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When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given e.g. AUTHOR (year of submission) "Full thesis title", University of Southampton, name of the University School or Department, PhD Thesis, pagination http://eprints.soton.ac.uk UNIVERSITY OF SOUTHAMPTON FACULTY OF NATURAL AND ENVIRONMENTAL SCIENCES Department of Chemistry Asymmetric synthesis of bioactive alkaloids from Amaryllidaceae Valerio Isoni Thesis for the degree of Doctor of Philosophy May 2013 UNIVERSITY OF SOUTHAMPTON ABSTRACT FACULTY OF NATURAL AND ENVIRONMENTAL SCIENCES SCHOOL OF CHEMISTRY Doctor of Philosophy ASYMMETRIC SYNTHESIS OF BIOACTIVE ALKALOIDS FROM AMARYLLIDACEAE By Valerio Isoni A new route towards the diasteroselective synthesis of (+)-maritidine, a bioactive alkaloid from Amaryllidaceae, has been proposed. In our approach, an intramolecular Heck reaction was used to form the quaternary stereocentre C10b driven by the stereochemical information at C4a of the precursor. Allylic oxidation of intermediate 3.25 followed by diasteroselective reduction, introduced the alcohol at C3 with the correct stereochemistry. An advanced intermediate (3.29) in the synthesis of (+)-maritidine was produced, and routes to complete the total synthesis were proposed. A series of polymer-supported sulfonate ester linkers were developed for use in the resin- linker-vector (RLV) approach for the synthesis of [18F]-radiopharmaceuticals used as imaging probes in positron-emission-tomography (PET). Upon exposure of the RLV construct to [18F]-fluoride, a small quantity of [18F]-radiotracer is released in solution which is separated from the unreacted material and cleaved resin, by simple filtration. The RLV strategy was successfully applied for the synthesis of the known radiopharmaceutical O-(2-[18F]-fluoroethyl)-L-tyrosine, [18F]-FET. A C-H activation-cyclisation sequence was used to achieve the synthesis of the Amaryllidaceae alkaloid oxoassoanine as well as a phenanthridinoid analogue, part of potential non-charged dual reactivators of acetylcholinesterase (AChE) poisoned by organophosphorous (OP) nerve agents. Contents Contents ............................................................................................................................ i Declaration ......................................................................................................................iii Acknowledgements ......................................................................................................... iv Abbreviations................................................................................................................... v Chapter 1 – Introduction ................................................................................................ 1 1.1 The Amaryllidaceae family ............................................................................... 1 1.2 Biosynthesis of Amaryllidaceae alkaloids ........................................................ 2 1.3 Pancratium maritimum: a source of crinine alkaloids ...................................... 3 1.4 Previous syntheses: an overview ....................................................................... 4 1.5 The Brown group approach to Amaryllidaceae alkaloids: synthesis of (−)-galanthamine ......................................................................... 12 1.6 Second generation synthesis of (−)-galanthamine .......................................... 15 1.7 The Brown group approach towards (+)-maritidine ....................................... 16 Chapter 2 – First approach to (+)-maritidine ............................................................ 19 2.1 Synthesis of propargylic alcohol (±)-1.59 ....................................................... 19 2.2 Synthesis of benzyl bromide 2.06 ................................................................... 20 2.3 Synthesis of cyclohexadiene (±)-2.08 ............................................................. 21 2.4 Synthesis of dimethoxybenzoates ................................................................... 25 2.5 Conclusions ..................................................................................................... 32 Chapter 3 – Towards the synthesis of (+)-maritidine ................................................ 33 3.1 A convergent, new approach to cyclohexadiene 2.07 ..................................... 33 3.2 Benzylic etherification: an extended study ..................................................... 36 3.3 The Heck reaction: a closer look ..................................................................... 43 3.4 Benzylic and Allylic oxidations ...................................................................... 49 3.5 Stereoselective reduction of enone 3.28.......................................................... 53 3.6 Introduction of nitrogen at C4a ........................................................................ 56 3.7 Conclusions ..................................................................................................... 60 3.8 Future work ..................................................................................................... 61 i Chapter 4 – Radiochemistry and C-H activation: development of neuroscientific tools within a European collaboration ................................................... 63 4.1 A Resin-Linker-Vector (RLV) approach to radiopharmaceuticals containing 18F ............................................................................................................. 63 4.1.1 Introduction .................................................................................................................... 63 18 4.1.2 The RLV strategy for the synthesis of radiotracers containing F ................................... 65 4.1.3 Synthesis of 4-alkylphenylsulfonate linkers .................................................................... 66 18 18 4.1.4 The RLV approach to O-(2-[ F]-fluoroethyl)-L-tyrosine ([ F]-FET) .............................. 71 4.1.5 Conclusions .................................................................................................................... 76 4.2 Development of dual AChE reactivators within a European collaboration .... 76 4.2.1 Background .................................................................................................................... 76 4.2.2 Synthesis of phenanthridinoid alkaloids and analogues via C-H activation-cyclisation .... 82 4.2.3 Conclusions .................................................................................................................... 87 18 18 4.2.4 The RLV approach to O-(2-[ F]-fluoroethyl)-L-tyrosine ([ F]-FET) .............................. 71 4.2.5 Conclusions .................................................................................................................... 87 Chapter 5 – Experimental Details ................................................................................ 89 References .................................................................................................................... 162 ii Declaration I declare that the work presented in this thesis is of my own composition and has been generated by me as a result of my own original research while in candidature at this university for the degree of Doctor of Philosophy, with the exception of the experiments carried out by scientists at GE Healthcare, Dr. Amy C. Topley and Dr. Lynda J. Brown, which are acknowledged. Where I have consulted the published work of others, this is clearly attributed. Where I have quoted from the work of others, the source is always given and with exception of such quotations this thesis is entirely my own work. No part of this work has previously been published, submitted for a degree or other qualification, with the exception of the radiochemistry section 4.1.1,2 This copy is supplied on the understanding that it is copyright material and that no quotation from this thesis may be published without proper acknowledgement. Valerio Isoni, May 2013 iii Acknowledgements I wish to thank the following people for their help, support and good moments spent together during the course of my PhD. A big thank you to the members of the Brown group, past and present, for the fun, productive and unique lab environment, where chemistry and different cultures blended, especially at tea breaks. Thanks to Alex H, Alex P, Ali, Amanda, Amy, Azzam, Dr Lynda Brown, Dr Joe Hill-Cousins, Maxime, Mohammad, Patrick, Paul, Rob G, Rob H, Sam and Sherif. From other departments within the school, I would like to thank Neil Wells for the NMR service, as well as John Langley and Julie Herniman for the mass spectrometry service. I gratefully acknowledge the European Regional Development Fund (ERDF, INTERREG IVa program 4061) for funding my studentship as part of the ISCE- Chem project. Special thanks to Dr. Cecile Perrio for her assistance with the