DOCSLIB.ORG

Understanding the Biosynthesis and Utilization of Non-Proteinogenic Amino Acids for the Production of Secondary Metabolites in Bacteria

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Understanding the Biosynthesis and Utilization of Non-Proteinogenic Amino Acids for the Production of Secondary Metabolites in Bacteria Understanding The Biosynthesis And Utilization Of Non-Proteinogenic Amino Acids For The Production Of Secondary Metabolites In Bacteria Author: Carl Victor Christianson Persistent link: http://hdl.handle.net/2345/967 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2008 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Chemistry UNDERSTANDING THE BIOSYNTHESIS AND UTILIZATION OF NON-PROTEINOGENIC AMINO ACIDS FOR THE PRODUCTION OF SECONDARY METABOLITES IN BACTERIA A dissertation by CARL VICTOR CHRISTIANSON Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2008 © Copyright by CARL VICTOR CHRISTIANSON 2008 Acknowledgements I would like to than the members of my thesis defense committee, Jianmin Gao, Larry McLaughlin, and James Morken for taking time to critically read this thesis and to attend my defense. I am grateful to Professor Steven Bruner for accepting me into his lab and for his guidance over the past 5 years. Steve fostered an atmosphere of scientific discussion that challenged me to constantly learn new things. I admire Steve’s steady demeanor and am grateful to him for keeping me grounded and headed in the right direction. I would like to thank Timothy Montavon for carefully reviewing this thesis. Tim also contributed the synthetic projects that benefited the work presented in this thesis. Tim has always been there for helpful scientific discussions in the four years that we have been working together. I have been fortunate to work with a good group of students in the Bruner lab. I would like to thank all the current and past members of the Bruner group. I would also like to than Deb Lynch who has helped me tremendously during my time at BC. I believe that the whole department would fall apart without her efforts. I thank her for her time, and for always having an open ear and full bowl of candy! Without the help and understanding of my family, I would not have been able to make it through these past five years. In particular I would like to thank my mother and father for always being there and believing in me. Finally, I would like to thank my wife, Jolene. It is through her love and understanding that all this has been possible. I love you and to you I dedicate this thesis. iv Table of Contents Chapter 1. A Review of Cofactor Independent Electrophilic Catalysis 1.1 Introduction 2 1.2 History of MIO 4 1.3 Ammonia Lyases 7 1.4 Structural Investigations of PAL 15 1.5 The Significance of -Amino Acids 24 1.6 MIO Dependent Aminomutases 29 1.7 Green Fluorescent Protein and Its Relation to MIO Enzymes 37 Chapter 2. The Structure of L-Tyrosine 2,3-Aminomutase From the C-1027 Enediyne Biosynthetic Pathway 2.1 Introduction 51 2.2 Crystallization and Structure Determination 56 2.3 The Overall Structure of SgTAM 57 2.4 The Active Site Containing MIO 59 2.5 Comparison of the SgTAM Active Site with Tyrosine Ammonia Lyase 64 2.6 Restricted Active Site of SgTAM 64 2.7 Recognition of the Substrate Tyrosine in SgTAM 65 2.8 Mechanistic Implications from the Structure of SgTAM 67 2.9 Comparison of SgTAM Active Site with Green Fluorescent Protein 68 v Chapter 3. The Mechanism of L-Tyrosine 2,3-Aminomutase and MIO Dependent Enzymes 3.1 Introduction 82 3.2 Mechanistic Probes of SgTAM 83 3.3 Synthesis of SgTAM Substrate Analogs 86 3.4 Inhibition Studies of the Substrate Analogs of SgTAM 87 3.5 Crystallization of SgTAM in the Presence of Substrate Analogs 88 3.6 Overall Structures of SgTAM bound to Analogs 89 3.7 Structures of Product Analogs Covalently Bound to MIO 89 3.8 Epoxide Analogs Bound to SgTAM 92 3.9 Mechanistic Conclusions of MIO Dependent Enzymes 93 Chapter 4. Investigation of LnmQ 4.1 