A one-pot domino synthesis and discovery of highly functionalized dihydrobenzo[b]thiophenes as AChE inhibitors

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles have been synthesized regioselectively in good yields through the one-pot domino reactions of 5-aryldihydro-3(2H)-thiophenones, malononitrile and aromatic aldehydes in the presence of morpholine. This transformation presumably involves Knoevenagel condensation–Michael addition–intramolecular Thorpe–Ziegler cyclization–Tautomerization–Elimination sequence of reactions. These compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile was found to be the most potent against AChE with IC₅₀ 4.16 μmol/L.     

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations

The major goal of this review is a critical discussion of the literature data on asymmetric synthesis of α-amino acids via Michael addition reactions involving Ni(II)-complexes of amino acids. The material covered is divided into two conceptually different groups dealing with applications of: (a) Ni(II)-complexes of glycine as C-nucleophiles and (b) Ni(II)-complexes of dehydroalanine as Michael acceptors. The first group is significantly larger and consequently subdivided into four chapters based on the source of stereocontrolling element. Thus, a chiral auxiliary can be used as a part of nucleophilic glycine Ni(II) complex, Michael acceptor or both, leading to the conditions of matching vs. mismatching stereochemical preferences. The particular focus of the review is made on the practical aspects of the methodology under discussion and mechanistic considerations.     

Direct asymmetric Michael addition of thioether‐based aryl sulfanyl‐propan‐2‐one to nitroalkenes catalyzed by a chiral amine‐thiourea bifunctional organocatalyst

Although the organocatalytic direct asymmetric Michael reactions of carbonyl compounds to nitroalkenes have been investigated intensely, the Michael reaction of the thioether‐based donors remains a rather undeveloped field. This work concerns the asymmetric Michael addition of aryl sulfanyl‐propan‐2‐one to nitroalkenes with benzoic acid as an additive, and chiral amine‐thiourea as a bifunctional organocatalyst. The reactions provided the highly functionalized chiral adducts with excellent enantioselectivities (up to 96% ee) and good yields. Moreover, the further transformed products exhibited excellent diastereoselectivity. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Anceaux's Glasses

The Kayapó (Disappearing World Series) Producer: Michael Beckham; Director: Michael Beckham; Camera: Michael Blakeley; Sound: David Woods; Editor: Paul Griffiths‐Davies; Consultant Anthropologist: Terence Turner; Distributor: Enquiries to Granada Television International, 1221 6th Avenue, Suite 3468, New York, NY 10020 USA, (212) 809–8480. 1987, 52 min., color. Original: 16mm, only available for distribution on video. Language: Original Kayapo, Narration English, Subtitles English.

Independent Films and Videos from Latin America: Producers’ Obstacles, National Diversity, and the Cultural Woes of Their Foreign Audiences Review of Democracy in Communication: Popular Film and Video in Latin America. A catalogue compilation of various videotapes. 1988, color. Original language: Spanish, English subtitles. Distributed by: Karen Ranucci, 124 Washington Place, New York, NY, tele. 212–463–9198.     

Highly enantioselective Michael addition of cyclohexanone to nitroolefins catalyzed by pyrrolidine‐based bifunctional benzoylthiourea in water

Organocatalysis and aqueous reactions are identified as the focus of the greening of chemistry. Combining these two strategies effectively remains an interesting challenge in organic synthesis. Herein, we used pyrrolidine‐based benzoylthiourea 1c to catalyze the asymmetric Michael addition of cyclohexanone to various nitroolefins in water to afford the corresponding compounds in moderate to good yields, and with excellent diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to 99% ee).     

