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Coversheet for Thesis in Sussex Research Online A University of Sussex DPhil thesis Available online via Sussex Research Online: http://eprints.sussex.ac.uk/ This thesis is protected by copyright which belongs to the author. 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 Please visit Sussex Research Online for more information and further details The Double [3+2] Photocycloaddition Reaction Jason A. Woolford Submitted to the University of Sussex in part fulfilment of the requirements of the degree of Doctor of Philosophy, September 2010 Declaration I hereby declare that this thesis has not been submitted in whole or in part form for the award of another degree. Signed Jason Antony Woolford UNIVERSITY OF SUSSEX JASON ANTONY WOOLFORD DOCTOR OF PHILOSOPHY OF CHEMISTRY THE DOUBLE [3+2] PHOTOCYCLOADDITION REACTION SUMMARY One of a synthetic organic chemists‟ greatest challenges is to create step-efficient routes toward compounds with high molecular complexity. Therefore, reactions such as the meta photocycloaddition of an olefin to a benzene derivative, which provide more than one bond in a single step are of significant importance. It this remarkable reaction three new σ bonds, three new rings and up to six new stereocenters are formed simultaneously. Additional complexity can be added by tethering the two reacting partners together and this form of the reaction has found many uses in natural product synthesis. In this work a remarkable double [3+2] photocycloaddition reaction is reported that results in the formation of a complex cis, cis, cis, trans-[5, 5, 5, 5] fenestrane derivative from a simple flat aromatic acetal with two branching alkenes. During this dramatic transformation four carbon- carbon bonds, five new rings and seven new stereocenters are created in a single one-pot process using only UV light. The reaction occurs in a sequential manner from the linear meta photocycloadduct, via a secondary [3+2] addition of the alkene across the cyclopropane of the adduct. In addition, an angular meta photocycloadduct also produced in the initial addition step, undergoes an alternative fragmentation-translocation photoreaction to afford a silphinene-like angular tricyclic compound. In this work the investigation of this newly discovered process is discussed via the synthesis and subsequent irradiation of a series of photosubstrates containing different functional groups in the arene-alkene tether. In addition, attempts toward the synthesis of alternative structures using the same double [3+2] photocycloaddition are reported. Contents Acknowledgments Abstract Abbreviations 1 Introduction and background 1 1.1 The Step economy 1 1.2 The arene-alkene meta photocycloaddition 4 1.2.1 Introduction: photocycloaddition of an alkene to a benzene derivative 4 1.2.2 Mechanism of the meta photocycloaddition reaction 10 1.2.3 Regio- and stereoselectivity issues 13 1.2.4 The importance of tether length 18 1.2.5 Reactions of meta photocycloadducts and their use in natural product synthesis 20 1.3 Previous Penkett group studies: Palladium catalysed reactions of meta photocycloadducts 26 2 Discovery of the double [3+2] photocycloaddition 30 2.1 Introduction: Original aim 30 2.2 Preliminary studies 32 2.3 Discovery of the double [3+2] photocycloaddition and structural elucidation 40 3 A brief discussion on fenestranes 47 3.1 Introduction 47 3.2 Synthesis of fenestranes 49 3.3 Naturally occurring fenestranes 53 4 Investigation of the double [3+2] photocycloaddition reaction for the synthesis of fenestranes 56 4.1 Investigating the synthesis of dioxafenestrane 4 56 4.2 Thermally induced fragmentation-re-addition of a linear meta adduct 64 4.3 Deuterium study of a dioxafenestrane 4 and characterisation of the oxasilphinene product 5 66 4.4 Triplet sensitization and quenching studies: optimisation and mechanistic analysis of the double [3+2] photocycloaddition 73 4.5 Mechanistic summary for the irradiation of the acetal photosubstrate 1 78 4.6 Synthesis of a methyl dioxafenestrane and confirmation of oxygen‟s importance in the pathway toward silphinene 5 80 4.7 Attempted synthesis of dioxafenestranes from photosubstrates with an additional aromatic para substituent. 84 4.8 Synthesis of oxafenestranes derived from ether photosubstrates. 89 4.8.1 Introduction 89 4.8.2 Synthesis of two methoxy oxafenestranes 91 4.8.3 Synthesis of two methyl oxafenestranes 100 4.9 Attempted formation of an all carbon [5.5.5.5] fenestrane 104 4.10 Attempted formation of a [5.5.5.6] fenestrane 105 4.11 Synthesis of a novel azafenestrane 109 4.12 Attempted double-[3+2]-photocycloaddition reaction involving a C=N double bond 121 5 Attempted synthesis of a “criss-cross” double [3+2] photocycloadduct 127 5.1 Introduction 127 5.2 Irradiation of butenyl tether photosubstrate 321 129 5.3 Irradiation of pentenyl tether photosubstrate 322 132 6 Attempts toward the synthesis of alternative structures via the double [3+2] photocycloaddition. 