DOCSLIB.ORG

Studies Towards the Total Synthesis of the Naturally-Occurring Anticancer Agent Halichomycin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Studies Towards the Total Synthesis of the Naturally-Occurring Anticancer Agent Halichomycin STUDIES TOWARDS THE TOTAL SYNTHESIS OF THE NATURALLY-OCCURRING ANTICANCER AGENT HALICHOMYCIN b y Maxine Lai-Fun Cheung Me, OMe Me 'NH Me Me Me Me A thesis presented to the University of London in partial fulfilment of the requirements for the degree of Doctor of Philosophy June 2003 The Christopher Ingold Laboratories Department of Chemistry University College London ProQuest Number: 10015856 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10015856 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 LIST OF ABBREVIATIONS Ac acetyl AIBN 2 ,2 -azoblsisobutyronjtrlle 9-BBN 9-borablcyclo[3.3.1]nonane Bn benzyl Bu^ f-butyl Cy cyclohexyl DBU 1,8-diazabicyclo[5.4.0]undec- DDQ 2,3-dlchloro-5,6-dicyano-1,4- DEAD diethyl azodicarboxylate DEIPS dlethylisopropylsllyl DET diethyl tartrate DIBAL diisobutylaluminium hydride DIPT diisopropyl tartrate DMAP 4-dimethylaminopyridine DMF A/,A/-dimethylformamide DMSO dimethyl sulfoxide EDCI 1 -(3-dimethylaminopropyl)-3- Et ethyl HMPA hexamethylphosphoramide LDA lithium diisopropylamide mCPBA 3-chloroperoxybenzoic acid Me methyl NMO 4-methylmorpholine A/-oxide PCC pyridinium chlorochromate PDC pyridinium dichromate Ph phenyl PMB 4-methoxybenzyl PPTS pyridinium 4-toluenesulfonate TBAF tetra-A7-butylammonium fluoride TBS fe/t-butyldimethylsilyl TES triethylsilyl Tf trifiuoromethanesulfonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran THP tetrahydropyranyl TMS trimethylsilyl TPAP tetra-n-propylammonium perruthenate TRIS tris(hydroxymethyl)aminomethane Ts 4-toluenesulfonyl Dedicated with love to Dean ACKNOWLEDGEMENTS I would like to thank Professor Karl J. Hale for his devoted and dedicated supervision over the last 3 years. I am grateful to him for giving me the opportunity to study such a remarkable molecule. I would especially like to thank all the people who helped me during my PhD, in particular Pascal for all his advice and guidance in the lab. To Soraya - Thanks for making me feel welcome and training me ‘from scratch’ when I arrived! Special thanks to all my friends in the lab who helped make my time at UCL enjoyable, especially Ying, Audrey, Sven, Marcus, Linos and Shahid - You will not be forgotten! Many thanks to all the technical staff for their excellent services, particularly Dr. Jorge Gonzalez Outereirino, Dr. Abil Aliev and Charles Willoughby for all their help and advice. I am thankful to Mike Cocksedge and staff at the London School of Pharmacy for HRMS, and to Jonathan Steed at King’s College London for performing the X-ray crystallography analysis. I am also grateful to the EPSRC and Pfizer for financial support. Finally, I am indebted to my parents for their love, support and help throughout my life, and especially to my boyfriend Dean for his never-ending patience, encouragement, devotion and invaluable advice, and it is to him that I dedicate this thesis. ABSTRACT This thesis is split into 4 sections, and is concerned with the development of a biomimetic total synthesis of the naturally-occurring antitumour agent, halichomycin. The first section describes a range of biomimetic natural product syntheses that have been devised since 1917, and shows the levels of complexity that have been transcended by various groups in these efforts. The second part of the thesis discusses the discovery and structure elucidation of halichomycin and Wood’s synthetic approach to a region of this compound. In addition to earlier ventures, our eventual biosynthetic proposal for tricyclic assembly in halichomycin is described in this thesis. Synthetic efforts towards halichomycin have so far resulted in the synthesis of an advanced AB-carbon backbone intermediate 252. In Chapter 3, our group’s original retrosynthetic analysis of halichomycin is described along with our attempts to implement this approach. A