This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Synthesis of the C(1)-C(9) Fragment of Disorazole C 1 and Novel Heterocyclic Analogues Helen S. Niblock A thesis submitted for the degree of Doctor of Philosophy University of Edinburgh 2012 Contents 1 Chapter 1: Introduction ........................................................................................ 1 1.1 Isolation and Biosynthesis ............................................................................ 1 1.2 Biological Activity ....................................................................................... 6 1.3 Structure Activity Relationship of the Disorazoles ...................................... 9 1.3.1 Disorazole A 1 ....................................................................................... 9 1.3.2 Disorazole C 1 ...................................................................................... 10 1.3.3 Disorazole Z ....................................................................................... 15 1.4 Synthesis of Disorazole C 1 and Analogues ................................................ 18 1.4.1 Meyers Partial Synthesis of Disorazole C 1 ......................................... 18 1.4.2 Hoffmann Synthesis of Tetradehydro-Disorazole C 1 ......................... 23 1.4.3 Wipf Total Synthesis of Disorazole C 1 .............................................. 29 1.5 Synthesis of Analogues .............................................................................. 33 1.5.1 t-Butyl Analogue ................................................................................ 33 1.5.2 C(17)-C(18) Cyclopropyl Analogue .................................................. 34 1.5.3 Attempted Synthesis of the C(6)-Desmethoxy Analogue .................. 35 1.5.4 Hydrogenated Disorazole C 1 .............................................................. 36 1.5.5 C(16)-Ketone Analogue ..................................................................... 36 1.5.6 (−)-CP 2-Disorazole C 1 ........................................................................ 37 1.5.7 Synthesis of Simplified Disorazole 18 ............................................... 41 1.6 Novel Disorazole C 1 Synthesis Utilising the Evans-Tishchenko Reaction and Ring Closing Alkyne Metathesis ..................................................................... 44 2 Chapter 2: Racemic Fragment Synthesis ............................................................ 46 2.1 Oxazole Natural Products ........................................................................... 46 2.2 Disorazole C 1 C(1)-C(9) Fragment Retrosynthesis .................................... 47 2.3 C(1)-C(5) Oxazole Syntheses ..................................................................... 48 2.3.1 Halomethyloxazole Syntheses ............................................................ 48 2.3.2 Methyloxazole Synthesis .................................................................... 50 2.4 C(6)-C(9) Aldehyde Synthesis ................................................................... 53 2.5 Halomethyloxazole and Aldehyde Coupling-Route A ............................... 55 2.5.1 Oxazole Zinc Barbier-Type Coupling ................................................ 56 I 2.5.2 Oxazole Samarium Barbier-type coupling ......................................... 57 2.5.3 Use of Other Metals in Oxazole Centred Barbier Reactions .............. 60 2.5.4 Route A: Attempted Synthesis of C(1)-C(9) fragment....................... 61 2.5.5 Fukuyama Coupling ........................................................................... 66 2.6 Methyloxazole and Aldehyde Coupling - Route B .................................... 67 2.6.1 Oxazole Lateral Lithiation Background ............................................. 67 2.6.2 Results: Initial Investigation into (2-Methyl-1,3-oxazol-4-yl)methanol Lithiation ……………………………………………………………………….69 2.6.3 Evans Group Investigation into Base Effect ...................................... 70 2.6.4 Proposed Lithiation Mechanism ......................................................... 72 2.6.5 Results: Base Optimisation ................................................................ 76 2.6.6 Alcohol Protecting Group Effect ........................................................ 77 2.7 Completion of the Racemic C(1)-C(9) Fragment of Disorazole C 1 ........... 79 2.8 Summary .................................................................................................... 80 3 Chapter 3: Enantiospecific Fragment Synthesis I .............................................. 81 3.1 Adaptation of Previous Disorazole C 1 Syntheses ....................................... 81 3.1.1 Meyers Based Approach .................................................................... 81 3.1.2 Wipf Based Approach ........................................................................ 86 3.1.3 Summary ............................................................................................ 88 3.2 C(4)-C(5) Disconnection Approach ........................................................... 89 3.2.1 C(1)-C(9) Fragment Retrosynthesis ................................................... 89 3.2.2 C(1)-C(4) Oxazole Synthesis ............................................................. 91 3.2.3 C(5)-C(9) Epoxide Retrosynthesis ..................................................... 94 3.2.4 C(7)-C(8) Alkene Bond Formation via Cross Metathesis -Route A .. 94 3.2.5 C(7)-C(8) Alkene Bond Formation via Wittig Reaction - Route B ... 99 3.2.6 Horner-Wadsworth-Emmons Reaction ............................................ 104 3.2.7 Epoxidation of C(6)-C(9) Aldehyde ................................................. 105 3.2.8 Summary .......................................................................................... 106 4 Chapter 4: Enantiospecific Synthesis II and Heterocyclic Analogues ............. 107 4.1 Retrosynthesis of C(1)-C(9) Fragment and Heterocyclic Analogues....... 107 4.2 Synthesis of C(5)-C(9) Tosylate ............................................................... 107 4.3 Investigations into Oxazole C(1)-C(4) and Tosylate Coupling ................ 112 II 4.3.1 Oxazole C-H Activation ................................................................... 112 4.3.2 Oxazole Lithiation ............................................................................ 121 4.3.3 Summary .......................................................................................... 126 4.4 Heterocyclic Analogues ........................................................................... 127 4.5 Summary .................................................................................................. 132 5 Future work ...................................................................................................... 134 5.1 Completion of C(1)-C(9) Fragment.......................................................... 134 5.2 Heterocyclic Analogues ........................................................................... 135 5.3 Evans-Tishchenko Coupling .................................................................... 136 5.4 Alkyne Metathesis .................................................................................... 137 5.4.1 Application to Disorazole C 1 Synthesis ........................................... 139 5.5 Sonogashira option ................................................................................... 140 6 Chapter 6: Experimental ................................................................................... 142 6.1 General Experimental ............................................................................... 142 6.2 Experimental for Chapter 2 ...................................................................... 144 6.3 Experimental for Chapter 3 ...................................................................... 166 6.4 Experimental for Chapter 4 ...................................................................... 182 7 References ........................................................................................................ 202 8 Abbreviations ................................................................................................... 208 III Declaration This thesis is submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy at the University of Edinburgh. Unless otherwise stated the work described in this thesis is original and has not been submitted previously in whole or in part for any degree or other qualification at this, or any other university. In accordance with the regulations this thesis does not exceed 70,000 words in length. Helen Sarah Niblock IV Acknowledgements Firstly, I would like to thank Dr.