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Thesis Submitted for the Degree of Doctor of Philosophy University of Bath PHD Aza-enolate alkylation reactions of lactim ethers Taylor, Piers Award date: 2005 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: 07. Oct. 2021 M v UNIVERSITY OF I BATH Aza-enolate alkylation reactions of lactim ethers Piers Taylor A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Chemistry 2 0 0 5 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 its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may not be consulted, photocopied or lent to other libraries without the permission of the author for yparc fmm of acceptance of the thesis. UMI Number: U488182 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. Dissertation Publishing UMI U488182 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, Ml 48106-1346 wwr* ve--&' ■ t ^saRJvsfiiaatfea'Xtftesfy «»*«: ■V1' CT-SATH I 3 0 i £ :: a r m .« i .. S E ^ v w a ^ a w w miwwiWBWEteigKMEiwawcaBW^a Contents 1 Contents vii Acknowledgments 2 1.1 Introduction 2 1.2 Heterocycles in Organic Chemistry 5 1.3. Imino ethers and lactim ethers 6 1.4. Methods commonly employed for the synthesis of imino ethers and lactim ethers 6 1.4.1 Pinner synthesis 8 1.4.2 Base catalysed reactions of nitriles 9 1.4.3. Formation of lactim ethers through addition of alcohols to iminoyl halides 11 1.4.4. Preparation of lactim ethers through the use of diazomethane and alkyl sulfates 13 1.4.5. Preparation of lactim ethers through the use of alkyl trichloroacetimidates 15 1.4.6. Preparation of lactim ethers using trialkyloxonium tetrafluoroboronates 16 1.5. The chemistry of imino ethers 17 1.5.1. Formation of amidines 20 1.5.2. Formation of N-substituted imino ethers 22 1.5.3. Reaction with amino acids and their derivatives 24 1.5.4. Addition of stabilised enols to lactim ethers 25 1.5.5. Alkyloxy substitution 30 1.5.6. Hydrolysis of imino ethers and lactim ethers 34 1.5.7. Tautomerisation 35 1.5.8. Triortho ester formation 38 1.5.9. Reaction with organometallic reagents 43 1.5.10. Oxidation and reduction 51 1.5.11. Pericyclic reactions of lactim ethers 53 1.5.12. The use of lactim ethers for the synthesis of heterocyclic compound ii 64 1.6. Conclusion 66 Chapter 2. Alkylation of the aza-e nolate of lactim ethers for the synthesis of 01- alkyl co-amino esters and a-alkyl lactams 66 2.1 a-alkyl amino esters and lactams 66 2.1.1. Current uses of a-alkyl lactams and amino esters 68 2.1.2. Current synthetic protocols for the production of a-alkyl lactams and co-amino esters 71 2.1.3. Literature precedent for the alkylation of lactim ethers 74 2.1.4. Nucleophilic substitution reactions of lactim ethers 74 2.1.5. Summary of literature precedent 75 2.1.6. New approach to the synthesis of a-alkyl amino esters and lactams 77 2.2. Development of an effective synthetic protocol 77 2.2.1. Preparation of valerolactim ether 15 using methyl trichloroacetimidate 3 78 2.2.2. Preparation of trimethyloxonium tetrafluoroboronate 221 (Meerwein’s salt) 79 2.2.3. Attempted preparation of tribenzyloxonium tetrafluoroboronate 223 80 2.2.4. Preparation of valerolactim ether 15 81 2.2.5. Alkylation of valerolactim ether 15 to afford a-benzyl valerolactim ether 217 84 2.2.6. Preparation of a range of a-alkyl valerolactim ethers 86 2.2.7. Preparation of a,a-dialkyl lactams 89 2.3. Application of aza-enolate alkylation methodology to seven and eight membered lactim ethers 89 2.3.1. Synthesis of a-alkyl caprolactim ethers 90 2.3.2. Unsuccessful attempts to prepare a-alkyl oenantholactim ethers 92 2.3.3. Preparation of benzyl capro and oenantholactim ethers using benzyl trichloroacetimidate 4 93 2.3.4. Preparation of benzyl capro and oenantholactim ethers 241 and 242 using a transesterification approach with benzyl alcohol 95 2.3.5. Hydrogenation of benzyl