CHIRAL LITHIUM AMIDES: REACTIVITY STUDIES AND APPLICATIONS TO TARGET SYNTHESIS MARK ROBERT PRESTLY, MSci Thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY. School of Chemistry College of Engineering and Physical Sciences University of Birmingham January 2013 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Chiral lithium amide bases allow the desymmetrisation of prochiral substrates and the production of enantiomerically enriched products, which are vital for the pharmaceutical industry and the total synthesis of natural products. Chapter 1 gives a brief review of this area and the progress that has been achieved over the last three decades. In Chapter 2 deprotonation of a ketone and an imide substrate using both chiral and achiral bases is described. Within the development of catalytic chiral lithium amide base methodology, competition reactions (Chapter 3) and lithium exchange experiments (Chapter 4) were carried out between two amine species. It was found that there were appreciable differences in the rate of deprotonation of the substrate between the lithium amides studied. Chapter 5 describes the design and synthesis of new fluorinated chiral diamines which we hoped could be used as effective chiral lithium amide bases in sub-stoichiometric amounts. Initial work was also carried out on the total synthesis of the diterpenoid alkaloid concavine. A chiral lithium amide base was used to introduce asymmetry into the synthetic route and the synthesis of the fused oxazepane ring moiety was completed (Chapter 6). ii Declaration I declare that this thesis is the result of my own work and has not, whether in the same or a different form, been presented to this or any other university in support of an application for any degree other than that for which I am now a candidate. ______________________ Mark Robert Prestly, MSci iii Acknowledgements Firstly, I would like to thank my supervisor Professor Nigel Simpkins for giving me the opportunity to work on this project and for his guidance. I would also like to acknowledge the University of Birmingham for such a pleasant working environment; our 6th floor lab/office, the School of Chemistry and the campus as a whole. I would also like to acknowledge the EPSRC for funding the studentship, which allowed this work to be carried out. I would like to thank the past and present members of the Simpkins research group for their help, support and friendship. In particular I would like to thank Mike, Cynthia, Damian, Jennifer, Seb, Alex, Yang, Pete, Ilias, Bick, Jimm and Fred. The analytical facilities in the School of Chemistry have been invaluable for this work to be carried out. I would like to acknowledge Dr. Neil Spencer for his hard work running and maintaining the NMR facility and carrying out the NOESY experiment within this thesis. I would also like to acknowledge Peter Ashton, Neil and Dr. Chi Tsang for obtaining mass spectra. I am also grateful for Dr. Louise Male obtaining the two X-ray crystal structures in this thesis. I am especially grateful to Graham Burns and Chi for all their assistance regarding the use of chiral GC and HPLC. Lastly, I would like to thank my wife, Amanda, for her patience, understanding and love during the time I have carried out this work. iv Table of Contents Abstract .......................................................................................................................................ii Declaration .................................................................................................................................iii Acknowledgements ....................................................................................................................iv Abbreviations ..............................................................................................................................x Chapter 1 – Introduction to Chiral Lithium Amide Deprotonations 1.1 Overview ...............................................................................................................................1 1.2 Asymmetric Deprotonations .................................................................................................3 1.2.1 Asymmetric Deprotonation of Epoxides ........................................................................3 1.2.2 Asymmetric Deprotonation of Ketones ..........................................................................7 1.2.3 Asymmetric Deprotonation of Imides ..........................................................................21 1.2.4 Asymmetric Deprotonation Adjacent to Sulfur ............................................................23 1.2.5 Asymmetric Deprotonation of Chromium Arene Complexes.......................................26 1.3 Kinetic Resolutions and Other Transformations .................................................................29 1.4 Sub-stoichiometric Chiral Base Use ...................................................................................32 1.5 Recoverable Chiral Bases ...................................................................................................35 1.6 The Structure of Lithium Amide Bases ..............................................................................39 1.7 Project Aims and Plan .........................................................................................................42 v Chapter 2 – Benchmark Enolisations of Ketone and Imide Systems 2.1 Enolisation of Ketone 1 with Chiral and Achiral Lithium Amide Bases ............................43 2.2 Enolisation of Imides 151 and 152 with Chiral and Achiral Lithium Amide Bases ...........50 2.3 Summary of Results.............................................................................................................59 Chapter 3 – Enolisation of Ketone and Imide Substrates Using Two Lithium Amide Bases 3.1 Literature Examples of Competition Reactions ..................................................................60 3.2 Deprotonation of Ketone 1 Using a Mixture of Two Lithium Amides ..............................64 3.3 Deprotonation of Imide 151 Using a Mixture of Two Lithium Amides .............................67 3.4 Summary and Conclusions ..................................................................................................71 Chapter 4 – Lithium Exchange Reactions 4.1 Introduction .........................................................................................................................76 4.2 Deprotonation of Ketone 1 Using a Mixture of a Lithium Amide and an Amine ..............79 4.3 Use of Substoichiometric Chiral Base (R)-122 ...................................................................82 4.4 Summary and Conclusions ..................................................................................................85 vi Chapter 5 – Design and Synthesis of Novel Fluorinated Chiral Bases 5.1 Introduction .........................................................................................................................87 5.2 Design of Fluorinated Diamine Base 187............................................................................88 5.3 Synthesis of Diamine 188 ...................................................................................................88 5.4 Use of Chiral Base 187........................................................................................................93 5.5 Design of Chiral Base 200...................................................................................................95 5.6 Synthesis of Chiral Amine 201............................................................................................96 5.7 Use of Chiral Base 200......................................................................................................101 5.8 Future Syntheses of Chiral Amines ...................................................................................102 5.9 Summary and Conclusions ...............................................................................................104 Chapter 6 – Towards the Total Synthesis of Concavine 6.1 Introduction .......................................................................................................................106 6.2 Diterpenoids ......................................................................................................................107 6.3 Structure Elucidation .........................................................................................................109 6.4 Initial Retrosynthesis .........................................................................................................110 6.5 Radical Cyclisation Attempts ............................................................................................118 6.6 Revised Retrosynthesis .....................................................................................................122 vii 6.7 Synthesis of the Fused Oxazepane Ring ...........................................................................130