Hobson, Stephen (2010) Applications of the achmatowicz rearrangement in natural product synthesis. PhD thesis. http://theses.gla.ac.uk/1660/ Copyright and moral rights for this thesis are retained by the author 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. Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Applications of the Achmatowicz Rearrangement in Natural Product Synthesis Stephen Hobson B.Sc (Hons) Submitted in fulfilment of the requirements for the Degree of Doctor of Philosophy Department of Chemistry Faculty of Physical Sciences University of Glasgow Submitted January 2010 ii Abstract The structurally related PM-94128 and Ajudazols A and B exhibit differing biological activities but share the isocoumarin core structure. PM-94128 belongs to a large family of compounds known as the aminodihydroisocoumarins and was isolated in 1997. It has been shown to be an inhibitor of DNA and RNA synthesis and have potent cytotoxic activity in vivo . The Ajudazols A and B were isolated in 2004 and have antifungal activity against several important food spoilers. The work that follows details the design and development of a novel method for the generation of the isocoumarin core from isobenzofuran utilizing the Achmatowicz rearrangement of α-hydroxyisobenzofurans. Spirocyclic pyrans such as Polymaxenolide are structurally complex molecules, containing large amounts of functionality. The biological activity of Polymaxenolide is unknown and there have been no total syntheses reported to date. ii iii Also reported in this thesis is the design and synthesis of a model system of Polymaxenolide, using the Achmatowicz rearrangement of α-hydroxyfurans. iii iv Table of Contents Abstract...................................................................................... ii Table of Contents ..........................................................................iv List of Figures ...............................................................................vi List of Tables............................................................................... vii List of Schemes ............................................................................ vii Acknowledgments ..........................................................................xi Author Declaration ........................................................................ xii Abbreviations ............................................................................. xiii 1. Introduction.............................................................................. 1 1.1. Isocoumarins...................................................................... 1 1.1.1. Bacillus isocoumarins ...................................................... 1 1.1.2. Streptomycetes isocoumarins ............................................ 2 1.1.3. Xenorhabdus isocoumarins................................................ 3 1.1.4. Bachiphelacin ............................................................... 3 1.1.5. PM-94128 and Y-05460M-A ................................................ 4 1.1.6. Amicoumacin A to C ....................................................... 5 1.1.7. AI-77s and Sg17-1-4 ........................................................ 9 1.1.8. Shioiri’s synthesis of AI-77-B............................................. 12 1.1.9. Kotsuki’s synthesis of AI-77-B ........................................... 15 1.1.10. Vallee’s sythesis of PM-94128......................................... 19 1.1.11. Other notable syntheses............................................... 21 1.2. Isochromanones................................................................. 24 1.2.1. Ajudazol A and B .......................................................... 24 1.2.2. Taylor’s synthesis of the C15-C29 fragment, 104..................... 28 1.2.3. Rizzacasa’s synthesis of the C9-C29 fragment 121 ................... 31 1.3. Other isocoumarin containing natural products............................ 35 1.4. Biosynthetic origin.............................................................. 38 2. Results and discussion ................................................................. 44 2.1. Synthesis of PM-94128 ......................................................... 44 2.1.1. Proline organocatalysis ................................................... 45 2.1.2. Initial synthetic efforts................................................... 48 2.2. An alternate approach ......................................................... 55 2.2.1. Model system synthesis................................................... 57 2.2.2. Studies towards the synthesis of Ajudazol A .......................... 67 2.2.3. Mitsunobu inversion....................................................... 73 2.2.4. An unexpected product .................................................. 75 2.2.5. Studies towards the Ajudazol A C15-C29 fragment. ................. 77 2.3. Future work...................................................................... 79 2.3.1. Introduction of the C8 hydroxyl......................................... 79 2.3.2. Alkylation regioselectivity ............................................... 81 2.3.3. Enantiopure Aldehyde .................................................... 81 2.3.4. Completion of the C1-C14 fragment.................................... 82 2.3.5. Further work ............................................................... 82 3. Experimental............................................................................ 85 4. Introduction............................................................................129 4.1. Spirocyclic pyrans .............................................................129 4.2. Isolation and characterization ...............................................129 4.3. Biosynthesis.....................................................................131 4.4. Structural features ............................................................133 iv v 4.5. Spirocyclic pyrans .............................................................134 4.5.1. Ring closing metathesis .................................................134 4.5.2. Spiroannulation...........................................................137 4.5.3. Prins cyclisations .........................................................138 4.5.4. Pauson Khand .............................................................140 4.5.5. Other methods............................................................141 5. Results and discussion ................................................................143 5.1. Spirocyclic natural products .................................................143 5.1.1. Initial findings ............................................................143 5.1.2. Retrosynthesis ............................................................145 5.1.3. Synthesizing lactol, 397. ................................................145 5.1.4. Other ring systems .......................................................148 5.1.5. Synthesis of the [4.5] spirocycle .......................................148 5.1.6. Optimisation of the cyclisation protocol..............................151 5.2. Methoxy directed cyclisations ...............................................152 5.2.1. First synthetic route .....................................................153 5.2.2. Palladium cross coupling reactions ....................................156 5.2.3. Molybdenum catalyzed allylic substitution...........................161 5.2.4. Original route .............................................................162 5.2.5. Cyclisation vs dehydration ..............................................162 5.3. Future Work ....................................................................166 5.3.1. Spirocyclic products .....................................................166 5.3.2. Methoxy directed cyclisations..........................................168 6. Experimental...........................................................................169 7. Appendices .............................................................................206 7.1. Appendix 1 - Reaction of diene 208 and dienophile 198 .................206 7.2. Appendix 2 - Reaction of modified dienes 202 and 206..................207 7.3. Appendix 3 - Microwave conditions. ........................................208 7.4. Appendix 4 - Neat Diels Alder series........................................209 7.5. Appendix 5 – X-ray data for 198 .............................................209 7.6. Appendix 6 – X-Ray data for 244.............................................211 7.7. Appendix 7 – X- Ray data for 261 ............................................214 7.8. Appendix 8 – X-Ray data for 264.............................................217 7.9. Appendix 9 – X-ray data for 276 .............................................221 7.10. Appendix 10 – X-ray data for 289 .........................................224 7.11. Appendix 11 – X-ray data for 298 .........................................228 7.12. Appendix 12 – Org. 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