Aziridines and their asymmetric conversion to bioactive compounds Approaches to terpestacin, oseltamivir and analogues Saúl Alves Graça Santos Silva Dissertation presented to obtain the degree of Doctor in Chemistry Instituto de Tecnologia Química e Biológica António Xavier | Universidade Nova de Lisboa Oeiras, September, 2017 Aziridines and their asymmetric conversion to bioactive compounds Approaches to terpestacin, oseltamivir and analogues Saúl Alves Graça Santos Silva Thesis supervisor: Professor Dr. Christopher D. Maycok Head of the Organic Synthesis Laboratory at Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa and associate professor at Faculdade de Ciências da Universidade de Lisboa This work was performed in the Organic Synthesis Laboratory at the Instituto de Tecnologia Química e Biológica, António Xavier, Universidade Nova de Lisboa. This work was supported by Fundação para a Ciência e Tecnologia and Fundo Social Europeu within the scope of Quadro Comunitário de Apoio through a PhD grant to Saúl Silva (SFRH/BD/84309/2012). “No one can pass through life, any more than he can pass through a bit of country, without leaving tracks behind, and those tracks may often be helpful to those coming after him in finding their way.” Robert Stephenson Smyth Baden-Powell Acknowledgments Acknowledgments Acknowledgements For this work I had the support of many people, some of them I had the good fortune to meet during this period, and I would like to express here my gratitude: To my supervisor, Prof. Maycock, for all the years working in his group. I wish to thank him for his support and trust and the challenging scientific discussions. I thank him also for providing me with such a well-equipped laboratory and his effort to keep everything working properly and for always being present whenever needed. I am glad to have had as supervisor someone who knows so much about chemistry and to have learned so much with him. To Dr. Rita Ventura for the support and the scientific work developed that served as base for this work. I wish you all the success as the excellent researcher you are. To Prof. Teresa Barros for her support and encouragement. To all my colleagues from the organic synthesis and bioorganic chemistry laboratories: Eva Lourenço; Filipa Almeida; João Cascão; Naiara Fernandez; Osvaldo Ascenso; Paula Rodrigues; Sofia Miguel; Vanessa Miranda; and others. Thank you for all the fun moments, for mutual respect, for the help and the stimulating environment. Having you as colleagues and friends was one of the most important things to make these 4 years equally pleasant and productive. I wish you all the best, because you are excellent and very talented people. To all my colleagues at the PhD course at ITQB. I’m glad to have met so many talented scientists during the course, that I can now call friends. We had many happy moments and always supported each other. I hope to see you with a successful scientific career and consequently we can collaborate in the future. ix Acknowledgements To ITQB-Nova for accepting me as a PhD student and providing such a multidisciplinary environment for their students. Also, a special thank you to researchers and professors involved in the PhD course, for all their effort and commitment. For the financial support, from the Fundação para Ciência e Tecnologia and Fundo Social Europeu within the scope of Quadro Comunitário de Apoio through the PhD grant SFRH/BD/84309/2012. To CERMAX for the NMR facilities, which are part of The National NMR Facility, supported by Fundação para a Ciência e a Tecnologia (RECI/BBBBQB/0230/2012). Special thanks to Helena Matias, who helped in some of the NMR experiments and maintained the machines. To the Analytical Services Unit, for the services provided. To my family and friends, for all their support. Particularly to my mother, who has always supported me in all my projects during my entire life. To my wife and son, a new family that was built during the same time as this work, thank you for all the happiness and comfort. Last but not least, to my sister and nephews. x Table of contents Table of contents Table of contents Acknowledgments................................................................................................ vii Table of contents .................................................................................................. xi Abbreviations ...................................................................................................... xxi Abstract ..............................................................................................................xxix Resumo ............................................................................................................ xxxiii Chapter 1 General Introduction ............................................................................. 1 Organic synthesis ............................................................................................... 3 Strategies for optically active molecules synthesis ............................................ 5 Aziridines ............................................................................................................ 9 Cyclic acylaziridines (azabicyclo[x.1.0]alkane-2-ones) ..................................... 12 Objectives ......................................................................................................... 14 Chapter 2 Asymmetric synthesis of cyclic 4-hydroxyacylaziridines via enzymic resolution ............................................................................................................. 17 Abstract ............................................................................................................ 19 Introduction...................................................................................................... 19 Preparation of racemic cyclic 4-hydroxyacylaziridines .................................... 21 Enzymic resolution ........................................................................................... 23 Conclusion ........................................................................................................ 27 Chapter 3 Terpestacin synthesis preliminary attempts ....................................... 29 Abstract ............................................................................................................ 31 Introduction...................................................................................................... 31 1st attempt ........................................................................................................ 33 2nd attempt ....................................................................................................... 36 3rd attempt ....................................................................................................... 40 Aziridine invertomers ....................................................................................... 47 xiii Table of contents Conclusion ........................................................................................................ 52 Chapter 4 Oseltamivir and tamiphosphor synthesis ........................................... 53 Abstract ............................................................................................................ 55 Introduction...................................................................................................... 55 Oseltamivir synthesis ....................................................................................... 59 Tamiphosphor synthesis .................................................................................. 61 Tamisulfur ......................................................................................................... 64 Conclusion ........................................................................................................ 67 Chapter 5 Alpha-chlorination of carbonyls under basic conditions using methyl chlorosulfate ........................................................................................................ 69 Abstract ............................................................................................................ 71 Introduction...................................................................................................... 71 Preparation of α-chloroketones ....................................................................... 72 Chlorination of substrates containing different functional groups ................. 75 Chlorination of mixtures of compounds .......................................................... 79 Conclusion ........................................................................................................ 83 Chapter 6 Sulfur abstraction under basic conditions .......................................... 85 Abstract ............................................................................................................ 87 Introduction...................................................................................................... 87 Reaction with β-oxo xanthates ........................................................................ 89 Reaction with β-oxo thioacetates .................................................................... 93 Reaction with different functional groups ....................................................... 95 Conclusion ...................................................................................................... 101 Conclusion .........................................................................................................