler; A. Kirschning (5765-5774).
Carolacton, a secondary metabolite isolated from the extracts of Sorangium cellulosum, causes membrane damage and cell death in biofilms of the caries- and endocarditis-associated bacterium Streptococcus mutans. Here, we report the total synthesis of several derivatives of carolacton. All new structural modifications introduced abolished its biological activity, including subtle ones, such as inversion of configuration at C9. However, a bicyclic bislactone derivative as well as the methyl ester of carolacton resulted in compounds with prodrug properties. Their inhibitory activity on S. mutans was proven to be based on enzymatic hydrolysis by S. mutans which provided native carolacton resulting in biofilm damage in vivo. Moreover, we demonstrate that carolacton acts also on S. gordonii, S. oralis and the periodontitis pathogen Aggregatibacter actinomycetemcomitans, causing elongated cells and growth inhibition.
High solid-state luminescence in propeller-shaped AIE-active pyridine–ketoiminate–boron complexes by Yanping Wu; Zhenyu Li; Qingsong Liu; Xiaoqing Wang; Hui Yan; Shuwen Gong; Zhipeng Liu; Weijiang He (5775-5782).
Two pyridine-ketoiminate-based organoboron complexes (2 and 3) were developed. 2 and 3 showed very weak emission in low-viscosity organic solvents because of the intramolecular rotation induced non-radiative process. Their emission can be dramatically enhanced by the increase in solvent viscosity or by molecular aggregation in the solid state. Moreover, 2 and 3 exhibited intense emission with high quantum yield of 0.53 and 0.46, respectively. X-ray crystallographic analysis showed that the weak intermolecular interactions such as C–H⋯F and C–H⋯π by fixing the molecular conformations of 2 and 3 were responsible for intense luminescence in the solid state. The large Stokes shifts and high efficient solid-state emission of 2 and 3 make them valuable AIE luminophores for further potential applications in the fields of fluorescence imaging and materials science.
Direct synthesis of a geminal zwitterionic phosphonium/hydridoborate system – developing an alternative tool for generating frustrated Lewis pair hydrogen activation systems by Jiangang Yu; Gerald Kehr; Constantin G. Daniliuc; Christoph Bannwarth; Stefan Grimme; Gerhard Erker (5783-5792).
A convenient way to a new class of geminal Mes2PH+/B(C6F5)2H− pairs is presented. It utilizes triflic acid addition to trans-Mes2PCHCHB(C6F5)2 followed by triflate/hydride exchange. Thermally induced ring-closure gave a phosphonium/boratacyclopropane zwitterion 8 which formed the Mes2PH(CHMe)B(C6F5)2H P/B FLP-H2 product 10 by subsequent treatment with triflic acid and a silane, or alternatively with dihydrogen at 90 °C. The product 10 is an active catalyst for the hydrogenation of a variety of unsaturated organic substrates, including a quinoline derivative. Treatment of compound 8 with HB(C6F5)2 gave a bifunctional borane 14 which selectively reduced carbon monoxide to the formyl stage.
Grignard-mediated reduction of 2,2,2-trichloro-1-arylethanones by Ali H. Essa; Reinner I. Lerrick; Eçe Çiftçi; Ross W. Harrington; Paul G. Waddell; William Clegg; Michael J. Hall (5793-5803).
2,2,2-Trichloro-1-aryl-ethanones can be reduced by RMgX to the corresponding 2,2-dichloro-1-arylethen-1-olates and trapped with a range of electrophiles resulting in either reduction, reduction/aldol, reduction/Claisen condensation or reduction/aldol-Tishchenko products. In addition we demonstrate that 2,2-dichloro-1-arylethen-1-olates undergo counter-ion controlled Darzens condensations, which can be followed by a thermal rearrangement as a route to 1,3-diaryl-3-chloropropane-1,2-diones.
Tri- and tetra-substituted cyclen based lanthanide(iii) ion complexes as ribonuclease mimics: a study into the effect of log Ka, hydration and hydrophobicity on phosphodiester hydrolysis of the RNA-model 2-hydroxypropyl-4-nitrophenyl phosphate (HPNP) by Ann-Marie Fanning; Sally. E. Plush; Thorfinnur Gunnlaugsson (5804-5816).
A series of tetra-substituted ‘pseudo’ dipeptide ligands of cyclen (1,4,7,10,-tetraazacyclododecane) and a tri-substituted 3′-pyridine ligand of cyclen, and the corresponding lanthanide(iii) complexes were synthesised and characterised as metallo-ribonuclease mimics. All complexes were shown to promote hydrolysis of the phosphodiester bond of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNP, τ1/2 = 5.87 × 103 h), a well known RNA mimic. The La(iii) and Eu(iii) tri-substituted 3′-pyridine lanthanide(iii) complexes being the most efficient in promoting such hydrolysis at pH 7.4 and at 37 °C; with τ1/2 = 1.67 h for La(iii) and 1.74 h for Eu(iii). The series was developed to provide the opportunity to investigate the consequences of altering the lanthanide(iii) ion, coordination ability and hydrophobicity of a metallo-cavity on the rate of hydrolysis using the model phosphodiester, HPNP, at 37 °C. To further provide information on the role that the log Ka of the metal bound water plays in phosphodiester hydrolysis the protonation constants and the metal ion stability constants of both a tri and tetra-substituted 3′pyridine complex were determined. Our results highlighted several key features for the design of lanthanide(iii) ribonucelase mimics; the presence of two metal bound water molecules are vital for pH dependent rate constants for Eu(iii) complexes, optimal pH activity approximating physiological pH (∼7.4) may be achieved if the log Ka values for both MLOH and ML(OH)2 species occur in this region, small changes to hydrophobicity within the metallo cavity influence the rate of hydrolysis greatly and an amide adjacent to the metal ion capable of forming hydrogen bonds with the substrate is required for achieving fast hydrolysis.
BINOL-Al catalysed asymmetric cyclization and amplification: preparation of optically active menthol analogs by Hisanori Itoh; Hironori Maeda; Shinya Yamada; Yoji Hori; Takashi Mino; Masami Sakamoto (5817-5825).
We report a highly selective asymmetric ring-closing ene reaction catalysed by aluminum complexes with chiral BINOL. This reaction yields optically active 6-membered cyclized alcohols from unsaturated aldehydes, with good diastereo- and enantioselectivities. Asymmetric amplification of this reaction was investigated by varying the ee of the BINOL employed in the catalyst.
Palladium-catalyzed asymmetric allylic amination of racemic butadiene monoxide with isatin derivatives by Gen Li; Xiangqing Feng; Haifeng Du (5826-5830).
Isatins and their derivatives are important functional moities and building blocks in pharmaceutical and synthetic chemistry. Numerous enantioselective transformations at the C-3 carbonyl group have been well developed. However, the asymmetric substitution reaction with isatins and their derivatives as nucleophiles based on the free N–H groups has been less studied due to the relatively weaker nucleophilicity resulting from the two electron-withdrawing carbonyl groups. In this paper, a palladium-catalyzed asymmetric allylic amination of racemic butadiene monoxide with isatin derivatives using a chiral phosphoramidite olefin hybrid ligand has been successfully developed under mild conditions. A variety of chiral amino alcohols were afforded in 55–87% yields with 10/1->20/1 regioselectivity ratios and 80–97% ees.
Back cover (5831-5832).