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Divergent Synthesis of Cyclopropane-Containing Fragments and Lead-Like Compounds for Drug Discovery

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Divergent Synthesis of Cyclopropane-Containing Fragments and Lead-Like Compounds for Drug Discovery Divergent Synthesis of Cyclopropane-Containing Fragments and Lead-Like Compounds for Drug Discovery A Thesis submitted by Stephen John Chawner In partial fulfilment of the requirement for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry Imperial College London South Kensington London SW7 2AZ United Kingdom 2017 1 I confirm that the work presented within this document is my own. Clear acknowledgement has been made when referring to the work of others, or where help has been received. The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 2 Acknowledgements Firstly, I would like to thank Imperial College London and Eli Lilly whose combined generosity through a CASE award made my PhD financially possible. I would like to thank my academic supervisor Dr James Bull for providing me with the opportunity to undertake a PhD in his group. I am grateful for the chemistry knowledge that he has shared, his encouragement to present at conferences and the freedom to follow new project ideas. In addition to funding, the CASE award provided me with the opportunity to collaborate with Dr Manuel Cases-Thomas at Erl Wood. Manuel was a constant source of enthusiasm throughout my PhD and has been a joy to work with. I would like to thank all the Bull, Armstrong and Bures groups, past and present, with whom I have had the pleasure to work alongside in the Heilbron lab. In particular, I would like to thank Dr Tom Boultwood for his early and valuable training on glovebox usage, Dr Owen Davis for the countless discussions on the applications and benefits of cyclopropanes and oxetanes within medicinal chemistry, and Dr Dominic Affron for sharing his extensive theoretical and practical chemistry knowledge, as well as his experiences with Swern reactions. In addition, I would like to thank Owen, Dom, Ethan, Rosie and Sahra for reading through sections of this thesis and providing valuable feedback. Thank you to all the scientists with whom I worked with whilst on my industrial placement at Erl Wood; you made my time there a fantastic experience. In addition, I would particularly like to thank the Eli Lilly HPLC and crystallography teams whose efforts are very much appreciated. I am grateful to the NMR staff at Imperial College London as well as the mass spectrometry staff at both Imperial College London and the EPSRC mass spectrometry centre. 3 I would like to thank Lisa for being supportive over the last few years and putting up with all the chemistry talk. I want to thank my late grandparents James and Joan, for helping me along the scientific path from an early age. Finally, I wish to express my utmost gratitude to my parents, John and Ann, for all their love and encouragement throughout the years. Their support helped give me the strength to overcome the challenges that stood between where I was and where I wanted to be. 4 Abstract The cyclopropane ring is key to a large number of medicinally-relevant compounds that possess a broad spectrum of biological activities. This thesis details the preparation of novel bifunctional cyclopropanes through a divergent functionalisation approach utilising two readily accessible cyclopropyl-scaffolds (Figure 1). The cyclopropanes generated sampled new areas of chemical space whilst being suitable 3-dimensional fragments and lead-like compounds for drug discovery. A) B) CO2Et CO2Et EtO2C Cyclopropanation SPh A N 2 SPh SPh Bifunctional B cyclopropyl scaffolds Figure 1: A) General concept for a bifunctional cyclopropyl-scaffold able to undergo divergent functionalisation on functional handles A and B. B) Synthesis of bifunctional cyclopropyl-scaffolds A novel CoII-catalysed cyclopropanation generates two diastereoisomeric bifunctional cyclopropyl-scaffolds from commercially available reagents in an excellent yield and can be conducted on multi-gram scales. Asymmetric cyclopropanation has been explored with max ee = 73%. Divergent functionalisation of the ester was explored, utilising hydrolysis, reduction and amidation reactions to create a variety of functionalised cyclopropyl sulfides. The sulfide synthetic handle was oxidised to give the corresponding sulfoxides or sulfone selectively. Sulfoxide–magnesium exchange was explored and the cyclopropyl-organometallic species generated was trapped with a variety of electrophiles to create a diverse range of cyclopropane-containing products. The cyclopropyl-organometallic species was also utilised in Negishi cross-coupling, proving to be a versatile method to attach an aromatic or heteroaromatic directly onto the cyclopropane ring. CO2Et Electrophile CO2Et CO2Et RMgX E Ph S MgX CO Et O (Het)aryl-X 2 (Het)aryl Scheme 1: Divergent functionalisation of the trans-substituted cyclopropyl-scaffold via sulfoxide–magnesium exchange followed by either electrophilic trapping or cross-coupling. The same methodology has been used to functionalise the cis-substituted cyclopropyl scaffold too. 5 Table of Contents a) Glossary of Abbreviations, Acronyms and Symbols .................... 