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Download (7MB) Mathieson, Michael (2014) Studies towards the synthesis of hexacyclinic acid. PhD thesis. http://theses.gla.ac.uk/5750/ 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] Studies towards the Synthesis of Hexacyclinic Acid Michael Mathieson (MChem) A thesis submitted in part fulfilment of the requirements of the degree of Doctor of Philosophy School of Chemistry College of Science & Engineering University of Glasgow November 2014 Contents Acknowledgements...................................................................... 4 Author’s Declaration....................................................................5 Abstract...................................................................................6 Abbreviations ..............................................................................7 1 – Introduction .........................................................................9 1.1 – Hexacyclinic acid and (−)-FR182877.................................10 1.2 – Literature syntheses of (−)-FR182877 ..............................13 1.2.1 – Sorensen ...........................................................13 1.2.2 – Evans ...............................................................17 1.2.3 – Nakada .............................................................21 1.3 – Literature syntheses of Hexacyclinic acid .......................24 1.3.1 – Clarke – ABC tricycle .............................................24 1.3.2 – Clarke – DEF tricycle .............................................27 1.3.3 – Landais – ABC tricycle ............................................30 1.3.4 - Kalesse – ABC tricycle ........................................... 33 1.3.5 – Nakada – DEF tricycle ............................................36 2 - Previous work in Prunet group on Hexacyclinic acid 1...........40 3 – Results and Discussion .........................................................46 3.1 – Project Aim ..............................................................46 3.2 - Synthesis of ABC system .............................................49 3.2.1 – Synthesis of A-Ring 113c/113d................................49 Retrosynthesis ...................................................50 Attempted transesterifications of A-ring ...................51 Synthesis of Crimmins chiral auxiliary 127..................51 Crimmins asymmetric aldol reaction ........................52 Protection and cleavage of auxiliary ........................57 Roskamp homologation and Knoevenagel ...................57 Ring-closing metathesis .......................................59 Synthesis of 2-(trimethylsilyl)ethyl analogue 113d ....... 59 3.2.2 – Synthesis of C-Ring 118........................................60 Retrosynthesis .................................................60 Synthesis of diene 149 .......................................61 Ring-closing metathesis and oxidation .................... 61 1 Conjugate addition .......................................... 62 3.2.3 – Diastereoselective Michael addition ........................63 3.2.4 – Formation of the B-ring .....................................65 Mechanism .....................................................66 3.2.5 – Attempted removal of tert-butyl ester .....................67 3.2.6 – Conclusion and future work ..................................68 3.3 – Current work towards DEF tricycle .............................71 Retrosynthesis ................................................71 3.3.1 - Synthesis of β-ketoester .....................................72 Synthesis of 4-pentenal 176 ................................ 72 Crimmins aldol reaction of 127 with 176.................72 Completion of β-ketoster synthesis .......................73 3.3.2 – Michael addition of 184 to cyclopentenone 185..........74 3.3.3 – Further functionalisations of 186............................75 3.3.4 – Aldol condensation attempts................................ 76 3.3.5 - Synthesis of chiral model C-ring .............................78 3.3.6 – Model CDEF synthesis ........................................ 80 3.3.7 – Conclusions and future work..................................83 4 - Diastereoselective synthesis of syn-1,3-diols..................................86 4.1 – Introduction.............................................................86 4.2 – Results and discussion............................................ 90 Synthesis of substrate ..........................................90 Conjugate addition reactions with CO2......................91 Conjugate addition reactions with 239..................... 91 4.3 – Conclusions and future work........................................93 5 - Investigation of a different base for Crimmins Aldol .................... 94 5.1 -Introduction .............................................................94 5.2 - Results and discussion ...............................................95 Bispidine synthesis ..............................................95 Aldol reactions using bispidine 243 ..........................95 5.3 – Conclusion.......................................................... 95 6 – Experimental........................................................................ 97 7 – References........................................................................... 159 8 – Appendix.............................................................................. 162 2 3 Acknowledgements Firstly I would like to extend my gratitude to my PhD supervisor Dr Joëlle Prunet (The boss, JP) for giving me the opportunity to undertake a PhD in her group. Joëlle has been incredibly supportive and encouraging throughout my time at Glasgow, not to mention her never-ending patience. I would also like to thank my fellow Prunets – Sébastien and Raphaël for all their help at the start of my PhD, Toni for enduring me for the last 4 years, Aurelien, Stéphane (The Beast), Alex (Phillibert), Amaia and also all past and present project students, it’s been great working with you all. Thanks to Dr David France for all his advice throughout my time here and to the France group – Jo and Pooja. Big shout out to the France Boyz, Lewis and Craig, for all the great laughs. Thanks to all the other members of the Raphael and Loudon labs for stimulating chemistry and non-chemistry chat. My gratitude goes to the EPSRC for funding my PhD. I would also like to show my appreciation to Olga, who has supported and encouraged me for these last few difficult months. I am just annoyed I have met you at the end of my time at Glasgow. Finally I would like to thank my family, specifically my parents for all their encouragement and support for the last 28 years, not to mention all the financial assistance they have given me. 4 Author’s Declaration This thesis represents the original work of Michael Mathieson unless otherwise explicitly stated and referenced in the text. The research was carried out at the University of Glasgow in the Loudon and Raphael Laboratories under the supervision of Dr Joëlle Prunet during the period from the 1st of October 2009 to 16th of December 2012. 5 Abstract Hexacyclinic acid is a polyketide isolated from Streptomyces cellulosae bacteria in 2001. It possesses a complex and challenging hexacyclic ring system with various oxygen functionalities throughout. Hexacyclinic acid has also demonstrated some cytotoxic activity, making it an attractive target for total synthesis. However to date no full synthesis has been reported. Previously within the group significant progress had been made towards the synthesis of hexacyclinic acid, with construction of the ABC 5/6/5 tricyclic core being achieved via a diastereoselective Michael addition and Snider radical cyclisation. The synthesis ran into difficulties however when hydrolysis of the ethyl ester could not be accomplished and removal of the superfluous carboxylic acid moiety could not be realised. The approach within the group for the formation of the ABC tricycle was to continue the current strategy, joining the A and C-rings via the diastereoselective Michael reaction, and the closure of the 6-membered B-ring by Snider radical cyclisation. Progress was made using the tert-butyl and 2,2,2-trimethylsilylethyl ester analogues in an attempt to improve diastereoselectivities Progress was also made on the synthesis of the CDEF tricyclic system, utilising (R)-isopropylcyclopentenone as a C-ring model system. The DEF framework was attached to the model by a Michael addition, with further functionalisation setting up the necessary functionalities for cyclisation. Conditions were attempted to effect a challenging aldol condensation to form the 9-membered ring, however all attempts effect this transformation were fruitless. It was discovered that 2,2,2-trifluoromethylacetophenone can act as a replacement for benzaldehyde in the synthesis of protected syn-1,3-diols from homoallylic alcohols, with comparable yields and easier purification. Finally, an investigation was also made into the
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