biosynthetic proposal for my assembly is then presented, and it will be shown how this served as a source of inspiration for a new synthetic strategy to halichomycin. Our progress towards this objective will then be reviewed. Specifically, the synthesis of an advanced precursor 252 of pre-halichomycin will be discussed. Noteworthy features of our synthesis include the Roush asymmetric crotylboration reaction between 210 and 211, en route to the anti-anti alcohol 212, and the face-selective enolate alkylation of 236 to give 237. Aldehyde 256 was converted to 254 via an Evans aldol reaction, followed by protection, then reduction. A Wittig-Stille sequence on 254 then completed the synthesis of 252. Evans Aldol, Wittig-Stille TE90 OTBS Protection Me sequence and Reduction 0PM B 254 OPMB Me C 02tt OPMB OMe 252 HO CHO B ''NH Me ,NH 2 Me . 24 i^e' 19 7 steps ^ Me Me Halichomycin Pre-Halichomycin 0 OTBOPS 250 210 Roush E n —/ Face-selective Asymmetric_ 3 steps^ i6\^y\Me Enolate Crotylboration Me Me Alkylation IPr02C ",/'''B Me iPiOgC IV CONTENTS List of Abbreviations I Acknowledgement ................................................................................................................... Ill Abstract ..................................................................................................................................... IV Contents .................................................................................................................................... V 1.0 INTRODUCTION 1.1 Biomimetic Syntheses 1 .1 . 1 Robinson’s Tropinone Synthesis ............................................................................... 2 1.1.2 O.L Chapman’s Biomimetic Synthesis of Carpanone ........................................... 6 1.1.3 W.S. Johnson’s Steroid Polyene Cyclisations ......................................................... 7 1.1.4 K.C. Nicolaou’s Biomimetic Approach to Endiandric Acids A-G ........................... 14 1.1.5 Heathcock’s Biomimetic Total Synthesis of Methyl Homosecodaphniphyllate .... 17 1 .1 . 6 W.S. Johnson’s Total Synthesis of d/-/?-Amyrin ...................................................... 28 1.1.7 Paterson’s Studies in Biomimetic Polyether Synthesis .......................................... 32 1.1.8 Baldwin’s Studies on the Biomimetic Synthesis of the Manzamine Alkaloids ....... 36 1.1.9 Sulikowski’s Progress toward a Biomimetic Synthesis of Phomoidride B ............ 44 1.1.10 Epilogue ....................................................................................................................... 48 2.0 BACKGROUND 2.1 The Discovery of the Antitumour Agent, Halichomycin .......................................... 49 2.2 The Yale Approach to the Synthesis of the C(1 )-C(7) Segment of Halichomycin: 52 The Wood Synthesis 3.0 RESULTS AND DISCUSSION 3.1 Original Retrosynthetic Analysis of Halichomycin and Preliminary Efforts to Implement a Conventional Synthetic Approach 3.1.1 Original Retrosynthetic Analysis of Halichomycin .................................................... 54 3.1.2 Attempted Implementation of the Original Retrosynthetic Strategy for Halichomycin 57 3.1.3 A Biogenetically-Modeiled Total Synthesis of Halichomycin ................................. 69 4.0 EXPERIMENTAL ........................................................................................................ 76 References V Chapter 1: Introduction 1.0 INTRODUCTION Numerous molecules have now been created by biomimetic approaches. A biomimetic synthesis is one that attempts to mimic the way Nature would biosynthesise the molecule. Given that much of this thesis will be spent discussing our attempts at implementing a biogenetically-modelled synthesis of the molecule halichomycin, we thought that it would be of interest to the reader to see what other types of biomimetic syntheses have been carried out during the 20*" Century. Below is a table outlining the biomimetic syntheses that will be discussed in this thesis by way of introduction to our own work in this field. Year