G‐quadruplex DNA‐based asymmetric catalysis of michael addition: Effects of sonication,ligands, and co‐solvents

There is an escalating interest of using double stranded DNA molecules as a chiral scaffold to construct metal‐biomacromolecule hybrid catalysts for asymmetric synthesis. Several recent studies also evaluated the use of G‐quadruplex DNA‐based catalysts for asymmetric Diels‐Alder and Friedel‐Crafts reactions. However, there is still a lack of understanding of how different oligonucleotides, salts (such as NaCl and KCl), metal ligands and co‐solvents affect the catalytic performance of quadruplex DNA‐based hybrid catalysts. In this study, we aim to systematically evaluate these key factors in asymmetric Michael addition reactions, and to examine the conformational and molecular changes of DNA by circular dichroism (CD) spectroscopy and gel electrophoresis. We achieved up to 95% yield and 50% enantiomeric excess (ee) when the reaction of 2‐acylimidazole 1a and dimethylmalonate was catalyzed by 5′‐G₃(TTAG₃)₃?3′ (G4DNA1) in 20 mM MOPS (pH 6.5) containing 50 mM KCl and 40 µM [Cu(dmbipy)(NO₃)₂], and G4DNA1 was pre‐sonicated in ice bath for 10 min prior to the reaction. G‐quadruplex‐based hybrid catalysts provide a new tool for asymmetric catalysis, but future mechanistic studies should be sought to further improve the catalytic efficiency. The current work presents a systematic study of asymmetric Michael addition catalyzed by G‐quadruplex catalysts constructed via non‐covalent complexing, and an intriguing finding of the effect of pre‐sonication on catalytic efficiency. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:891–898, 2016     

Reactions of withaferin-A with model biological nucleophiles

Withaferin-A was reacted with three model biological nucleophiles: ethyl mercaptan, thiophenol, and -cysteine ethyl ester. Under neutral or alkaline conditions, each of the thiols underwent facile Michael addition with the antitumor agent. The most chemically reactive site for Michael Addition reactions with the model thiols was the unsaturated A-ring of withaferin-A. The possible significance of this reaction with regard to antitumor activity is discussed.     

Asymmetric Stetter reactions catalyzed by thiamine diphosphate-dependent enzymes

The intermolecular asymmetric Stetter reaction is an almost unexplored transformation for biocatalysts. Previously reported thiamine diphosphate (ThDP)-dependent PigD from Serratia marcescens is the first enzyme identified to catalyze the Stetter reaction of α,β-unsaturated ketones (Michael acceptor substrates) and α-keto acids. PigD is involved in the biosynthesis of the potent cytotoxic agent prodigiosin. Here, we describe the investigation of two new ThDP-dependent enzymes, SeAAS from Saccharopolyspora erythraea and HapD from Hahella chejuensis. Both show a high degree of homology to the amino acid sequence of PigD (39 and 51 %, respectively). The new enzymes were heterologously overproduced in Escherichia coli, and the yield of soluble protein was enhanced by co-expression of the chaperone genes groEL/ES. SeAAS and HapD catalyze intermolecular Stetter reactions in vitro with high enantioselectivity. The enzymes possess a characteristic substrate range with respect to Michael acceptor substrates. This provides support for a new type of ThDP-dependent enzymatic activity, which is abundant in various species and not restricted to prodigiosin biosynthesis in different strains. Moreover, PigD, SeAAS, and HapD are also able to catalyze asymmetric carbon–carbon bond formation reactions of aldehydes and α-keto acids, resulting in 2-hydroxy ketones.     

Michael acceptor properties of 6-bicycloaryl substituted (R)-5,6-dihydro-2H-pyran-2-ones

The mechanism of action for α,β-unsaturated lactones can be explained by their Michael acceptor properties. They have the potential of being covalently binding inhibitors by accepting nucleophiles from target proteins. In this work, Michael addition reactions of ethanethiol with 6-bicycloaryl substituted 5,6-dihydro-2H-pyran-2-ones were studied to explore the existence of such interactions. Three of the Michael addition products were isolated and tested over PC3 (human prostate cancer) and MCF-7 (human breast adenocarcinoma) cancer cell lines and no cytotoxicity was observed. It was revealed that biological activity depends on the existence of a Michael acceptor, but potency probably depends upon the 3D structure of the substituent on lactone ring. The primary chemical-quantum properties of the lactones were also calculated using the Spartan’08 computer program.     