Introduction 110 4.2 Leinamycin 112 4.3 Cloning of LnmQ, a D-Ala Specific A-Domain 113 4.4 Isolation and Purification of LnmQ 115 4.5 Selenomethionine preps of LnmQ 116 4.6 Substrate and Substrate Analog Studies with LnmQ 118 Chapter 5. Conclusions and Future Directions vi Table of Abbreviations A Adenine AIP 2-aminoindan-2-phosphonate Ala Alanine Arg Arginine Asn Asparagine ME beta-mercaptoethanol C Cytosine Cys Cysteine DMSO Dimethylsulfoxide DNA -D-2’-Deoxyribofuranosyl Nucleic Acid dNTPs Deoxyribonucleotide Triphosphates DTT Dithiothreitol G Guanine GFP Green Fluorescent Protein Gly Glycine HAL Histidine Ammonia Lyase HCA Hydroxycinnamic Acid His Histidine HPLC High Pressure Liquid Chromatography MIO 4-methylideneimidazole-5-one vii NRP Non-Ribosomal Peptide NRPS Non-Ribosomal Peptide Synthetase OPA o-Phtalaldehyde PAL Phenylalanine Ammonia Lyase PAM Phenylalanine Aminomutase PCR Polymerase Chain Reaction Phe Phenylalanine PKS Polyketide Synthase PLP Pyridoxal Phosphate SAM S-Adenosylmethionine Se-Met Selenomethionine Ser Serine Sg Streptomyces globisporus T Thymine TAL Tyrosine Ammonia Lyase TAM Tyrosine Aminomutase TFA Trifluoroacetic Acid THF Tetrahydrofuran TMAO Trimethylamine-N-oxide Tyr Tyrosine viii Understanding The Biosynthesis And Utilization Of Non-Proteinogenic Amino Acids For The Production Of Secondary Metabolites In Bacteria Carl Victor Christianson Professor Steven D. Bruner October 24, 2008 Research Advisor Abstract Bacteria utilize complex enzymatic machinery to create diverse secondary metabolites. The architectural complexities of these small molecules are enhanced by nature’s ability to synthesize non-proteinogenic amino acids for incorporation into these scaffolds. Many of these natural products are utilized as therapeutic agents, and it would be advantageous to understand how the bacteria create various non-natural amino acid building blocks. With a greater understanding of these systems, engineering could be used to create libraries of potentially useful natural product analogs. The tyrosine aminomutase SgTAM from the soil bacteria Streptomyces globisporus catalyzes the formation of -tyrosine in the biosynthestic pathway of the antitumor enediyne C-1027. SgTAM is homologous to the histidine ammonia lyase family of enzymes whose activity is dependent on the methylideneimidazole-5-one (MIO) prosthetic group. Unlike the lyase enzymes, SgTAM catalyses additional chemical transformations resulting in an overall 2,3 amino shift in the substrate L- ix tyrosine to generate (S)--tyrosine. The precise mechanistic role of MIO in this novel family of aminomutases has not been established. We report the first X-ray crystal structure of an MIO based aminomutase and confirm the structural homology of SgTAM to ammonia lyases. Further work with mechanistic inhibitors provide structural evidence of the mechanism by which MIO dependent enzymes operate. We have also investigated LnmQ, an adenylation domain in the biosynthetic pathway of leinamycin. Leinamycin is an antitumor antibiotic that was isolated from soil samples in 1989. LnmQ is responsible for the specific recognition of D-alanine and subsequent activation as an aminoacyl adenylate species. We have cloned the gene into a DNA vector and expressed it in E. coli. Upon purification of the protein, crystallization conditions have been tested. Synthesis of an inhibitor that mimics the aminoacyl adenylate product catalyzed by LnmQ has been completed. Crystallization with this inhibitor will provide better quality crystals and a catalytically informative co-complex. x Chapter 1: A Review of Cofactor Independent Electrophilic Catalysis 1 1.1 Introduction The study of enzymes and the reactions they catalyze has been an active field of research since the mid-19th century.1 Originally, enzyme activity was thought to be a ‘living’ process that was inherent in the cellular cultures being investigated; it was not until the work of Buchner regarding the fermentation of