5-Endo-Die. Approaches to Pyrroles A thesis submitted to Cardiff University By Jirada Singkhonrat BSc, MSc In candidature of Doctor of Philosophy September 2004 Department of Chemistry Cardiff University UMI Number: U584670 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 U584670 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 Declaration This work has not previously been accepted in substance for any degree and is not being concurrently submitted in candidature for any degree. Signed a toJfl (candidate) Date QS_____________ Statement one This thesis is the result of my own investigations, except where otherwise stated. Other sources are acknowledged by footnotes giving explicit references. A bibliography is appended. Signed vo ________ (candidate) Date k y ja * } Q 5__ Statement two I hereby give consent for my thesis, if accepted, to be made available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed — aofg errs (candidate) Date wJXv* 0 5 Abstract This project required developing new practical routes towards pyrroles and could help the project of total synthesis of (-)-rhazinilam. In chapter one, the most widely used methods for constructing the pyrrole ring system are reviewed. The origins of this project were to investigate further uses for the iodocyclization reactions developed previously. In chapter 2, a new approach to such highly substituted pyrroles in which the key step is a 5-endo-dig halocyclisation of substituted homopropargylic sulfonamides was successfully achieved. Key to the success of this novel method is the rapid preparation of suitable starting materials, from 1-alkynes by sequential formylation and condensation with a tin(II) enolate of A-tosyl glycinate. Also, in chapter 2, a transition metal-catalyzed cyclisation using silica-supported silver nitrate was investigated and found to be effective. The reaction is clean and proceeds in quantitative yields. Obviously this fundamental research project is of a great interest because (-)-rhazinilam acts as an antimitotic agent like taxol, which are powerful anticancer agents. Different strategies of this approach are reviewed in chapter 3. In chapter 4 and 5, various aspects of separate approaches to the anti-tumor compound rhazinilam are described. In the former, both the synthesis of suitable 3-arylpyrrole cores and strategies for extending this methodology by the incorporation of a suitable substituent based on a cleavable cyclohexene are outlined. In the second section, chapter 5, similar issues are addressed but, in contrast, the Ag(I) methodology is used to construct a suitable arylpyrrole, the synthesis of which also features construction of the key precusor by aziridine ring hydrolysis. An efficient route to an enantiopure precusor of the necessary side chain is also described. This thesis is completed by a full experimental section and reference list. Acknowledgements I would like to take this opportunity to thank my supervisor Professor David W. Knight for his enthusiasm, guidance and support throughout this project. I am very grateful to all members of the academic staff and the technicians of the chemistry department at Cardiff university, especially Mr. Rob Jenkins and Rob for their assistance and to Prof.Knighf s secretary, Mrs Fran Godwin, for her encouragement and constant support. I would like also to thank Dr. K. M. A. Malik and Dr. Liling Ooi for their help on the X-ray crytal structures; all other students of the department, past and present, especially Chris, Lilian, Amjad, John, Emily, Nick, Mel, Xu, Charlie boy, Ian, Heizi, Lars, Shaista, and any others for making my time at Cardiff so pleasurable. I am so grateful to my great friends, Charlie, Sian and Nigel for proofreading my Thai-english thesis. I must thank my family for their great support; my mother for her belief, my father for his encouragement, my sister and my brother for their enthusiasm, and finally my sweetest guy, Edmond for being here and helped me through a difficult time in my life. Finally, I could not make it without the help from Royal Thai Government and EPRSC for financial support. Thank you so much. JIRADA CONTENTS Chapter one: Classical Pyrrole Syntheses 1.1 Introduction 1 1.2 Synthesis of pyrroles 1 1.2.1 Paal-Knorr synthesis 2 1.2.2 Knorr synthesis 3 1.2.3 Hantzsch synthesis 5 1.2.4 By using dipoles 6 1.2.5 From 1,3-dicarbonyl compounds and glycine esters 8 1.2.6 Synthesis by