Organic Chemist Work 1901 R. Willstatter First Synthesis of Tropinone via a long sequence of reactions 1917 R. Robinson Synthesis of Tropinone in one step 1923 R. Willstatter Synthesis of Cocaine 1971 O.L. Chapman Biomimetic Synthesis of Carpanone 1976 W.S.Johnson Biomimetic Approaches to Polyene Cyclisations 1982 K.C. Nicolaou Biomimetic Approaches to Endiandric Acids A-C: The Endiandric Acid Cascade 1992 C.H. Heathcock Biomimetic Studies on the Daphniphyllum Alkaloids: Total Synthesis of Homo secodaphniphyllate 1993 W.S.Johnson Total Synthesis of p-Amyrin 1993 1. Paterson Studies in Biomimetic Polyether Synthesis 1999 J.E. Baldwin Studies on the Biomimetic Synthesis of the Manzamine Alkaloids 2 0 0 2 C.A. Sulikowski Studies on the Biomimetic Synthesis of Phomoidride B Table 1: Overview of Biomimetic Synthetic Studies Covered in this Introduction Chapter 1: Introduction 1.1 BIOMIMETIC SYNTHESES 1.1.1 Robinson’s Tropinone Synthesis^ (1917) Me N COgMe OCOPh Fig. 1 : Structures of atropine 1, tropinone 2, and cocaine 3 Atropine (the racemate of structure 1) is an abundant alkaloid with remarkable physiological properties, its most
Load more

Recommended publications
  • Hans Renata – Strategic Redox Relay Enables a Scalable Synthesis Of
    Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide A thesis presented by Hans Renata to The Scripps Research Institute Graduate Program in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Chemistry for The Scripps Research Institute La Jolla, California February 2013 UMI Number: 3569793 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMI 3569793 Published by ProQuest LLC (2013). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, MI 48106 - 1346 © 2013 by Hans Renata All rights reserved ! ii! ACKNOWLEDGEMENTS To Phil, thank you for taking me under your wing, the past five years have been a wonderful learning experience. You truly are a fantastic teacher, both in and out of the fumehood and your unbridled enthusiasm, fearlessness and passion for chemistry are second to none. In the words of Kurt Cobain, I am “forever indebted to your priceless advice.” To the members of the Baran lab, in the words of Kurt Cobain, “Our little (?) group has always been and always will until the end.” See what I did there? Oh well, whatever, nevermind.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2005/0044778A1 Orr (43) Pub
    US 20050044778A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0044778A1 Orr (43) Pub. Date: Mar. 3, 2005 (54) FUEL COMPOSITIONS EMPLOYING Publication Classification CATALYST COMBUSTION STRUCTURE (51) Int. CI.' ........ C10L 1/28; C1OL 1/24; C1OL 1/18; (76) Inventor: William C. Orr, Denver, CO (US) C1OL 1/12; C1OL 1/26 Correspondence Address: (52) U.S. Cl. ................. 44/320; 44/435; 44/378; 44/388; HOGAN & HARTSON LLP 44/385; 44/444; 44/443 ONE TABOR CENTER, SUITE 1500 1200 SEVENTEENTH ST DENVER, CO 80202 (US) (57) ABSTRACT (21) Appl. No.: 10/722,127 Metallic vapor phase fuel compositions relating to a broad (22) Filed: Nov. 24, 2003 Spectrum of pollution reducing, improved combustion per Related U.S. Application Data formance, and enhanced Stability fuel compositions for use in jet, aviation, turbine, diesel, gasoline, and other combus (63) Continuation-in-part of application No. 08/986,891, tion applications include co-combustion agents preferably filed on Dec. 8, 1997, now Pat. No. 6,652,608. including trimethoxymethylsilane. Patent Application Publication Mar. 3, 2005 US 2005/0044778A1 FIGURE 1 CALCULATING BUNSEN BURNER LAMINAR FLAME VELOCITY (LFV) OR BURNING VELOCITY (BV) CONVENTIONAL FLAME LUMINOUS FLAME Method For Calculating Bunsen Burner Laminar Flame Velocity (LHV) or Burning Velocity Requires Inside Laminar Cone Angle (0) and The Gas Velocity (Vg). LFV = A, SIN 2 x VG US 2005/0044778A1 Mar. 3, 2005 FUEL COMPOSITIONS EMPLOYING CATALYST Chart of Elements (CAS version), and mixture, wherein said COMBUSTION STRUCTURE element or derivative compound, is combustible, and option 0001) The present invention is a CIP of my U.S.
