Durham E-Theses Synthesis of Polyene Natural Products MADDEN, KATRINA,SOPHIE How to cite: MADDEN, KATRINA,SOPHIE (2017) Synthesis of Polyene Natural Products, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/12052/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk Synthesis of Polyene Natural Products A thesis submitted as partial fulfilment of the requirements for the degree of Doctor of Philosophy at the Department of Chemistry, Durham University, UK Submitted by Katrina Sophie Madden Under the supervision of Professor Andy Whiting Supported by the EPSRC 2016 2 Declaration The work described in this thesis was carried out by the author unless stated otherwise or referenced. The material contained has not been submitted previously for any qualification. The copyright of this thesis rests with the author and any information derived from it should be correctly acknowledged. 3 4 Table of Contents Declaration .......................................................................................................................... 3 Acknowledgements ........................................................................................................... 11 Abstract ............................................................................................................................. 13 Abbreviations ................................................................................................................... 15 Introduction ...................................................................................................................... 19 Tetraenes ....................................................................................................................... 20 Macrocyclic tetraenes ................................................................................................. 20 Linear tetraenes ........................................................................................................... 22 Viridenomycin ............................................................................................................ 23 Marinomycins A-C ..................................................................................................... 27 Pentaenes ....................................................................................................................... 33 Macrocyclic pentaenes ................................................................................................ 33 Linear pentaenes ......................................................................................................... 36 RK-397........................................................................................................................ 37 Spirangien A and B ..................................................................................................... 39 Hexaenes ........................................................................................................................ 41 Cyclic hexaenes .......................................................................................................... 41 Linear hexaenes .......................................................................................................... 42 Dermostatin A and B .................................................................................................. 42 Etnangien .................................................................................................................... 44 Heptaenes ...................................................................................................................... 46 Cyclic heptaenes ......................................................................................................... 46 Linear heptaenes ......................................................................................................... 49 Amphotericin B........................................................................................................... 49 Fucoxanthin ................................................................................................................ 51 Octaenes and above ...................................................................................................... 55 Correlation between polyene chemical structure and biological activity................ 56 Conclusion ..................................................................................................................... 58 Section 1 Synthesis of polyene natural products ............................................................... 59 Section 1.1 Synthesis of Xanthomonas pigments- introduction and proposed targets ...... 61 Section 1.1.1 Xanthomonas pigments ............................................................................ 61 Section 1.1.2 Characterisation of Xanthomonas pigments ............................................ 64 Section 1.1.3 Summary .................................................................................................. 64 5 Section 1.1.4 Previous work done within the group ...................................................... 65 Section 1.1.5 Project aims and objectives...................................................................... 66 Section 1.2.1 Synthesis of a range of aryl building blocks ............................................ 69 Section 1.2.2 Selection of cross-coupling reactions to form Xanthomonas pigment and their analogues ......................................................................................................... 74 Section 1.2.2.1 HM couplings .................................................................................... 75 Section 1.2.2.2 Other cross-couplings........................................................................ 82 Section 1.2.2.3 Revisiting the SM couplings ............................................................. 85 Section 1.2.3 Summary .................................................................................................. 92 Section 1.3 Synthesis of Xanthomonas pigments - synthesis of polyene chains using the Heck-Mizoroki/iododeboronation iterative cross coupling methodology ................... 93 Section 1.3.1 Propagation of polyene chains from iodoacrylate 1, using HM/IDB ICC methodology ........................................................................................................... 94 Section 1.3.2 Propagation from the aryl end using the HM/IDB ICC methodology ... 101 Section 1.3.3 Application of the HM/IDB ICC methodology to give a trienyl building block ............................................................................................................... 103 Section 1.3.4 Attempted construction of a bismetallated building block .................... 105 Section 1.3.5 Temperature studies and reoptimisation of the HM methodology ........ 108 Section 1.3.6 Summary ................................................................................................ 112 Section 1.4 Synthesis of Xanthomonas pigments - new retrosynthetic routes to access mono- and di-brominated xanthomonadin, along with truncated analogues ........ 113 Section 1.4.1 Attempts to access xanthomonadin via a heptaenyl iodide ................... 113 Section 1.4.2 Redesigning the retrosynthetic route ..................................................... 115 Section 1.4.3 Sonogashira couplings to give alkynyl analogues ................................. 119 Section 1.4.5 Summary ................................................................................................ 132 Section 1.5 Synthesis of Xanthomonas pigments- spectroscopic properties .................. 133 Section 1.5.1 NMR observations and studies .............................................................. 133 Section 1.5.2 UV-Vis and fluorescence data ............................................................... 152 Section 1.5.3 Summary ................................................................................................ 156 Section 2 Novel methods of polyene synthesis ............................................................... 159 Section 2.1 Use of vinyl iodide as a Heck-Mizoroki coupling partner ........................... 161 Section 2.1.1 Optimisation of Heck-Mizoroki coupling to form 2-[(1E)-buta-1,3- dien-1-yl]-4,4,6-trimethyl-1,3,2-dioxaborinane ........................................................... 162 Section 2.1.2 Expanding substrate scope ..................................................................... 171 Section 2.1.3 Derivatisation of dienes ......................................................................... 180 Section 2.1.4 Capability of (E)-2-(buta-1,3-dienyl)-4,4,6-trimethyl-1,3,2- dioxaborinane to act as a four-carbon building block for polyene synthesis ............... 187 6 Section 2.1.5 Summary ...............................................................................................