sugars, that proteins, not whole cells, were shown to be responsible for this activity. This work began a period of research focused more on the structure and nature of these enzyme catalysts than the catalyzed reaction. Much work was done using the relatively new technique of X-ray crystallography to obtain a ‘snap-shot’ of the enzyme on a molecular level. The first X-ray structure of a complete protein was not obtained until 1960 when the structure of hemoglobin was solved by Perutz.2 Myoglobin had been solved in 1958, but was not completely modeled until 1961. Having X-ray crystallography as a tool at the enzymologist’s disposal would cause many new questions to arise. Enzymologists were no longer satisfied with only knowing the starting materials and products associated with the enzymatic transformations. The question of how these macro-catalysts were facilitating the reactions being observed was now becoming an increasingly important question. The field of mechanistic enzymology evolved, using the tools of the enzymologist and the organic chemist. The study of mechanistic organic chemistry was being applied to the transformations being observed in these biological systems. Like all fields in the physical sciences, the continual advance of technology has benefited the field of mechanistic enzymology a great deal. To be able to structurally 2 characterize molecules on the range of kilo-daltons at the molecular level has allowed for a clear understanding of many reaction processes. However, it is not always clear what is occurring in reaction pathways, and often times, conclusions drawn from structural data alone can be misleading. Mistakes in the literature will go unchallenged for years until a new technique or the application of other techniques is able to shed light on the problem.3 One problem that has drawn a great deal of interest over the years is enzyme mediated electrophilic catalysis. Proteins are made up of amino acids that contain acid, basic, and nucleophilic residues; however there are no naturally occurring electrophilic groups available in the functional repertoire of proteins. Enzymes are known to catalyze such reactions by employing Figure 1.
Load more

Recommended publications
  • Significance and Implications of Vitamin B-12 Reaction Shema- ETH ZURICH VARIANT: Mechanisms and Insights
    Taylor University Pillars at Taylor University Student Scholarship: Chemistry Chemistry and Biochemistry Fall 2019 Significance and Implications of Vitamin B-12 Reaction Shema- ETH ZURICH VARIANT: Mechanisms and Insights David Joshua Ferguson Follow this and additional works at: https://pillars.taylor.edu/chemistry-student Part of the Analytical Chemistry Commons, Inorganic Chemistry Commons, Organic Chemistry Commons, Other Chemistry Commons, and the Physical Chemistry Commons CHEMISTRY THESIS SIGNIFICANCE AND IMPLICATIONS OF VITAMIN B-12 REACTION SCHEMA- ETH ZURICH VARIANT: MECHANISMS AND INSIGHTS DAVID JOSHUA FERGUSON 2019 2 Table of Contents: Chapter 1 6 Chapter 2 17 Chapter 3 40 Chapter 4 59 Chapter 5 82 Chapter 6 118 Chapter 7 122 Appendix References 3 Chapter 1 A. INTRODUCTION. Vitamin B-12 otherwise known as cyanocobalamin is a compound with synthetic elegance. Considering how it is composed of an aromatic macrocyclic corrin there are key features of this molecule that are observed either in its synthesis of in the biochemical reactions it plays a role in whether they be isomerization reactions or transfer reactions. In this paper the focus for the discussion will be on the history, chemical significance and total synthesis of vitamin B12. Even more so the paper will be concentrated one of the two variants of the vitamin B-12 synthesis, namely the ETH Zurich variant spearheaded by Albert Eschenmoser.Examining the structure as a whole it is observed that a large portion of the vitamin B12 is a corrin structure with a cobalt ion in the center of the macrocyclic part, and that same cobalt ion has cyanide ligands.
