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Towards Organoboron-Mediated Functionalization of Erythromycin a and Synthesis of Its Aglycon

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Towards Organoboron-Mediated Functionalization of Erythromycin a and Synthesis of Its Aglycon Towards Organoboron-mediated Functionalization of Erythromycin A and Synthesis of its Aglycon by Christopher D. Adair A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto © Copyright by Christopher D. Adair 2014 Towards Organoboron-mediated Functionalization of Erythromycin A and Synthesis of its Aglycon Christopher D. Adair Master of Science Department of Chemistry University of Toronto 2014 Abstract Many natural products, including antibiotics, are structurally complex and contain a wide variety of functional groups. As a consequence, the selective functionalization of these molecules often requires the use of inefficient protecting group strategies. Inspired by this obstacle, our group recently developed a borinic acid-catalyzed method to regioselectively functionalize the equatorial position of cis-vicinal diols in carbohydrates with limited use of protecting groups. The work presented in this thesis describes progress made towards selective functionalization of the cis-vicinal diol present in the macrolide antibiotic erythromycin A. This was attempted using the boronic and borinic acid-mediated methodologies developed previously in our group. Finally, a semisynthesis of erythronolide A was carried out with the goal of using our methodology to prepare novel analogues for biological evaluation. ii Acknowledgements There was a time when I believed that personal success was driven solely by hard work and perseverance. While the definition of success is dependent on whom you ask, I think that many will agree that it is very difficult to be successful without the love and support from others. Firstly, I would like to acknowledge my parents. They continue to serve as my primary inspiration and always will. Perhaps unknowingly, they’ve instilled within me a sense of ambition, pride and humbleness that I will always cherish. My mother has always been there to support me through the toughest times of my academic career and, for that, I am forever grateful. My father has served a complementary role, pushing me to realize that I have the potential to accomplish anything that I desire. I should note that my choice to pursue synthetic organic chemistry wasn’t made until the fourth year of my undergraduate career. As such, I have to thank to Professor France- Isabelle Auzanneau for taking a chance on a student with limited synthesis experience. She provided me with a wonderful introduction to carbohydrate chemistry and catalyzed my passion for a very interesting branch of synthesis. I would also like to thank Professor Mark S. Taylor. He taught me how to think like a scientist and suggested a project that challenged me to go above and beyond what I thought possible. A big thank you to the Taylor group! Being a part of such a smart and talented group of people was truly a pleasure. A special thank you to Kyan D’Angelo and Kashif Tanveer for sharing their vast knowledge of chemistry and contributing to many insightful conversations about my work over the year. And of course, I’m thankful for my brother and friends. There were times when I had to make sacrifices to succeed academically and they were always supportive. Lastly, thank you to Craig McDougall for being the best friend anyone could ask for. iii Table of Contents Abstract .................................................................................................................................... ii Acknowledgements .................................................................................................................. iii Table of Contents ..................................................................................................................... iv List of Tables ........................................................................................................................... vi List of Figures .......................................................................................................................... vii List of Schemes ........................................................................................................................ viii Abbreviations ........................................................................................................................... xi Chapter 1: Boron-Diol Interactions 1.0 Introduction ...................................................................................................... 1 1.1 Organoboron methodology in carbohydrate synthesis .................................... 3 1.2 Application of organoboron methodology to natural products ........................ 5 1.3 Conclusions ...................................................................................................... 8 Chapter 2: The Evolution of Antibiotics 2.0 Introduction ...................................................................................................... 10 2.1 Historical overview .......................................................................................... 10 2.2 Antibiotic resistance ......................................................................................... 13 2.3 Exploring new antibiotic landscape with chemical synthesis .......................... 14 2.4 Biosynthesis of novel antibiotic analogues ...................................................... 17 2.5 Conclusions and outlook .................................................................................. 19 Chapter 3: Application of Organoboron-mediated Transformations to Erythromycin A 3.0 Introduction ...................................................................................................... 20 3.1 Biosynthesis of erythromycin A ...................................................................... 21 3.2 Total synthesis of the erythromycins ............................................................... 25 3.3 Acid-catalyzed rearrangements of erythromycin A ......................................... 28 3.4 Semisynthetic analogues of erythromycin A ................................................... 30 3.5 Regioselective functionalization of erythromycin A ....................................... 31 3.6 Research goals ................................................................................................. 33 3.7 Results and discussion ..................................................................................... 34 iv 3.7.1 Organoboron-mediated glycosylation of erythromycin A ................... 34 3.7.2 Organoboron-mediated benzoylation of erythromycin A .................... 37 3.7.3 NMR experiments with erythromycin A ............................................. 44 3.8 Conclusions and outlook .................................................................................. 48 3.9 Experimental details ......................................................................................... 49 3.10 Characterization data ....................................................................................... 50 Chapter 4: Semisynthesis of Erythronolide A 4.0 Introduction ...................................................................................................... 57 4.1 Semisynthesis of erythronolide A .................................................................... 57 4.2 Research goals ................................................................................................. 60 4.3 Results and discussion ..................................................................................... 60 4.4 Conclusions and outlook .................................................................................. 65 4.5 Experimental details ......................................................................................... 67 4.6 Characterization data ....................................................................................... 68 Appendix A: NMR spectra ..................................................................................................... 75 v List of Tables Table 3.1 – Borinic acid-mediated glycosylationa .................................................................. 35 Table 3.2 – Boronic acid-mediated glycosylationa ................................................................. 36 Table 3.3 – Organoboron-mediated benzoylation at 23 °Ca ................................................... 39 Table 3.4 – Organoboron-mediated benzoylation at 80 °Ca ................................................... 41 vi List of Figures Figure 1.1 – Deprotected pentasaccharide target of our synthesis (1.1) and pentasaccharide derived target of the Du synthesis (1.2) ........................................................ 7 Figure 2.1 – Dimer, trimer and pentamer forms of arsphenamine (Salvarsan) effective for treating syphilis ........................................................................................................................ 11 Figure 2.2 – Selected antibiotics discovered in the 20th century of historical importance ..... 12 Figure 2.3 – Overview of the cephalosporin scaffold and examples of modern adaptations ............................................................................................................................... 15 Figure 3.1 – Components of the macrolide antibiotic erythromycin A .................................. 20 Figure 3.2 – Polyketide synthase-mediated chain elongation process to form 6- deoxyerythronolide B [adopted from (47)] .............................................................................
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