Transition Metal Catalysed Reactions for the Synthesis of Heteroaromatic Compounds Stephen Christopher Pelly A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Doctor of Philosophy January 2007 DECLARATION I declare that the work presented in this thesis was carried out exclusively by myself under the supervision of Professor C.B. de Koning. It is being submitted for the degree of Doctor of Philosophy in the University of the Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination in any other University. _________________ 27th day of January, 2007 i ABSTRACT The carbazole and 2-isopropenyl-2,3-dihydrobenzofuran structures are widely found in many naturally occurring compounds. For example, the naturally occurring anti-cancer compound, rebeccamycin, contains an indolocarbazole core. Rotenone, which contains an (R)-2-isopropenyl-2,3-dihydrobenzofuran moiety, is widely used today as an effective naturally occurring pesticide. In the carbazole section of this thesis, the synthesis of the naturally occurring furanocarbazole, furostifoline is described. As key steps in this sequence, a Suzuki coupling reaction is utilised to couple appropriately functionalised indole and furan moieties. After further functional group transformations, a metathesis reaction is employed to construct the carbazole system, leading to furostifoline. The synthesis of the unnatural thio-analogue of furostifoline was similarly conducted and is described. Finally, in a somewhat different approach, the synthesis of the indolocarbazole core is described, utilising a Madelung approach initially to form the bis-indole system, 2,2’-biindolyl. After several functional group transformations, a metathesis reaction was once again successfully employed to form the carbazole system, thereby synthesising di(tert-butyl) indolo[2,3-a]carbazole-11,12-dicarboxylate. In the benzofuran section of this thesis, the successful chiral synthesis of two 2- isopropenyl-2,3-dihydrobenzofuran systems is described. As a precursor to rotenone, the synthesis of (R)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol is described starting from resorcinol. The key step in this synthesis is a stereoselective intramolecular Pd π-allyl mediated cyclisation utilising the R,R’-Trost ligand, thereby forming (R)-2-isopropenyl- 2,3-dihydrobenzofuran-4-ol in excellent yield and enantiomeric excess. The alternative enantiomer, (S)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol, was similarly synthesised. Finally, a similar approach was utilised to synthesise both (S)- and (R)-2-isopropenyl-2,3- dihydrobenzofuran, starting from 2-allyl-phenol, and thereby completing a formal synthesis of the naturally occurring compounds, (S)-fomannoxin and (R)-trematone, respectively. ii ACKNOWLEDGMENTS Personal acknowledgments First and foremost, to my supervisor, Professor Charles de Koning, for his guidance and wisdom in this project, but so much more so for his guidance and wisdom for life. You were, and continue to be an inspiration to me, both in and out of chemistry. Professor J.P. Michael, with whom many valuable discussions led to interesting and valuable results – more importantly, these humbling discussions made me realise just how little I really know. Thank you to Dr W.A.L. van Otterlo, Dr C.J. Parkinson and Dr A. Dinsmore for many helpful discussions. To my family – My mother, and my sisters Tina and Lynne, whose support and encouragement was just wonderful. Without you, this PhD would not have been possible. Family truly is everything. Mr Richard Mampa for the seemingly endless amount of NMR spectra – without you, all we would have is a yellow splodge at the bottom of a flask. I also express my gratitude to Mr Tommy van der Merwe for the similarly numerous mass spectral analyses. For the crystallographic analyses, I’d like to thank Dr Manuel Fernandes and Andreas Lemmerer. To all the guys and girls in the lab – specifically (and in no particular order), Sameshnee, Darren, Jenny, Eddie, Simon, Phil, Angie and Garreth. And let’s not forget Theo, whom by now I hope has finally come to realisation that when you spray water on the girls three floors below and they run away screaming, it’s probably NOT because they like it. I’m going to miss you weirdo’s. A special mention to Joni who is so pure in heart, and kind in every thought and deed. You are constantly in my thoughts, and how I hope the sun will always shine warmly upon you. To Dr Mandy Rousseau who so kindly edited large parts of this thesis when I just couldn’t bear to look at it any more – and promptly kicked me in the foot if I didn’t keep those chapters coming. And finally, to my closest friend and lifelong partner, Sameshnee Govender. Who would have thought that we could come from such different worlds and yet we think so alike, and dream such similar dreams. How I look forward to a wonderful journey with you. Moreover, this thesis would probably never have been written were it not for you giving me numerous scoldings, forcing me to sit in front of my computer and threatening to take away my motorbike. It’s all about the right motivation. iii Actually, if I may squeeze in one more – to Samesh’s mother Mrs G (otherwise known as Mom-in- law, or battle-axe), who, besides having a heart of gold could never quite grasp the fact that although I am studying at University I don’t actually write exams to complete this degree. May I just say, yes, I have finished studying now (er, I’ve written the exams), but no, this does not mean that babies are forthcoming – well, not as far as I know anyhow. Acknowledgements for funding Without the funding I received, this PhD would not have been possible and I would like to express my sincere appreciation to the following organisations: To the CSIR, for their generous bursary, as well as for the opportunity to continue working in this field I love upon completing my PhD. The University of the Witwatersrand for several scholarships and awards, including the Post Graduate Merit Award, the Backeberg Scholarship and the University Council Award. iv Declaration ........................................................................................................................................................ i Abstract.............................................................................................................................................................ii Acknowledgments...........................................................................................................................................iii Personal acknowledgments .....................................................................................................................................iii Acknowledgements for funding ..............................................................................................................................iv PREFACE.........................................................................................................................................................XII A note to the reader ........................................................................................................................................xii Regarding the thesis layout.......................................................................................................................xii Interpretation of 1H NMR spectra and 13C NMR spectra.........................................................................xii CHAPTER 1 - ABOUT CARBAZOLE ALKALOIDS ................................................................................... 1 1.1 An introduction to carbazole based natural products........................................................................... 1 1.1.1 The isolation of interesting carbazoles and associated biological activity .................................. 1 1.1.2 Indolo[2,3-a]pyrrolo[3,4-c]carbazoles, and the cell cycle ......................................................... 10 1.1.3 A new generation of potent Ru containing carbazoles............................................................... 13 1.2 Selected syntheses of carbazole compounds...................................................................................... 16 1.2.1 Total syntheses of furostifoline................................................................................................... 16 1.2.1.1 The first total synthesis of furostifoline – An iron mediated synthesis...............................................16 1.2.1.2 An improved iron mediated synthesis..................................................................................................18 1.2.1.3 A Stille coupling and oxidative photocyclisation method ...................................................................19 1.2.1.4 Thermal electrocyclisation of a 2,3-disubstituted indole.....................................................................21 1.2.1.5 Cyclisation using a nitrene ...................................................................................................................23 1.2.1.6 Synthesis of furostifoline by a tetrabutylammonium fluoride promoted ring formation....................24 1.2.2 Selected syntheses of indolo[2,3-a]carbazoles and ruthenium carbazole complexes ............... 26 1.2.2.1 Synthesis of the indolo[2,3-a]carbazole core.......................................................................................27 1.2.2.2 Total synthesis of staurosporinone.......................................................................................................30