SYNTHESIS OF 3,4-PYRROLIDINE-FUSED BICYCLIC b-LACTAMS AS POTENTIAL b-LACTAMASE INHIBITORS Bram Van Den Bossche Student number: 01507249 Promoter: prof. dr. ir. Matthias D’hooghe Tutor: ir. Sari Deketelaere Master’s Dissertation submitted to Ghent University in partial fulfilment of the requirements for the degree of Master of Science in Bioscience Engineering: Chemistry and Bioprocess Technology Academic year: 2019-2020 SYNTHESIS OF 3,4-PYRROLIDINE-FUSED BICYCLIC b-LACTAMS AS POTENTIAL b-LACTAMASE INHIBITORS Bram Van Den Bossche Student number: 01507249 Promoter: prof. dr. ir. Matthias D’hooghe Tutor: ir. Sari Deketelaere Master’s Dissertation submitted to Ghent University in partial fulfilment of the requirements for the degree of Master of Science in Bioscience Engineering: Chemistry and Bioprocess Technology Academic year: 2019-2020 Deze pagina is niet beschikbaar omdat ze persoonsgegevens bevat. Universiteitsbibliotheek Gent, 2021. This page is not available because it contains personal information. Ghent Universit , Librar , 2021. ACKNOWLEDGEMENTS Tempus fugit. In the perpetuum mobile of everyday life, it is astonishing how time flies, and how quickly and unnoticeably days pass into weeks, which become months, and eventually turn into years. My journey of becoming a bioscience engineer, which set out five years ago, now comes to an end. Throughout this demi-decade of exploratory turmoil, I have grown substantially on both an intellectual and personal level. Student life at the "Boerekot" has given me all I could have asked for, and more. Intrigued by nature in all its aspects, the bachelor courses satisfied my curiosity by providing a broad basis in the various scientific fields, while the last two master years allowed me to dig deeper into the wondrous world of organic chemistry, for which I genuinely have grown a profound intrinsic passion. Furthermore, Fortuna bestowed on me the marvellous opportunity of gaining valuable experiences and forging some lifelong friendships. To conclude these joyful times in Ghent and beyond, I am delighted and extremely proud to present this Master’s thesis as the pièce de résistance of my studies and as a token for what was, and what is to come. In that respect, I wish to acknowledge and express my gratitude to all people, without whom this work could not possibly have been accomplished. In the first place, thanks are due to my promoter, prof. D’hooghe, for numerous reasons. To this very day, your reactivity in organic chemistry course remains my favourite, not in a small way because the vim and vigour, with which you taught, grasped my immediate attention and helped pass along your enthusiasm for and knowledge of the field. It is the cornerstone for my current scientific interests, and it made doing my Master’s thesis at the SynBioC research group feel like the only right decision for me. I thank you for having granted me this incredible opportunity, and moreover for honouring my wish of getting a thesis subject, which fully focused on organic synthesis and the chemistry, per se. During the course of past year, you provided me with all kinds of helpful advice, and I really appreciate the positive ambience that was ever-present midst our monthly meetings. Sari, you rightfully deserve a sincere thank you as I am very glad to be able to call you my tutor. I think that the combination of a cheerful vibe, a patient and supportive nature, a strong eye for detail, and keen intellect is all what one could ask for. I know it has been a busy year for you, having multiple thesis students, which is why your willingness to put aside your work when I was in need of help is appreciated even more, as well as your swift and thorough corrections of my thesis. In addition, I want to thank you for allowing me the freedom of exploring ideas of my own, and for the trust you have put in me by giving me this level of independence. However, when facing problems, whether it were difficult reactions, laborious purifications, or challenging structural elucidations, I could always count on your in-depth knowledge and chemical expertise, as I knew I could. For all this, I am truly grateful. Next, I wish to properly thank everyone, who contributed to making the SynBioC laboratory not only a professional and energetic research environment, but also a place with a great atmosphere. To that end, I say thank you to prof. Stevens, prof. Mangelinckx, Pieter, Maarten, Els, Ans, and all PhD students. A special thanks goes to Carlos, who made my first few weeks of practical work even more pleasant, and whose chemical experience and preliminary research really kick-started my Master’s thesis. Furthermore, I thank my fellow thesis