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Thesis of Endophosphonopeptides

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Thesis of Endophosphonopeptides University of Bath PHD Studies on the synthesis of endophosphonopeptides. Vicker, Nigel Award date: 1984 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 06. Oct. 2021 STUDIES ON THE SYNTHESIS OF ENDOPHOSPHONOPEPTIDES. Submitted by NIGEL VICKER For the degree of Ph.D of the University of Bath 1984 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that no quotation from the thesis and no information derived from it may be published without prior written consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purpose of consultation. ProQuest Number: U344500 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 U344500 Published by ProQuest LLC(2015). 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 UMIVERSITY'QF DATH 4 "Z I n !■ ' ( V\'4 ■ < ^ W — X ^C)ll I IIS Cl o f TO MY PARENTS ACKNOWLEDGEMENTS I would like to thank my supervisor Professor Malcolm M. Campbell for his friendship, advice and considerable patience and understanding during the course of my research. 1 would also extend my thanks to all members of staff with whom 1 have had helpful discussions during my research. 1 am indebted to my industrial supervisor Mr. R. Cotton of l.C.T. Pharmaceuticals for his kindness and helpful thoughts during my work. My thanks go also to the technical staff of Bath University, especially Sue Green and Richard Hunter for whom nothing was too much trouble. 1 extend my gratitude to Mr. C. Cryer (Mass Spectrometry) 13 Mr. R. Kartell ( C N.M.R. Spectroscopy) and Mr. D. Wood (^H N.M.R. Spectroscopy). Finally 1 would like to thank Mrs. V. Edwards for her efficient and accurate typing of this thesis. 11 FOREWORD The following abbreviations occur in the text. Ac Acetyl ACE Angiotensin Converting Enzyme Ala Alanine Aq Aqueous B . p . Boiling point ^Bu Tertiary-butyl CPA Carboxypeptidase A DCC N,N-dicyclohexylcarbodiimide DCU Dicyclohexylurea DPPCl Diphenylphosphinyl chloride DMF N ,N-D ime thyIformami d e DMSG Dimethylsulphoxide ^ e c n-decyl Et Ethyl Ft Phthalimido Gly Glycine Glu Glutamic acid GPI Guinea pig ilium hr hour ^ e x n-hexyl H.P.L.C. High Pressure liquid chromatography I.R. Infra-red Leu Leucine Me Methyl Met Methionine m/z Mass to charge ratio min minute Ill mmol millimole m . p . melting point M.S. Mass spectrum MVD Mouse vas deferens Nle nor-leucine N.M.R. nuclear magnetic resonance Ph Phenyl Phe Phenylalanine ^Pr iso-propyl R. t. Room temperature RVD Rat vas deferens T.l.c. Thin layer chromatography TMS Trimethylsilane TMSBr T r ime thylsilylbromide Trp Tryptophan Tyr Tyrosine u. V. ultra-violet benzyloxycarbonyl IV Summary The work described in this thesis was conducted between October 1981 and September 1984 and is concerned with the synthesis of endophosphonopeptides as possible transition state surrogates. Various coupling methods for phosphonamide formation have been studied and several N-protecting functionalities evaluated in our synthetic strategy. The synthesis of an endophosphonoenkephalin an analogue of the naturally occurring pentapeptide leucine-enkephalin has been accomplished V Contents Page INTRODUCTION 1 I. Objectives ^ II. Synthesis of a-aminophosphonic and a-aminophosphonic acids 1 A. Mannich type procedures -j. B. Addition of Phosphorus Nucleophiles to Carhon-Nitrogen Double Bonds. ^ 1. Imines 4 2. Aldazines and Ketazines 9 3, Isothioacetamides 10 4, Nitrones H C. Procedures which occur via Michaelis-Becker or Arbuzov reactions 13 1. Arbuzov reaction with alkyl halides 14 2. Arbuzov reaction with acyl halides 15 3. Arbuzov and Michaelis-Becker reactions or a- 3-unsaturated compounds 16 4. Isothiocyanates in Arbuzov reactions 18 5. Other Arbuzov reactions 20 D. Rearrangement reactions 22 1, Curtivj" reaction 22 2. Hofmann rearrangement 24 E. Other methods of preparing a-aminophosphonic and a-aminophosphinic acids 26 1. Phosphorus trichloride 26 2. Phosphorus acid 28 3. Urea arid thiourea derivatives 30 4. Carbamates 35 5. Halomethyl phosphorus species 36 6 . Hydroxymethyl phosphorus precursors 37 VI III. a -Aminophosphonic and a -Aminophosphinic acid analogues of the naturally occurring &-amino acids 37 IV. Phosphonic and Phosphinic acids of biological interest 42 A. Phosphonic acid antibiotics 42 B. Other biologically active phosphonic and phosphinic acids 44 V. Biologically active peptides with a terminal phosphonic or phosphinic moiety 47 VI. Peptide analogues containing a phosphoramide moiety 51 VII. Endophosphonopeptides: Peptide analogues containing a phosphonamide bond 53 VIII. The Enkephalins 57 A. Identification of functional groups required for biological activity in the Enkephalins 60 B. Enkephalin analogues containing aminophosphonic and aminosulphonic acid residues at the C-terminus 62 IX. Conclusion. 