Simple chemical tools to expand the range of proteomics applications

Proteomics is an expanding technology with potential applications in many research fields. Even though many research groups do not have direct access to its main analytical technique, mass spectrometry, they can interact with proteomics core facilities to incorporate this technology into their projects. Protein identification is the analysis most frequently performed in core facilities and is, probably, the most robust procedure. Here we discuss a few chemical reactions that are easily implemented within the conventional protein identification workflow. Chemical modification of proteins with N-hydroxysuccinimide esters, 4-sulfophenyl isothiocyanate, O-methylisourea or through β-elimination/Michael addition can be easily performed in any laboratory. The reactions are quite specific with almost no side reactions. These chemical tools increase considerably the number of applications and have been applied to characterize protein-protein interactions, to determine the N-terminal residues of proteins, to identify proteins with non-sequenced genomes or to locate phosphorylated and O-glycosylated.     

Synthesis of Cyclopropane Isosteres of the Antiepilepsy Drug Vigabatrin and Evaluation of their Inhibition of GABA Aminotransferase

The antiepilepsy drug vigabatrin (1; 4-aminohex-5-enoic acid; γ-vinyl GABA) is a mechanism-based inactivator of the pyridoxal 5'-phosphate (PLP)-dependent enzyme γ-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M. and Silverman, R. B. (1991) J. Am. Chem. Soc. 113, 9341–9349), a Michael addition pathway (Scheme 2, pathway a) and an enamine pathway (Scheme 2, pathway b). Analogs of vigabatrin with a cyclopropyl or cyanocyclopropyl functionality in place of the vinyl group (2–5) were synthesized as potential inactivators of GABA-AT that can inactivate the enzyme only through a Michael addition pathway, but they were found to be only weak inhibitors of the enzyme.     

In silico strategy to rationally engineer metabolite production: A case study for threonine in Escherichia coli

Genetic engineering of metabolic pathways is a standard strategy to increase the production of metabolites of economic interest. However, such flux increases could very likely lead to undesirable changes in metabolite concentrations, producing deleterious perturbations on other cellular processes. These negative effects could be avoided by implementing a balanced increase of enzyme concentrations according to the Universal Method [Kacser and Acerenza (1993) Eur J Biochem 216:361–367]. Exact application of the method usually requires modification of many reactions, which is difficult to achieve in practice. Here, improvement of threonine production via pyruvate kinase deletion in Escherichia coli is used as a case study to demonstrate a partial application of the Universal Method, which includes performing sensitivity analysis. Our analysis predicts that manipulating a few reactions is sufficient to obtain an important increase in threonine production without major perturbations of metabolite concentrations. Biotechnol. Bioeng. 2009;103: 609–620. © 2009 Wiley Periodicals, Inc.     

Design,synthesis and application of chiral tetraoxacalix[2]arene[2]triazine‐based organocatalysts in asymmetric Michael addition reactions

A novel type of oxacalix[2]arene[2]triazine‐based organocatalysts for asymmetric Michael reactions are reported for the first time. Chiral subunits were attached to the heteroatom‐bridged calixaromatic platform by a reaction of (R)‐ and (S)‐1‐aminotetraline with tetraoxacalix[2]arene[2]triazine in both enantiomeric forms. To evaluate the catalytic efficiency of the novel organocatalysts, isobutyraldehyde reacted with various substituted and unsubstituted aromatic trans‐β‐nitrostyrenes in tetrahydrofuran (THF), leading to Michael adducts in excellent yields and enantioselectivites (up to 97% yield and 99% ee).     

Investigation of the inhibition pathway of glucosamine synthase by N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid by semiempirical quantum mechanical and molecular mechanics methods

Glucosamine synthase (E.C. 2.6.1.16) is a promising target in antifungal drug design. It has been reported that its potent inhibitor, N³-(4-methoxyfu-maroyl)-L-2,3-diaminopropanoic acid (FMDP), inactivates the enzyme by the Michael addition of the S-H group to the FMDP molecule followed by cyclisation reactions. In this study we have investigated, by means of semiempirical MNDO, PM3 and molecular mechanics methods, the energetics and kinetic possibility of the formation of various stereoisomers of the products of cyclisation of the Michael addition products detected experimentally. It was found that the substituted 1,4-thiazin-3-one can be formed in one step under alkaline conditions; the stereoisomers of this compound predicted to be the most stable on the basis of theoretical calculations are also the dominant ones in reality.Abbreviations FMDP N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid - MNDO Modified Neglect of Diatomic Overlap - AM1 Advanced Method 1 - PM3 (full abbreviation: MNDOPM3) Modified Neglect of Diatomic Overlap, Parametrised Method 3 Correspondence to: A. Liwo     

Anthropology's Homer: Michael Young's Malinowski

Book reviewed in this article: Michael W. Young. Malinowski: Odyssey of an Anthropologist 1884–1920.     