reduction of exiting rings 9 1.2.7 Metal-mediated cyclizations 9 1.2.8 Electrophile-induced cyclisation 10 1.3 5-endo-dig cyclisation 11 1.3.1 Iodocyclisation 13 1.3.2 Synthesis of p-hydroxy-oc-amino ester 17 1.3.2.1 Glycine Enolate Aldol Reactions 17 1.3.2.2 Reterosynthesis Analysis 21 1.3.2.3 Initial Studies 23 1.3.2.4 A generally applicable method for pyrrole synthesis 24 1.4 Silver-mediated cyclisation 27 1.5 Alternative syntheses of a-Amino alcohols 28 1.5.1 Addition to a-Aminocarbonyls 29 1.5.2 Asymmetric Aminohydroxylation 29 1.5.3 Pinacol Coupling 31 1.5.4 Addition of Nitronates (Henry reaction) 32 1.5.5 Nucleophile addition to imines 33 Chapter two: Results and Discussion 2.1 Synthesis of a-amino alcohols 34 2.1.1 Initial Studies 34 2.1.2 Further studies 36 2.1.3 Further studies of this aldol reaction 41 2.2 Alternative Synthesis of a-amino alcohols 42 2.2.1 Addition to a-Aminocarbonyls 42 2.2.2 Asymmetric Aminohydroxylation 43 2.3 Studies of Iodocyclization 49 2.3.1 Initial Studies 49 2.3.2 Suzuki coupling 54 2.3.3 Further studies 60 2.3.3.1 An attempt to establish models 60 2.3.3.2 Hindered substitution 63 2.4 A generally applicable method for pyrrole synthesis 71 2.4.1 Palladium-catalysed Coupling Reactions 71 2.4.2 Stille Coupling Reaction 71 2.4.3 Heck Reaction 72 2.4.4 Suzuki Reaction 72 2.5 Silver-mediated cyclisation 73 2.6 Conclusion 81 Chapter three: (-)-Rhazinilam 3.1 Introduction 82 3.2 Biological activity 83 3.2.1 Antimitotic agent 83 3.2.2 Taxol 84 3.3 Synthesis 85 3.3.1 An Overview 85 3.3.2 First Total Synthesis of Rhazinilam 85 3.3.3 Total Synthesis of (-)-Rhazinilam 88 3.3.4 The synthesis of new substituted biphenyl analogs 89 3.3.5 Hetero-ring cross coupling 94 Chapter four: The first synthetic approach to Rhazinilam 4.1 Introduction 100 4.2 Synthesis 102 4.2.1 Route A 102 4.2.2 Route B 104 4.2.3 Route C 108 4.2.4 Route D (alternative of route A) 111 4.3 Conclusion 114 Chapter five: The second synthetic approach to Rhazinilam 5.1 Application of Silver-Mediated Cyclization 115 5.2 Aziridination 116 5.2.1 Alkene Aziridination 116 5.2.2 Ylide Mediated Catalytic Aziridination 117 5.3 Synthesis 120 5.3.1 Approaching the aziridine 120 5.3.2 Ring Opening of the aziridine 124 5.3.3 Approaching the pyrrole 127 5.3.4 Carbon-nitrogen bond formation 131 5.4 Retrosynthetic Analysis and strategy 134 5.4.1 The synthesis of (S)-y -hydroxymethyl-y-butyrolactone 136 5.4.2 Synthesis of chiral quaternary carbon (C-3) 138 5.4.3 Reducetive opening of the lactone ring 141 5.5 Aziridination of the imine 144 5.6 Conclusion 146 Chapter six: Experimental 6.1 General Details 147 6.2 Experimental 148 References 229 Appendices: X-ray data 235 7.1 Methyl (2SR, 3SR)-3 -hydroxy-6,6-dimethyl-2- (4-methylphenylsulfonylamino)-hept-4-ynoate 162 235 7.2 Methyl 4-(2’-nitrophenyl)-5-phenyl-l- (4’-methylphenylsulfonyl)-pyrrole-2- carboxylate 281 243 7.3 Methyl 4-(2-nitro-phenyl)-5-butyl-l- (4-methylphenylsulfonyl)-pyrrole-2-carboxylate 282 249 7.4 Methyl (2SR,3&S)-5-t-butyl-3-hydroxy-4-iodo-1 - (4’-methylphenylsulfonyl)-2,3-dihydro-pyrrole-2-carboxylate 296 256 7.5 Methyl 4-tert-butyl-5-(2’-nitrophenyl)-l -(4’-methylphenylsulfonyl)- pyrrole-2-carboxylate 305 261 7.6 1 -(2 ’ -Bromobenzoyl)-3,3 ■-dimethyl-2- (4-Methyl-phenylsulfonamino)-butan- 1 -one 457 269 Abbreviations AcOH acetic acid APcI atmospheric pressure chemical ionisation Bn benzyl Bu butyl BOC /-butoxycarbonyl bp boiling point Bz benzoyl c concentrated COSY correlation spectroscopy DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N, N ’-dicyclohexylcarbodiimide DCM dichloromethane DEPT distortionless enhancement by polarization transfer DIBAL-H di-/so-butylaluminium hydride DMAP 4-dimethylaminopyridine DMF A,A’-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2[l H]-pyrimidinone DMSO dimethyl sulphoxide ee enantiomeric excess EDCI 1 -ethyl-3-(3 ’-dimethylaminopropyl)carbodiimide El electron ionization eq equivalents ES electrospray EtOAc ethyl acetate A heat h hours HOBT 1-Hydroxybenzotriazole, monohydrate HMPA hexamethylphosphoramide HRMS high resolution mass spectrometry LiAlH lithium aluminium hydride LHMDS lithium bis(trimethylsilyl) amide LDA lithium diisopropylamine M molar mp melting point min minutes mol mole >?-BuLi normal butyl lithium Ms methanesulphonyl NMR nuclear magnetic resonance nOe nuclear Overhauser effect PCC pyridinium chlorochromate PPTS pyridinium /7-toluenesulphonate pyr pyrrole r.t.