    [Show full text]
  • Rare-Earth Metal Methylidene Complexes with Ln3 (Μ3-CH2)(Μ3
    Dalton Transactions View Article Online PAPER View Journal | View Issue Rare-earth metal methylidene complexes with Ln3(μ3-CH2)(μ3-Me)(μ2-Me)3 core structure† Cite this: Dalton Trans., 2015, 44, 18101 Dorothea Schädle,a Melanie Meermann-Zimmermann,b Cäcilia Maichle-Mössmer,a Christoph Schädle,a Karl W. Törnroosc and Reiner Anwander*a Trinuclear rare-earth metal methylidene complexes with a Ln3(µ3-CH2)(µ3-Me)(µ2-Me)3 structural motif were synthesized by applying three protocols. Polymeric [LuMe3]n (1-Lu) reacts with the sterically demand- ing amine H[NSiMe3(Ar)] (Ar = C6H3iPr2-2,6) in tetrahydrofuran via methane elimination to afford isolable monomeric [NSiMe3(Ar)]LuMe2(thf)2 (4-Lu). The formation of trinuclear rare-earth metal tetramethyl methylidene complexes [NSiMe3(Ar)]3Ln3(µ3-CH2)(µ3-Me)(µ2-Me)3(thf)3 (7-Ln; Ln = Y, Ho, Lu) via reaction of [LnMe3]n (1-Ln; Ln = Y, Ho, Lu) with H[NSiMe3(Ar)] is proposed to occur via an “intermediate” species of the type [NSiMe3(Ar)]LnMe2(thf)x and subsequent C−H bond activation. Applying Lappert’s concept of Lewis base-induced methylaluminate cleavage, compounds [NSiMe3(Ar)]Ln(AlMe4)2 (5-Ln; Ln = Y, La, Nd, Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Ho) were converted into methylidene complexes 7-Ln (Ln = Y, Nd, Ho) in the presence of tetrahydrofuran. Similarly, tetramethylgallate complex [NSiMe3(Ar)]Y(GaMe4)2 (6-Y) could be employed as a synthesis pre- cursor for 7-Y. The molecular composition of complexes 4-Ln, 5-Ln, 6-Y and 7-Ln was confirmed by elemental analyses, FTIR spectroscopy, 1H and 13C NMR spectroscopy (except for holmium derivatives) Received 30th July 2015, and single-crystal X-ray diffraction.
    [Show full text]
  • Identification of a Novel Substrate-Derived Spermine
    ЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИ UDK 577.152.1 Identification of a Novel Substrate- Derived Spermine Oxidase Inhibitor T. T. Dunston1, M. A. Khomutov2, S. B. Gabelli1,3,4, T. M. Stewart1, J. R. Foley1, S. N. Kochetkov2, A. R. Khomutov2*, R. A. Casero Jr.1* 1Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA 2Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia 3Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 4Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA *E-mail: [email protected], [email protected] Received May 08, 2020; in final form, July 07, 2020 DOI: 10.32607/actanaturae.10992 ABSTRACT Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in μM-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of poly- amine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an es- sential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The deve- lopment of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors.