lactim ethers iii 95 2.3.6. Attempted alkylation of the az<z-enolates of benzyl capro and oenantholactim ethers 96 2.4. Investigation into alkylation of the aza-enolate of butyrolactim ether 39 96 2.4.1. Preparation of a-alkyl butyrolactim ethers 100 2.4.2. Mechanism of aza-e nolate formation versus imine formation for lactim ethers 105 2.5. Preparation of a range of a-alkyl amino esters hydrochloride salts 105 2.5.1. Hydrolysis of a-alkyl valerolactim ethers 106 2.5.2. Preparation of a range of a-alkyl co-amino ester hydrochloride salts 109 2.5.3. Direct formation of a,a-alkyl valerolactams 110 2.5.4. Preparation of a-alkyl valerolactams 111 2.6. Summary 114 Chapter 3. Asymmetric alkylation of czza-enolates of lactim ethers 114 3.1. Introduction 114 3.1.1. A chiral auxiliary approach 115 3.1.2. Synthesis of enantiopure a-alkyl valerolactim ethers 115 3.1.3. Biological relevance of enantiopure a-alkyl lactams and a- alkyl co-amino esters 117 3.1.4. Current methodologies for the production of enantiopure a-alkyl lactams and a-alkyl co-amino esters 120 3.1.5. Precedent for asymmetric alkylations of aza-e nolate of imino ethers using chiral auxiliaries for stereocontrol 122 3.1.6. Alkylation of Schollkopfs 6/s-lactim ether chiral auxiliaries 123 3.1.7. New approach to the synthesis of enantiomerically enriched a-alkyl lactim ethers 124 3.1.8. Review of the use of chiral auxiliaries 126 3.2. Development of effective asymmetric aza-enolate alkylation methodology 126 3.2.1. Preparation of (-)-menthol lactim ether 288 127 3.2.2. Attempted formation of a (-)-menthol derived valerolactim ether via an iminoyl halide intermediate iv 128 3.2.3. Attempted preparation of terpene derived lactim ethers via trichloroacetimidate methodology 129 3.2.4. Preparation of terpene derived lactim ethers via transesterification 129 131 3.2.5. Preparation of a-allyl menthol lactim ether 291a/292a 136 3.3.6. Formation of a series of diastereomerically enriched 01- alkyl (-)-menthol lactim ethers 137 3.2.7. Removal of the (-)-menthol chiral auxiliary via transesterification 138 3.2.8. Preparation of co-amino a-allyl (-)-menthol ester 293 140 3.2.9. Hydrolysis of a-allyl (-)-menthol valerolactim ether 143 3.3. Development of effective asymmetric czza-enolate alkylation methodology 143 3.3.1. Preparation of enantiopure a-alkyl lactim ether derived from a chelating chiral auxiliary 145 3.3.2. Attempted preparation of a-allyl (\S,2S)-2- methoxycyclohexyloxy lactim ether 303 146 3.4. Asymmetric alkylation of lactim ethers using a chiral ligand approach 146 3.4.1. Alkylation of the aza-e nolate of lactim ethers in the presence of (-)-sparteine as a chiral ligand 147 3.4.2. Asymmetric synthesis of a-methyl valerolactim ether 254 using (-)-sparteine as a chiral ligand 151 3.5. Conclusion 153 Chapter 4. Extension of Schollkopf’s Ms-lactim ether methodology 153 4.1. Schollkopf s fo's-lactim ether methodology 153 4.1.1. Formation of enantiopure amino esters using bis-lactim ether methodology 155 4.2. Potential improvements of Schollkopf’s fr/s-lactim ether chiral auxiliary methodology 155 4.2.1. Transesterification precedent for lactim ethers 156 4.2.2. Isotopic labelling precedent for lactim ethers 157 4.2.3. Potential applications of transesterification and isotopic labelling reactions on Schollkopf’s bis-lactim ether methodology v 158 4.3. Synthesis and use of orthogonally protected bis-lactim ether 158 4.3.1. Practical problems associated with the use of Schollkopfs chiral auxiliary 160 4.3.2. Synthesis of dipeptide species using orthogonally protected bis-lactim ether 162 4.3.3. Preparation of &z.s-lactim ether 328 163 4.3.4. Production of O-methyl O-benzyl bis-lactim ether 328 165 4.3.5. Confirmation of the structure of O-methyl O-benzyl bis- lactim ether 328 169 4.3.5.
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