65 DISCUSSION 66 Introduction 66 1. Modes of peptide hydrolysis by carboxypeptidase 66 2. Evaluation of coupling methods for the formation of phosphonamide peptide analogues (a) Attempted coupling of aminophosphonic acids by the mixed anhydride method ^0 (b) Coupling reactions of phosphonochloridates with C-protected amino acids and peptides 75 (c) Summary 86 3. Kinetic studies on the hydrolysis of a phosphonamide dipeptide analogue 87 (a) H.P.L.C. studies on the dipeptide analogue 87 99 (b) Summary vil 4. Studies on N-phthaloyl deprotection of phosphonopeptides (a) Removal of phthalimide by hydrazinolysis 100 (b) Removal of phthalimide using sodium borohydride 102 (c) Summary 1®^ 5. Synthesis of some novel N-protected phosphonate esters 105 (a) The N,N-dibenzyl protecting group 105 (b) The N,N-diallyl protecting group 107 (c) Mono- and dithiophthalimide as protecting groups 109 (d) Summary ^^4 6 . The synthesis of some novel phosphonic acids 114 (a) Some novel phosphonic acids 114 (b) Summary EXPERIMENTAL 119 158 REFERENCES INTRODUCTION 1. I. Objectives Structural variants of biologically important peptides are attracting increasing attention in the search of chemo- therapeutically useful drugs. This research programme was concerned with the synthesis of peptide analogues in which key amide linkages were replaced by phosphohamide (1). The Object was to synthesise endophosphonamide transition state surrogates for the cleavage of scissile peptide bonds. NH— OR (1) R = H or Alkyl II. Synthesis of a-aminophosphonic and a-aminophosphinic acids A range of synthetic routes to a-aminophosphonic acids has been developed, but novel strategies are necessary as emerging data points to their potential use as chemical regulators of biological mechanisms. The synthesis of a-aminophosphjoic acids has been previously reviewed^ and Redmore has published a 2 comprehensive review of the chemistry of P-C-N systems. A. Mannich type procedures 3 Many such examples have been reported in the literature . The reaction is that in which a phosphorus species has replaced the carbon nucleophile of the normal Mannich reaction. In 1952 2 . 4 Kaoachnik and Medved described the first synthesis of a -aminophosphonic acids from readily available starting materials, employing the reactions of aldehydes with ammonia 5 and dialkylphosphites. Subsequently they showed that a similar reaction occurred with ketones. The general reaction can be represented as : RgOgPH + R^R^CO + NHg' ^R^O^PCOXR^ )(R ^ )NH2 The methodology was further developed by improving yields and establishing conditions for hydrolysis of the phosphonate ester.^ Fields^ has investigated the mechanism of this reaction and showed that a-aminoalcohols yielded a-aminophosphonates on treatment with diethylphosphite. It was therefore suggested that a-aminoalcohols are likely intermediates in this process. Phosphorous acid, formaldehyde and amines heated under strongly acidic conditions afforded good yields of a-amino- methylphosphonic acid. The procedure, originally described by Moedritzer and Irani ^ may oe represented by the equation; R^ NH + nCILO+ nHPO_H^ »R_ N(CH^PO.H^) + nH^O 3-n n L 3 2 3-n 2 3 2 n 2 However, the method is limited. Primary amines treated with one equivalent of formaldehyde and phosphorous acid yielded mixtures of mono- and di-phosphonic acid derivatives. With one exception, 9 in the patent literature , formaldehyde has been the choice of 3 . carbonyl component. Redmore^^ prepared several a-aminoaryl phosphonic acids by this procedure using arylaldehydes as the carbonyl components. Polish workers ^ reported that phosphorous acid and benzylamine reacted with a range of carbonyl compounds, including acetone, propionaldéhyde, and methyl ethyl ketone, affording the corresponding a-aminoalkylphosphonic acids.
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