    [Show full text]
  • Trisubstituted Push-Pull Nitro Alkenes
    The Free Internet Journal Review for Organic Chemistry Archive for Arkivoc 2020, part vii, 401-421 Organic Chemistry Trisubstituted push-pull nitro alkenes Branislav Pavilek* and Viktor Milata Institute of Organic Chemistry, Catalysis, and Petrochemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia Email: [email protected] Dedicated to Professor Jan Bergman on the occasion of his 80th birthday. Received 02-18-2021 Accepted 04-19-2021 Published on line 04-30-2021 Abstract Properties, preparations, and utilization in the organic synthesis of the trisubstituted push-pull nitroalkenes are summarized from all the relevant results published until 2020. Preparation of these nitroalkenes is versatile due to numerous of the starting materials. The importance of reviewed nitroalkenes is outlined by their frequent exploitation in the synthesis of biologically active compounds, as well as a vast range of heterocyclic derivatives. Keywords: Push-pull nitroalkenes, nucleophilic vinylic substitution, heterocycles formation, nitroalkenes cycloadditions DOI: https://doi.org/10.24820/ark.5550190.p011.495 Page 401 ©AUTHOR(S) Arkivoc 2020, vii, 401-421 Pavilek, B. et al. Table of Contents 1. Introduction 2. Review 2.1. Isomerism 2.2. Preparation 2.2.1. Formation of nitroenolethers (A) 2.2.2. Formation of mono-N-substituted nitroenamines (B) 2.2.3. Formation of di-N,N-substituted nitroenamines (C) 2.2.4. Other preparations (D) 2.3. Utilization in organic synthesis 2.3.1. Reactions with mono-nucleophiles (E) 2.3.2. Reactions with 1,2-binucleophiles (F) 2.3.3. Reactions with 1,3-binucleophiles (G) 2.3.4.
    [Show full text]
  • Studies in Multicyclic Chemistry
    Studies in Multicyclic Chemistry This thesis is submitted in fulfillment of the requirements for the degree of Doctor of Philosophy by Djamal Sholeh Al Djaidi Supervisor Professor Roger Bishop School of Chemistry The University of New South Wales Sydney, Australia December, 2006 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: AL DJAIDI First name: DJAMAL Other name/s: SHOLEH Abbreviation for degree as given in the University calendar: PhD School: CHEMISTRY Faculty: SCIENCE Title: STUDIES IN MULTICYCLIC CHEMISTRY Abstract 350 words maximum: (PLEASE TYPE) * A series of investigations has been carried out on multicyclic organic systems. The Ritter Reaction was used to obtain bridged imines containing an azacyclohexene functionality. The crystal structure of the benzene inclusion compound of one of these was determined, and also that of another spontaneously oxidised example. The reactivity of these bridged imines was then investigated using mercaptoacetic acid, and also dimethyl acetylenedicarboxylate (DMAD). The three bridged imines studied were found to react with DMAD in totally different ways and produced most unusual products whose structures were proved using X-ray crystallography. Mechanistic explanations are provided for the formation of these novel and totally unexpected products. * 6-Methylidene-3,3,7,7-tetramethylbicyclo[3.3.1]nonan-2-one was reacted with acetonitrile and sulfuric acid to deliberately combine molecular rearrangement with Ritter Reaction chemistry. Five different products were obtained and the pathway of formation of these products was uncovered. The structures of three of these rearranged substances were confirmed by X-ray methods. * The rare tricyclo[5.3.1.1 3,9]dodecane ring system is known to contain severe skeletal distortions due to the nature of its skeleton.
    [Show full text]
  • Electronic Or Optoelectronic Device Comprising an Anchored Thin Molecular Layer, Process for Its Preparation and Compound Used Therein
    (19) TZZ Z _T (11) EP 2 840 622 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 25.02.2015 Bulletin 2015/09 H01L 51/10 (2006.01) H01L 51/50 (2006.01) (21) Application number: 13180827.1 (22) Date of filing: 19.08.2013 (84) Designated Contracting States: • Lüssem, Björn AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 01127 Dresden (DE) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO •Leo,Karl PL PT RO RS SE SI SK SM TR 01219 Dresden (DE) Designated Extension States: • Fischer, Axel BA ME 01097 Dresden (DE) (71) Applicant: Novaled GmbH (74) Representative: Bittner, Thomas L. 01307 Dresden (DE) Boehmert & Boehmert Anwaltspartnerschaft mbB (72) Inventors: Patentanwälte Rechtsanwälte • Nicht, Sylvia Pettenkoferstrasse 20-22 01187 Dresden (DE) 80336 München (DE) •Blochwitz-Nimoth, Jan 01097 Dresden (DE) (54) Electronic or optoelectronic device comprising an anchored thin molecular layer, process for its preparation and compound used therein (57) The application concerns materials for self as- (EWG) group, such as tetrafluorotetracyanoquin- sembled (SAM) charge injection layers on electrodes of odimethane (F4TCNQ), hexaazatriphenylene (HAT) and organic electronic devices. The materials comprise an hexaazatriphenylene hexacarbonitrile (HATCN). The anchoring group, such as a thiol, a spacer group selected spacer group is connected to the EWG via a single bond from nitrogen aromatic heterocycles and aromatic rings from a nitrogen of the spacer group to a mehtylidenyl substituted with an amine, and an electron withdrawing group of the EWG. EP 2 840 622 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 840 622 A1 Description [0001] The present invention relates to an electronic or optoelectronic device comprising an anchored thin molecular layer.