    [Show full text]
  • US5169929.Pdf
    |||||||||||| USOO5169929A United States Patent (19) 11) Patent Number: 5,169,929 Tour et al. 45 Date of Patent: Dec. 8, 1992 (54) LITHIUM/HMPA-PROMOTED SYNTHESIS Noren, et al. Macromolecular Reviews (1971) 5. pp. OF POLY(PHENYLENES) 386-431. Yamamoto, et al. Bulletin Che. Soc. of Japan (1978) 51. 75 Inventors: James M. Tour; Eric B. Stephens, (7) pp. 2091-2097. both of Columbia, S.C. Shacklette, et al. J. Chem. Soc., Chem. Commun. (1982) 73 Assignee: University of South Carolina, pp. 361-362. Columbia, S.C. Ivory, et al. J. Chem. Phys. (1979) 71. (3) pp. 1506-1507. Shacklette, et al. J. Chem. Phys. (1980) 73. (8) pp. 21 Appl. No.: 543,673 4098-4102. 22 Filed: Jun. 25, 1990 Kovacic, et al. J. Org. Chem. (1963) 28. pp. 968-972, 1864-1867. I51) Int. Cl. .............................................. CO8G 61/00 Kovacic, et al. J. Org. Chem. (1964) 29. pp. 100-104, 52 U.S.C. .................................................... 528/397 2416-2420. 58 Field of Search ......................................... 528/397 Kovacic et al. J. Org. Chem. (1966) 31. pp. 2467-2470. (56) References Cited Primary Examiner-John Kight, II U.S. PATENT DOCUMENTS Assistant Examiner-Terressa M. Mosley Attorney, Agent, or Firm-Brumbaugh, Graves, 4,576,688 3/1966 David .................................. 528/397 Donohue & Raymond OTHER PUBLICATIONS 57 ABSTRACT Kovacic, et al. Chem. Rev. (1987) 87, pp. 357-379. Poly(phenylene) that is substantially free of insoluble Elsenbaumer, et al. Handbook of Conducting Polymers material is prepared by the polymerization of a lithi (1986), T. A. Skotheime ed. pp. 213-263. oarylhalide compound in the presence of a polar aprotic Perlstein, Angew.
    [Show full text]
  • Endiandric Acid Derivatives and Other Constituents of Plants from the Genera Beilschmiedia and Endiandra (Lauraceae)
    Biomolecules 2015, 5, 910-942; doi:10.3390/biom5020910 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Review Endiandric Acid Derivatives and Other Constituents of Plants from the Genera Beilschmiedia and Endiandra (Lauraceae) Bruno Ndjakou Lenta 1,2,*, Jean Rodolphe Chouna 3, Pepin Alango Nkeng-Efouet 3 and Norbert Sewald 2 1 Department of Chemistry, Higher Teacher Training College, University of Yaoundé 1, P.O. Box 47, Yaoundé, Cameroon 2 Organic and Bioorganic Chemistry, Chemistry Department, Bielefeld University, P.O. Box 100131, 33501 Bielefeld, Germany; E-Mail: [email protected] 3 Department of Chemistry, University of Dschang, P.O. Box 67, Dschang, Cameroon; E-Mails:[email protected] (J.R.C.); [email protected] (P.A.N.-E.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +2376-7509-7561. Academic Editor: Jürg Bähler Received: 3 March 2015 / Accepted: 6 May 2015 / Published: 14 May 2015 Abstract: Plants of the Lauraceae family are widely used in traditional medicine and are sources of various classes of secondary metabolites. Two genera of this family, Beilschmiedia and Endiandra, have been the subject of numerous investigations over the past decades because of their application in traditional medicine. They are the only source of bioactive endiandric acid derivatives. Noteworthy is that their biosynthesis contains two consecutive non-enzymatic electrocyclic reactions. Several interesting biological activities for this specific class of secondary metabolites and other constituents of the two genera have been reported, including antimicrobial, enzymes inhibitory and cytotoxic properties. This review compiles information on the structures of the compounds described between January 1960 and March 2015, their biological activities and information on endiandric acid biosynthesis, with 104 references being cited.
