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Strategies for the Synthesis of Glycosylated Small Molecule University of Connecticut Masthead Logo OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 4-11-2019 Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds Zachary Cannone University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Cannone, Zachary, "Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds" (2019). Doctoral Dissertations. 2089. https://opencommons.uconn.edu/dissertations/2089 Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds Zachary Cannone Ph.D., University of Connecticut, 2019 Abstract: The synthesis of glycosylated small molecule compound libraries remains a difficult challenge in the field of organic chemistry. Leading techniques are hindered by the requirement of optimization based on substrate, and the generation of non-classical glycoside products. The development of a platform which takes advanced glycoside intermediates and utilizes reactive handles on the aglycone for rapid diversification to final products has been completed in this research. Use of amino sugars, derived from known antibiotics, as the carbohydrate component of final compounds was intended to exploit known binding interactions with biomacromolecules. Final compounds indeed showed ability to inhibit bacterial protein synthesis in vitro and limit growth in culture, suggesting binding interactions were retained. Development of new generations of therapeutics based on current classes of antibiotics remains a primary means of new drug discovery. The aminoglycoside family of antibiotics is no exception to this, as current members of this class show promise of improved pharmacological properties with diversification to their structures. Studies have been conducted but have not addressed novel alkylation patterns on the amino sugar component of these compounds. In this work we have shown the development of a synthetic methodology to access mono-, di-, and mixed- alkyl kanosamine sugars. Elaboration to glycosides and subsequent diversification efforts have led to the finding of novel bacterial protein synthesis inhibitors. New catalytic methodologies can lead to powerful synthetic transformations which would be inaccessible or of great difficulty otherwise. In particular, asymmetric hydrogenation reactions, while simple in terms of chemical transformation, yield enantiomerically pure compounds which are of great importance to drug discovery efforts. In this work, the use of prochiral starting materials and an Iridium based catalytic system using bidentate chiral phosphine ligands has been shown to yield a wide range of 2-substituted 1,4-benzodioxanes with excellent enantioselectivities. Compound bearing this chemical motif are known to be privileged structures in medicinal chemistry and have great potential for further development to lead compounds. Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds Zachary Cannone B.S., University of Connecticut, Storrs, CT 06269 A dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut [2019] i Copyright by Zachary Cannone [2019] ii APPROVAL PAGE Doctor of Philosophy Dissertation Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds Presented by Zachary Cannone, B.S. Major Advisor ___________________________________________________________________ Mark W. Peczuh Associate Advisor ___________________________________________________________________ Nicholas Leadbeater Associate Advisor ___________________________________________________________________ Dennis Wright University of Connecticut [2019] iii Acknowledgements First and foremost, I would like to thank my family for their love and support during the course of my graduate career, and throughout my life. Particular appreciation is given to my parents, whose unbounding love have kept me driven, motivated, and focused. The work presented in this thesis would not have come to fruition without their instilling a desire to pursue higher education and bettering myself. For that, I dedicate this work to them. A very special thank you is extended to my advisor, mentor, and sage, professor Mark W. Peczuh. The wisdom and patience he has displayed in the course of our time together has guided me to become not just a better scientist, but a better person. I will forever be grateful for the advice and support he has extended, and hope to continue