Recyclable Merrifield resin‐supported organocatalysts containing pyrrolidine unit through A3‐coupling reaction linkage for asymmetric Michael addition

Merrifield resin‐supported pyrrolidine‐based chiral organocatalysts A ? D through A³‐coupling reaction linkage have been developed and found to be highly effective catalysts for the Michael addition reaction of ketones with nitrostyrenes. The reactions generated the corresponding products in good yields (up to 92%), excellent enantioselectivities (up to 98% ee), and high diastereoselectivities (up to 99:1 dr). In addition, the catalysts can be reused at least five times without a significant loss of catalytic activity and stereoselectivity. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Highly Enantioselective Michael Addition Promoted by a New Diterpene‐Derived Bifunctional Thiourea Catalyst: A Doubly Stereocontrolled Approach to Chiral Succinimide Derivatives

A doubly stereocontrolled organocatalytic asymmetric Michael addition to the synthesis of substituted succinimides is described. Starting from aldehydes and maleimides, both enantiomers of the succinimides could be obtained in high to excellent yields (up to 98%) and enantioselectivities (up to 99%) when one of the two special chiral diterpene‐derived bifunctional thioureas was individually used as a catalyst. Moreover, these catalysts can be efficiently used in large‐scale catalytic synthesis with the same level of yield and enantioselectivity. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc.     

The lipase-catalyzed asymmetric C–C Michael addition

The example of enzyme-catalyzed asymmetric C–C Michael addition was observed using Lipozyme TLIM (immobilized lipase from Thermomyces lanuginosus) in organic medium in the presence of water. This biocatalysis is applicable to the Michael additions of a wide range of 1,3-dicarbonyl compounds and cyclohexanone to aromatic and heteroaromatic nitroolefins and cyclohexenone. The enantioselectivities up to 83% ee and yields up to 90% were achieved. The enzyme can be reused for three cycles.     

BOOK REVIEWS

Book reviewed in this article: Bain Attwood and Fiona Magowan (eds) . Telling Stories: Indigenous History and Memory in Australia and New Zealand. Piya Chatterjee . A Time For Tea: Women, Labor, and Post/Colonial Politics on an Indian Plantation. Jean and John L. Comaroff (eds) . Millennial Capitalism and the Culture of Neoliberalism. Michael Humphrey . The Politics of Atrocity and Reconciliation: From Terror to Trauma. S. Jaarsma and Marta Rohatynskyj (eds) . Ethnographic Artifacts: Challenges to a Reflexive Anthropology. Gaynor Kavanagh . Dream Spaces: Memory and Museum. Fred R. Myers . Painting Culture: The Making of an Aboriginal High Art. Nigel A. Stephenson . Kastom or Komuniti: A Study of Social Process and Change among the Wam People, East Sepik Province, Papua New Guinea. Ida Susser and Thomas C. Patterson (eds) . Cultural Diversity in the United States: A Critical Reader. Elizabeth Wood‐Ellem . Queen Salote of Tonga: The Story of an Era, 1900–1965. Michael W. Young and Julia Clark . An Anthropologist in Papua: The Photography of F. E. Williams, 1922–39.     

SYNTHESIS OF 1-(2-NAPHTHYLSULFONYL)PYRAZOLE-C-GLYCOSIDES

ABSTRACT

2-Naphthylsulfonylhydrazine was reacted with aromatic aldehydes or aldehydo sugars to give the corresponding hydrazones which undergo Michael addition reactions with malononitrile or ethyl cyanoacetate to form pyrazole derivatives.