    [Show full text]
  • Front Matter
    Towards the Total Synthesis of 1!,25-dihydroxylumisterol A. Simon Partridge Julia Laboratory, Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom September 2012 A thesis submitted as partial fulfilment of the requirements for the degree of Doctor of Philosophy, Imperial College London. Abstract This thesis is divided into three chapters. The first chapter provides a brief review on recent work in the application of cascade cyclisations to the total synthesis of natural products. This is followed by a review of the decarboxylative Claisen rearrangement (dCr), a novel variant of the Ireland-Claisen reaction in which tosylacetic esters of allylic alcohols are transformed into homoallylic sulfones using BSA and potassium acetate, and its applications. The second chapter discusses the results of our studies towards the total synthesis of 1!,25-dihydroxylumisterol via a proposed route containing two key steps; a cascade-inspired, Lewis-acid mediated cyclisation to form the steroid B-ring in I, and the dCr reaction of tosylacetic ester IV to give diene III. Successful syntheses, as well as problems encountered along this route will be discussed, as well as the measures taken to adapt the synthesis to circumvent these problems. OH PGO H O OH H H H H H PGO PGO H H HO Ts Ts 1!,25-dihydroxylumisterol I II OH O H + O H O H HO Ts PGO OPG H Ts Ts OPG VI V IV III The third and final chapter contains experimental procedures and characterisation data for the prepared compounds. Declaration I certify that all work in this thesis is solely my own, except where explicitly stated and appropriately referenced.
    [Show full text]
  • Stable Lithium Diisopropylamide and Method of Preparation
    Europaisches Patentamt J European Patent Office Publication number: 0 205 583 Office europeen des brevets B1 EUROPEAN PATENT SPECIFICATION (45) Date of publication of patent specification: 30.01.91 Intel.5: C 07 C 211/65 (3) Application number: 86900522.3 @ Date of filing: 17.12.85 (8) International application number: PCT/US85/02509 ® International publication number: WO 86/03744 03.07.86 Gazette 86/14 STABLE LITHIUM DIISOPROPYLAMIDE AND METHOD OF PREPARATION. (M) Priority: 24.12.84 US 685318 Proprietor: LITHIUM CORPORATION OF AMERICA, INC. Post Office Box 795 Date of publication of application: Bessemer City, NC 28016 (US) 30.12.86 Bulletin 86/52 Inventor: MORRISON, Robert, Charles Publication of the grant of the patent: 1946 Elmwood Drive 30.01.91 Bulletin 91/05 Gastonia, NC 28054 (US) Inventor: HALL, Randy, Winf red Route 4 Box 697 (M) Designated Contracting States: Kings Mountain, NC 28086 (US) AT BE CH DE FR GB IT LI LU NL SE Inventor: RATHMAN, Terry, Lee 3843 Gardner Park Drive Gastonia, NC 28054 (US) References cited: US-A-3197 516 US-A-3 694516 US-A-3388178 US-A-4 006187 Representative: Gore, Peter Manson et al US-A-3446 860 US-A-4399 078 W.P. THOMPSON & CO. Coopers Building Church Street JOURNAL OF ORGANOMETALLIC CHEMISTRY, Liverpool L1 3AB (GB) vol. 4, 1965; GILMAN et al.: "Stabilities of some n-alkyllithium compounds in mixed solvent CO I References cited: 00 systems", pp. 483-487 JOURNAL OF ORGANOMETTALIC CHEMISTRY, m JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 29, 1971; HONEYCUTT: "Kinetics of the in vol.