    [Show full text]
  • Thiazolo[3,2-B][1,2,4]Triazolium Cationic Surfactant
    Article Volume 11, Issue 6, 2021, 13885 - 13892 https://doi.org/10.33263/BRIAC116.1388513892 Synthetic Strategy and Structure Characterization of a New [1,3]Thiazolo[3,2-b][1,2,4]Triazolium Cationic Surfactant Maksym Fizer 1,* , Mikhailo Slivka 2 , Oksana Fizer 3 1 Department of Organic Chemistry, Faculty of Chemistry, Uzhhorod National University, Fedinets', Str. 53/1, 88000, Uzhhorod, Ukraine; [email protected] (M.F.); [email protected] (M.S.); [email protected] (O.F.); * Correspondence: [email protected]; (M.F.); Scopus Author ID 55823743600 Received: 20.01.2021; Revised: 21.02.2021; Accepted: 24.02.2021; Published: 1.03.2021 Abstract: Here, we present a synthetic strategy to access a new [1,3]thiazolo[3,2-b][1,2,4]triazolium- based cationic surfactant via the use of proton-induced heterocyclization method for quaternization of a nitrogen atom. The two-step synthesis of 2-heptyl-6,6-dimethyl-3-phenyl-5,6-dihydro-3H- [1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium perchlorate is described in details. The analysis of NMR spectra unequivocally proved the formation of the 1,3-thiazolinium ring upon cyclization reaction. PM7 semiempirical calculations testify to the similar electronic structure of the newly synthesized surfactant cation and 1-heptylpyridinium cation. Keywords: 1,2,4-triazole; alkylation; cyclization; surfactant; NMR; cation; PM7; semiempirical. © 2021 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
    [Show full text]
  • United States Patent (19) 11 Patent Number: 4,952,690 Gosteli Et Al
    United States Patent (19) 11 Patent Number: 4,952,690 Gosteli et al. 45) Date of Patent: Aug. 28, 1990 (54) 6-SUBSTITUTED THIA-AZA COMPOUNDS 4,447,360 5/1984 Gosteli et al. .................. 260/239 A 4,500,457 2/1985 Gosteli et al. ... 260/245.2 R 75 Inventors: Jacques Gosteli, Basel; Ivan Ernest, 4,515,717 5/1985 Gosteli et al. ..... as a s 260/239 A Birsfelden, both of Switzerland; 4,518,533 5/1985 Gosteli et al...... ... 260/245.4 Marc Lang, Mulhouse, France; 4,524,028 6/1985 Gosteli et al. ..... ... 260/239 A Robert B. Woodward, Cambridge, 4,543,257 9/1985 Cama et al. ... ... 540/310 ... 540/359 Mass. 4,614,614 9/1986 Ernest et al. 4,616,007 10/1986 Lang ................................... 514/192 73) Assignee: Ciba-Geigy Corporation, Ardsley, 4,656,165 4/1987 Lang ................................... 514/192 N.Y. 4,826,832 5/1989 Lang ................................... 540/310 21 Appl. No.: 396,783 Primary Examiner-Mark L. Berch (22 Filed: Aug. 21, 1989 Attorney, Agent, or Firm-JoAnn Villamizar 57) ABSTRACT Related U.S. Application Data The invention relates to azetidin-2-ones of the formula 60 Continuation of Ser. No. 152,526, Feb. 5, 1988, aban doned, which is a division of Ser. No. 57,082, Jun. 3, 1987, abandoned, which is a division of Ser. No. 208,105, Nov. 18, 1980, Pat. No. 4,692,442, which is a continuation of Ser. No. 7,453, Jan. 29, 1979, aban doned. (30) Foreign Application Priority Data Feb. 2, 1978 CH) Switzerland.....................