134 6.1 Introduction 134 6.2 Attempt toward a Type II motif 135 6.3 Attempt toward a Type III motif 138 7 Conclusion 141 8 Experimental 143 8.1 General procedures 143 8.1.1 Reagents and solvents 143 8.1.2 Spectroscopy and naming 143 8.1.3 Chromatography 144 8.1.4 Photochemistry 145 8.2 Experimental data 146 9 References 248 10 Appendix I 256 Acknowledgements A PhD is an interesting experience, a pain and a pleasure in equal measure. It‟s very much like going on a journey when you don‟t know the exact route. There are frustrations and disappointments along the way, but also much laugher, camaraderie, encouragement and tremendous excitement and pride when you finally get to the peak. This journey is never travelled alone and words are somewhat inadequate to express my gratitude to all those people who have helped me along the way. Firstly, I would like to thank my supervisor and close friend, Dr. Clive Penkett. It has been a great honour to be able to participate in this project under his careful guidance. His advice in matters both academic and personal has always pointed me in the correct direction. Clive‟s unfortunate departure from the University of Sussex will be a great loss to the current Chemistry cohort and all future undergraduates as I believe him to be one of the best teachers I have ever been taught by. I wish him luck in all future endeavours. My thanks also go out to his lovely family - Caroline, Robert (Sproglet) and Anna (Froglet) plus the lovely felines Buni and Mushi. Special thanks are also given to Prof. Philip Parsons for his friendship, advice and support throughout the course of my time at Sussex and with who I look forward to collaborating with further in the future. Other academic colleagues I‟d like to thank are Dr. Iain Day, Dr. Ali Abdul-Sada and Dr. Martin Coles for their expertise in NMR, Mass spectroscopy and X-ray crystallography respectively. In addition, Dr. John Turner and Dr Eddy Viseux are thanked for useful discussions. During the course of this study I have had the pleasure of supervising and working with a series of talented masters and undergraduate students. Paul Brann, Varun Deo, Simon Cole and Rachel Kahan are all thanked for their company and good humour in the laboratory, as well as their contributions to the work of the group. Gratitude must also go out to Timothy Read for helping to complete the synthetic route toward the azafenestrane. I have also been fortunate to share both time and office space with a diverse fellowship of people from other groups, who have all contributed toward making my PhD all the more fun: Mariusz Bobin, Chris Gallop, Tara Williams (going to miss new penguin day!), Kayla Keller (plus Joe and little Jacob!), Bill Knowledon, Becky Joyce, Laura Nicholls (especially for the proof-reading), Rhys Williams, Brandon Kilduff, Morgan Taylor, Mat Stanley (thanks for the tea and conversation), and the many members of the Parsons group. In addition, thank you to all the undergraduates that I have taught in the last three years, it has been an education for me as much as you. Finally, I am hugely grateful to my family. Thanks to my brother Paul for putting up with living with me for three years and doing so much of the work around the house while this thesis has been completed. Thank you to my other brother David and his lovely wife Emma and also to my sister Laura. Finally to my Mum and Dad, who I hope to always make proud and have never failed to support me. This is for you. Abstract In this work a remarkable double [3+2] photocycloaddition reaction is reported, that results in the formation of a complex cis, cis, cis, trans-[5, 5, 5, 5] fenestrane derivative 4 from a simple aromatic acetal 1. During this dramatic transformation, four carbon-carbon bonds, five new rings and seven new stereocenters are created in a single one-pot process. The reaction occurs in a sequential manner from the linear meta photocycloadduct 2, via a secondary [3+2] addition of the alkene across the cyclopropane of the adduct. In addition, the angular meta photocycloadduct 3 undergoes an alternative fragmentation-translocation photoreaction to afford the silphinene-like angular tricycle 5 (Scheme 1.0). Scheme 1.0: Example of the photochemical reactions of arenyl-diene photosubstrates, including the double [3+2] photocycloaddition reaction. This work presents the investigation of this newly discovered process discussed via the synthesis and subsequent irradiation of a series of photosubstrates, derived from 1, containing different functional groups in the arene-alkene tether.
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