    [Show full text]
  • Safe Handling of Organolithium Compounds in the Laboratory
    FEATURE Safe handling of organolithium compounds in the laboratory Organolithium compounds are extremely useful reagents in organic synthesis and as initiators in anionic polymerizations. These reagents are corrosive, flammable, and in certain cases, pyrophoric. Careful planning prior to execution of the experiment will minimize hazards to personnel and the physical plant. The proper personal protective equipment (PPE) for handling organolithium compounds will be identified. Procedures to minimize contact with air and moisture will be presented. Solutions of organolithium compounds can be safely transferred from the storage bottles to the reaction flask with either a syringe or a cannula. With the utilization of these basic techniques, organolithium compounds can be safely handled in the laboratory. By James A. Schwindeman, oxides (typi®ed by lithium t-butoxide). various classes of organolithium com- Chris J. Woltermann, and These organolithium compounds have pounds, with pKa from 15.2 (lithium Robert J. Letchford found wide utility as reagents for methoxide) to 53 (t-butyllithium).5 organic synthesis in a variety of appli- Fourth, organolithium reagents demon- cations. For example, they can be strate enhanced nucleophilicity com- INTRODUCTION employed as strong bases (alkyl- pared to the corresponding organo- When properly handled, organo- lithiums, aryllithiums, lithium amides magnesium compound. Finally, they lithiums provide unique properties and lithium alkoxides), nucleophiles are convenient, as a variety of organo- that allow for
    [Show full text]
  • Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned About Rate Limitation Russell F
    Perspective pubs.acs.org/joc Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation Russell F. Algera, Lekha Gupta, Alexander C. Hoepker, Jun Liang, Yun Ma, Kanwal J. Singh, and David B. Collum* Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, United States *S Supporting Information ABSTRACT: The kinetics of lithium diisopropylamide (LDA) in tetrahydrofuran under nonequilibrium conditions are reviewed. These conditions correspond to a class of substrates in which the rates of LDA aggregation and solvation events are comparable to the rates at which various fleeting intermediates react with substrate. Substrates displaying these reactivities, by coincidence, happen to be those that react at tractable rates on laboratory time scales at −78 °C. In this strange region of nonlimiting behavior, rate-limiting steps are often poorly defined, sometimes involve deaggregation, and at other times include reaction with substrate. Changes in conditions routinely cause shifts in the rate-limiting steps, and autocatalysis is prevalent and can be acute. The studies are described in three distinct portions: (1) methods and strategies used to deconvolute complex reaction pathways, (2) the resulting conclusions about organolithium reaction mechanisms, and (3) perspectives on the concept of rate limitation reinforced by studies of LDA in tetrahydrofuran at −78 °C under nonequilibrium conditions. ithium diisopropylamide (LDA), a highly reactive and at −78 °Cconditions that are of singular importance in L selective Brønsted base, stands among the most prominent organic synthesisoccur at nearly the rates at which the reagents in organic synthesis.1 A survey of 500 total syntheses aggregates in Scheme 1 exchange.
    [Show full text]
  • Development of an Assay for a Diels-Alderase Enzyme
    Development of an Assay for a Diels-Alderase Enzyme A Thesis submitted in part fulfilment of the requirements of the degree of Doctor of Philosophy Graeme Douglas McAllister Department of Chemistry University of Glasgow Glasgow G12 8QQ February 2000 ©Graeme D. McAllister ProQuest Number: 13818648 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13818648 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Dedicated to iny family "Do they give Nobel prizes for attempted chemistry? Do they!?" from 'The Simpsons' by Matt Groening Acknowledgements First of all my sincerest thanks go to my supervisor, Dr Richard Hartley, for his expert guidance over the last 3 years. I would also like to thank Dr Mike Dawson and Dr Andy Knaggs of GlaxoWellcome for their supervision and ideas in the biological areas of this project, and for helping a chemist adjust to life in a biology lab! Dr Chris Brett of the University of Glasgow and Mrs Jyoti Vithlani of GlaxoWellcome deserve a mention for all their expertise in the growing of cell cultures and for helping me in the feeding studies.