    [Show full text]
  • Decomposition of Ruthenium Olefin Metathesis Catalyst
    catalysts Review Decomposition of Ruthenium OlefinOlefin Metathesis CatalystMetathesis Catalyst Magdalena Jawiczuk 1,, Anna Anna Marczyk Marczyk 1,21,2 andand Bartosz Bartosz Trzaskowski Trzaskowski 1,* 1,* 1 1 CentreCentre of of New New Technologies, Technologies, University University of of Warsaw, Warsaw, Banacha Banacha 2c, 2c, 02-097 02-097 Warsaw, Warsaw, Poland; [email protected]@cent.uw.edu.pl (M.J.); (M.J.); [email protected] [email protected] (A.M.) (A.M.) 2 Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland 2 Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland * Correspondence: [email protected] * Correspondence: [email protected] Received: 28 28 June 2020; Accepted: 02 2 AugustAugust 2020;2020; Published:Published: 5date August 2020 Abstract: RutheniumRuthenium olefin olefin metathesis metathesis catalysts catalysts are are one one of of the most commonly used class of catalysts. There There are are multiple multiple reviews reviews on on their their us useses in in various branches of chemistry and other sciences but a detailed review of their decomposition is missing, despite a large number of recent and important advances advances in in this this field. field. In In particular, particular, in in the the last last five five years years several several new new mechanism mechanism of decomposition,of decomposition, both both olefin-driven olefin-driven as well as well as induc as induceded by external by external agents, agents, have have been been suggested suggested and usedand usedto explain to explain differences differences in the decomposition in the decomposition rates and rates the metathesis and the metathesis activities activitiesof both standard, of both N-heterocyclicstandard, N-heterocyclic carbene-based carbene-based systems and systems the recently and the developed recently developed cyclic alkyl cyclic amino alkyl carbene- amino containingcarbene-containing complexes.
    [Show full text]
  • Deprotonation of C-Alkyl Groups of Cationic Triruthenium Clusters Containing Cyclometalated C-Alkylpyrazinium Ligands: Experimental and Computational Studies
    __________________________________________________FULL PAPER DOI: 10.1002/chem.201204250 Deprotonation of C-Alkyl Groups of Cationic Triruthenium Clusters Containing Cyclometalated C-Alkylpyrazinium Ligands: Experimental and Computational Studies Javier A. Cabeza,*[a] José M. Fernández-Colinas,[a] Pablo García-Álvarez,[a] Enrique Pérez- Carreño,[b] Vanessa Pruneda,[a] and Juan F. Van der Maelen[b] Abstract: The C-alkyl groups of cationic in all cases, the deprotonated C–H bond is decacarbonyl complexes and the way these triruthenium cluster complexes of the type that having the smallest electron density at ligands coordinate to the metal atoms in the 2 1 2 + [Ru3(µ-H)(µ-κ N ,C -L)(CO)10] (HL the bond critical point, the greatest nonacarbonyl products. The mechanisms of represents a generic C-alkyl-N- Laplacian of the electron density at the bond these decacarbonylation processes have methylpyrazium) have been deprotonated to critical point, and the greatest total energy been investigated by DFT methods, which give kinetic products that contain density ratio at the bond critical point have rationalized the structures observed for unprecedented C-alkylidene derivatives and (QTAIM calculations). The kinetic the final products and have shed light on the maintain the original edge-bridged decacarbonyl products evolve, under different kinetic and thermodynamic decacarbonyl structure. When the starting appropriate reaction conditions that depend stabilities of the reaction intermediates, complexes contain various C-alkyl groups, upon the position of the C-alkylidene group explaining the reaction conditions the selectivity of these deprotonation in the heterocyclic ring, toward face-capped experimentally required by each reactions is related to the atomic charges of nonacarbonyl derivatives (thermodynamic transformation.