9 b) Stereochemical Notation ................................................................ 13 1. Introduction ..................................................................................... 14 1.1. Overview of the Drug Discovery Process ................................................. 14 1.2. Attrition in Drug Discovery ......................................................................... 15 1.3. Introduction to Chemical Space as a Tool for Medicinal Chemists ........ 18 1.4. Molecular properties for Drug-Like Compounds ...................................... 19 1.4.1. Molecular weight (MW) ....................................................................... 20 1.4.2. Lipophilicity ........................................................................................ 21 1.4.3. Polar Surface Area (PSA) .................................................................. 22 1.4.4. Fsp3 ..................................................................................................... 22 1.4.5. Aromatic Ring Count ......................................................................... 23 1.4.6. Undesirable Functional Groups ........................................................ 23 1.5. Physicochemical Guidelines for Drug-Like Compounds ........................ 23 1.6. Compound Library Construction Approaches ......................................... 25 1.6.1. Combinatorial Chemistry .................................................................. 25 1.6.2. Lead-Oriented Synthesis (LOS) ........................................................ 27 1.6.3. Fragment-Based Drug Discovery (FBDD) ........................................ 29 1.7. Cyclopropanes within Drug Discovery ...................................................... 34 1.8. Common Methods to Synthesise Functionalised Cyclopropanes ......... 37 1.8.1. Michael-Initiated Ring Closure (MIRC) ............................................. 37 1.8.2. Simmons-Smith Cyclopropanation .................................................. 41 1.8.3. Diazo Compound-Derived Carbene Insertion into an Alkene ........ 44 1.8.4. Cross-Coupling of a Pre-Functionalised Cyclopropyl-Species ..... 53 1.9. Project Aims ................................................................................................. 55 2. Results and Discussion ................................................................. 58 2.1. Transition Metal-Catalysed Cyclopropanation of Phenyl Vinyl Sulfide with Ethyl Diazoacetate ............................................................................... 58 2.1.1. Bomb Calorimetry of PVS, EDA and Product Cyclopropanes ....... 59 2.1.2. CuI-Catalysed Cyclopropanation of PVS with EDA ......................... 61 6 2.1.3. CoII-Catalysed Cyclopropanation of PVS with EDA ........................ 77 2.1.3.1. CoII-Catalysed Cyclopropanation Optimisation ...................... 76 2.1.3.2. Purification of Large-Scale Cyclopropanation Reactions ..... 82 2.1.3.3. Open-Flask CoII-Catalysed Cyclopropanation ........................ 93 2.1.3.4. Cyclopropanation of Alternative Reagents ............................. 97 2.1.3.5. Conclusions ............................................................................. 101 2.1.4. Asymmetric Transition Metal-Catalysed Cyclopropanation ........ 102 2.1.4.1. Asymmetric CuI-Catalysed Cyclopropanation of PVS with EDA ............................................................................................... 106 2.1.4.2. Asymmetric CoII-Catalysed Cyclopropanation of PVS with EDA ............................................................................................... 110 2.1.4.3. Isolation and Characterisation of Single Enantiomers ........ 121 2.1.4.4. Conclusions ............................................................................. 123 2.2. Scaffold Functionalisation: Ester Derivatisation .................................... 125 2.2.1. Hydrolysis ......................................................................................... 125 2.2.2. Amidation .......................................................................................... 127 2.2.3. Reduction
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