    [Show full text]
  • Hexamethylphosphoramide for Jet Fuels
    Report on Carcinogens, Fourteenth Edition For Table of Contents, see home page: http://ntp.niehs.nih.gov/go/roc Hexamethylphosphoramide for jet fuels. It also can be used as a flame­retarding additive in lith­ ium­ion batteries; however, it reduces the performance of the bat­ CAS No. 680-31-9 tery (Izquierdo­Gonzales et al. 2004). Reasonably anticipated to be a human carcinogen Production First listed in the Fourth Annual Report on Carcinogens (1985) In 2009, hexamethylphosphoramide was produced by one manufac­ Also known as HMPA or hexamethylphosphoric triamide turer worldwide, in the United States (SRI 2009), and was available from 21 suppliers, including 14 U.S. suppliers (ChemSources 2009). H3C CH3 No data on U.S. production, import, or export volumes were found. N H3C CH3 NP N Exposure H C CH 3 O 3 The routes of potential human exposure to hexamethylphosphoramide Carcinogenicity are inhalation, ingestion, and dermal contact (HSDB 2009). The ma­ jor source of exposure is probably occupational; however, the general Hexamethylphosphoramide is reasonably anticipated to be a human population potentially could be exposed through release of hexameth­ carcinogen based on sufficient evidence of carcinogenicity from stud­ ylphosphoramide to the environment. No environmental releases of ies in experimental animals. hexamethylphosphoramide were reported in the U.S. Environmental Protection Agency’s Toxics Release Inventory (TRI 2009). Hexameth­ Cancer Studies in Experimental Animals ylphosphoramide exists in the air solely in the vapor phase and will Exposure of rats to hexamethylphosphoramide by inhalation caused be degraded by photochemically produced hydroxyl radicals, with a nasal tumors, which are rare in this species.
    [Show full text]
  • Isolation and Identification of Cyclic Polyketides From
    ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS Mohamad Nurul Azmi Mohamad Taib, Yvan Six, Marc Litaudon, Khalijah Awang To cite this version: Mohamad Nurul Azmi Mohamad Taib, Yvan Six, Marc Litaudon, Khalijah Awang. ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS . Chemical Sciences. Ecole Doctorale Polytechnique; Laboratoires de Synthase Organique (LSO), 2015. English. tel-01260359 HAL Id: tel-01260359 https://pastel.archives-ouvertes.fr/tel-01260359 Submitted on 22 Jan 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS MOHAMAD NURUL AZMI BIN MOHAMAD TAIB FACULTY OF SCIENCE UNIVERSITY
    [Show full text]
  • Ross G. Murray Phd Thesis
    THE SYNTHESIS OF 5-SUBSTITUTED HYDANTOINS Ross George Murray A Thesis Submitted for the Degree of PhD at the University of St Andrews 2008 Full metadata for this item is available in Research@StAndrews:FullText at: http://research-repository.st-andrews.ac.uk/ Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/571 This item is protected by original copyright This item is licensed under a Creative Commons License The Synthesis of 5-Substituted Hydantoins School of Chemistry and Centre for Biomolecular Sciences, Fife, Scotland Ross Murray February 2008 Thesis submitted to the University of St Andrews in application for the degree of Doctor of Philosophy Supervisor: Dr Stuart J. Conway Abstract The Bucherer-Bergs reaction is a classical multi-component reaction that yields hydantoins, which can be hydrolysed to afford α-amino acids. Hydantoins have many uses in modern organic synthesis, and this moiety has been included in a number of therapeutic agents, which have a wide range of biological activities. Herein, we report a mild synthesis of 5- and 5,5-substituted hydantoins from α- aminonitriles using Hünig’s base and carbon dioxide (Scheme 1). This reaction can be performed in excellent yields, using a variety of organic solvents and is applicable to a range of substrates. O NC NH2 i HN NH R1 R2 R1 2 O R R1 = alkyl, aryl or cyclic 14 examples R2 = H, alkyl or cyclic 4 - 96 % yield Scheme 1 - Recently developed conditions for the transformation of α-aminonitriles to hydantoins. Reagents and conditions: (i) Hünig’s base (3 equiv.), CO2 (g), CH2Cl2, RT.
    [Show full text]