    [Show full text]
  • New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties As Carbonic Anhydrase Inhibitors
    pharmaceuticals Article New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties as Carbonic Anhydrase Inhibitors Andrea Angeli 1,2,* , Victor Kartsev 3, Anthi Petrou 4 , Mariana Pinteala 2 , Roman M. Vydzhak 5, Svitlana Y. Panchishin 5 , Volodymyr Brovarets 5, Viviana De Luca 6, Clemente Capasso 6 , Athina Geronikaki 4,* and Claudiu T. Supuran 1 1 Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy; claudiu.supuran@unifi.it 2 Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, 707410 Iasi, Romania; [email protected] 3 InterBioScreen, Chernogolovka, 142432 Chernogolovka, Moscow Region, Russia; [email protected] 4 Department of Pharmacy, School of Health, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; [email protected] 5 Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine 1, Murmanska St, 02094 Kyiv, Ukraine; [email protected] (R.M.V.); [email protected] (S.Y.P.); [email protected] (V.B.) 6 Institute of Biosciences and Bioresources, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy; [email protected] (V.D.L.); [email protected] (C.C.) * Correspondence: andrea.angeli@unifi.it (A.A.); [email protected] (A.G.); Tel.: +30-230-199-7616 (A.G.) Citation: Angeli, A.; Kartsev, V.; Abstract: Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease Petrou, A.; Pinteala, M.; Vydzhak, conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge R.M.; Panchishin, S.Y.; Brovarets, V.; for the discovery of potential drugs devoid of off-target side effects.
    [Show full text]
  • Mechanistic Insights Into the Methylenation of Ketone by A
    Article pubs.acs.org/Organometallics Mechanistic Insights into the Methylenation of Ketone by a Trinuclear Rare-Earth-Metal Methylidene Complex † ‡ † † † ‡ Gen Luo, , Yi Luo,*, Jingping Qu, and Zhaomin Hou*, , † State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, People’s Republic of China ‡ Advanced Catalysis Research Group, RIKEN Center for Sustainable Resource Science, and Organometallic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan *S Supporting Information ABSTRACT: Trinuclear rare-earth-metal methylidene 2− (CH2 ) complexes are an emerging class of compounds that serve as methylidene transfer agents for methylenation of carbonyl compounds. Herein, the reaction of a trinuclear scandium methylidene complex with acetophenone was used as a model reaction of the multimetallic-cooperating methylidene transfer case, and its detailed mechanism has been investigated by the DFT approach. The analyses of Wiberg bond index, electron occupation, the frontier molecular orbital, and natural charge provide us a clear and 2− 2− comprehensive understanding of the CH2 /O group interchange process assisted by cooperating multimetal sites. The mechanism presented here is markedly different from μ conventional Wittig and transition-metal-mediated Wittig-type reactions. In addition, the behavior of 3-CH2 in a multinuclear complex system is also demonstrated. This study not only enriches the chemistry of metal Wittig-type reactions but also sheds light on the intermetallic cooperation for methylidene transfer. ■ INTRODUCTION Chart 1. Homometallic Trinuclear Rare-Earth-Metal Methylidene Complexes The terminal alkene is an essential motif in many natural products, and the methods toward its synthesis have been investigated intensively in the past decades.
    [Show full text]