students, with whom I have grown close in the past year. My fifth floor boys Jordy, Bjarne and Helder; my fifth floor girls Dalia and Cato; my fourth floor flow fellas Nick, Renaat, Stefan, Ewoud, Lies, Jef and Hanne: because of you all and the many laughs we shared, every moment in the lab was a joy, as were the unforgettable moments outside of it. Lastly, I would like to mention my closest friends among the vast amount of happy souls and memorable people I was lucky to have encountered along the course of my student life. My Ghent buddies Annelien, Arthur, Cedric, Elias, Fien, Guillaume, Julie, Nick, Renaat, Stijn and Wolf; my Erasmus buddies Nicolas, Théo and Timon: I am extremely grateful for having met all of you, for the awesome times we have had, and for those which are still to come. To finish, I say the biggest thank you of all to my parents and sisters, whose aid, encouragement and support is unconditional and beyond question, as I know it always will be. With this chapter of my life concluding, I look forward, excited. I seek to broaden my view, to explore the world, to further discover myself, to be amazed. Additionally, I wish to be engulfed by what organic chemistry undoubtedly still has to offer, and I hope to fulfil my ambition of pursuing a fruitful career of research in this fascinating field. How I wonder things will turn out. Sic Parvis Magna. Bram Van Den Bossche, June 5th, 2020 v PREAMBLE This preamble was drawn up in mutual agreement between the author and the promoter. During the course of this Master’s thesis, a new human coronavirus, i.e. SARS-CoV-2, emerged in Wuhan, China, in late 2019. Ever since, it spread rapidly on a global scale, making that by spring 2020 this virus, and the pneumonia disease it causes (COVID-19), had grown to pandemic proportions. In compliance with the stringent measures imposed by the Belgian government, safety measures were taken by Ghent University in an effort to slow down the spread of the virus as much as possible. All research activities within the context of a Master’s thesis, which required physical presence on Ghent University premises, had therefore to be terminated immediately as of March 19th, 2020. Due to the early cease of lab work, i.e. one month prior to the expected date, some of the goals set for this Master’s thesis could not be achieved. Concretely, it has resulted in: (i) incomplete characterisation data for some of the novel b-lactam compounds in this work; (ii) no further experiments in order to clarify the outcome of some reactions; (iii) no new experiments in order to synthesise some of the initial target structures. The relevance of constructing latter molecules and their proposed synthetic procedures will be elaborated among other perspectives near the close of this Master’s thesis (section 3.4) as a guideline for future research that might wish to continue on the results achieved in this work. vii TABLE OF CONTENTS Note about copyright iii Acknowledgements v Preamble vii List of abbreviations xi 1 SCOPE AND GOAL 1 1.1 Scope . .1 1.2 Goal . .4 2 LITERATURE OVERVIEW 7 2.1 Synthesis of C -fused bicyclic b-lactams starting with the b-lactam . .7 2.1.1 Intramolecular nucleophilic attacks . .7 2.1.1.1 Halocyclisations . .8 2.1.1.2 Intramolecular nucleophilic substitutions of non-halogen leaving groups . 10 2.1.2 Intramolecular pericyclic reactions . 12 2.1.2.1 Alkene-allenol [2+2] cycloadditions . 12 2.1.2.2 Domino [3+3] sigmatropic rearrangement/Diels-Alder reactions . 13 2.1.2.3 1,3-Dipolar cycloadditions . 15 2.1.2.4 Lewis acid-promoted carbonyl-ene cyclisations . 16 2.1.3 Other reaction types . 16 2.2 Synthesis of C -fused bicyclic b-lactams starting with the ring structure . 18 2.2.1 Alkene-isocyanate [2+2] cyclocondensations . 18 2.2.2 Transition metal-catalysed cyclisations . 19 2.2.2.1 Palladium- and copper-catalysed reactions via C(sp3)-H bond activation . 19 2.2.2.2 Manganese-catalysed reactions via C(sp2)-H bond activation . 21 2.2.3 Ugi four-center three-component reactions . 21 2.2.4 Group transfer radical cyclisations with dithiocarbamates . 22 2.3 Synthesis of C -fused bicyclic b-lactams starting with acyclic precursors . 22 2.3.1 Organocatalysis with N -heterocyclic carbenes . 22 2.3.2 One-pot [1C+2C+1N] three-component synthesis in ionic liquids . 23 2.4 Biological activity of C -fused bicyclic b-lactams . 24 2.5 Conclusion . 28 3 RESULTS AND DISCUSSION 30 3.1 Synthesis of cis-3-acylamino-4-(3-phenyloxiran-2-yl)azetidin-2-ones . 31 3.1.1 Staudinger b-lactam synthesis of cis-3-phthalimido-4-((E)-styryl)azetidin-2-one building blocks . 31 3.1.2 N -phthaloyl deprotection and subsequent N -acylation of cis-3-phthalimido- 4-((E)-styryl)azetidin-2-ones .