to view him as a mentor as I embark on my post graduate career. I would like to thank the chemical development team at Boehringer Ingelheim for my time their as an intern. My mentors, Eugene Chong, and Bo Qu displayed great patience and a true desire to teach the techniques and skills required in an industrial setting. I look at this work as rounding off my graduate training as a chemist, and as an enlightening period in my life. Lastly, a very sincere thank you to my best friends, sons, and muses; King Guaps Donald Hulio Esperanzo Poops, First of his name, Duke of Enfield, Ruler of Kingdom 778A and Prince Oliver Sebastian Bojangles Poops, First of his name, Duke of Willington, and rightful heir to the throne of Kingdom 778A *With the submission and acceptance of this dissertation, by virtue of the authority vested in me by the University of Connecticut as an alumnus (B.S. 2013, Ph.D. 2019), I hereby confer the degree of honorary co-PhD to the aforementioned Guaps and Oliver, and do declare they are entitled to all rights, honors, privileges, titles, and responsibilities bestowed by such degree. iv Table of contents 1. Post Glycosylation Diversification 1-2 1.1. Introduction to antibiotics 3-7 1.2. Classes of antibiotics 7-9 1.3. Carbohydrate library synthesis 9-15 1.4. Fluorescent probes used in drug discovery 15-20 1.5. Project design 20-22 1.6. Results and discussion 22-41 1.7. Conclusion 41 1.8. Experimental 42-56 1.9. References 57-62 2. A Versatile Method for the Preparation of Alkylated Kanosamine Sugars 63-4 2.1. Introduction to amines 65 2.2. synthetic utility of amines 65-69 2.3. Aminoglycosides 69-72 2.4. Mechanism of action 72-73 2.5. Resistance mechanisms and diversification efforts 73-79 2.6. Project design 79 2.7. Results and discussion 79-92 2.8. Conclusion 92 2.9. Experimental 93-146 2.10. References 147-150 v 3. Iridium Catalyzed Hydrogenations to Access 2-substituted 1,4-benzodioxanes 151-2 3.1. Introduction to catalysis 153 3.2. Developments of hydrogenation reactions 153-155 3.3. Homogeneous catalysis 155-158 3.4. 2-substituted 1,4-benzodioxanes 158-164 3.5. Project design 164-165 3.6. Results and discussion 165-180 3.7. Conclusion 180 3.8. Experimental 181-204 3.9. References 205-208 vi List of schemes 1.1. Glycorandomization of vancomycin aglycone 12 1.2. Neo glycorandomization 13 1.3. “Building block” strategy for macrolide total synthesis 14 1.4. Post Glycosylation Diversification (PGD) 21 1.5. Synthesis of thioglycoside donor from erythromycin 23 1.6. Glycosylation to PGD intermediates 26 1.7. Synthesis of hydroxymethyl acceptor 34 1.8. Synthesis of modified aglycone mesityl derivatives 35 1.9. Synthesis of erythromycin-BODIPY probe 38 1.10. Initially proposed lincosamide probe and E2 elimination product 39 1.11. Synthesis of lincosamide-BODIPY probe 40 2.1. Azithromycin semisynthesis from erythromycin 66 2.2. Alkylation with alkyl halides 68 2.3. Aryl amines via Buckwald-Hartwig coupling 69 2.4. Techniques for the mono alkylation of amines 70 2.5. Synthesis of dimethyl kanosamine through key triflate intermediate 80 2.6. Acid catalyzed diacetonide cleavage 83 2.7. Mono deprotection of dimethyl diacetonide substrate 83 2.8. One pot mixed alkylation to dialkyl peracetyl kanosamine 85 2.9. Synthesis of neamine glycosyl acceptor and dimethyl kanosamine thioglycoside donor 86 2.10. Kanosamine lactol to anomeric bromide glycosyl donor 90 vii 2.11. Palladium coupling diversifications on kanosamine PGD intermediates 91 2.12. Cylcoaddition diversifications of kanosamine PGD intermediate 91 3.1. Hydrogenation of molecular oxygen 154 3.2. Hydrogenation of carbon dioxide 154 3.3. Hydrogenation of molecular nitrogen 155 3.4. General transformation from prochiral starting material 165 3.5. Synthesis of 2-bromo 1,4-benzodioxine starting material 166 viii List of tables 1.1. Proof of concept alkyl and macrolide glycosylations 24 1.2. Desosamine PGD cycloaddition derivatives 27 1.3. Desosamine PGD aminoethyl derivatives 28 1.4. Desosamine PGD palladium coupling meta derivatives 30 1.5. MIC data for meta PGD derivatives 31 1.6. Desosmaine PGD palladium coupling para derivatives 32 1.7. MIC data for para PGD derivatives 33 1.8. MIC data for modified aglycone mesityl derivatives 36 2.1. C-4 modified kanamycin derivatives and their MIC activity 76 2.2. Conformationally constrained kanamycin derivatives and their MIC activity 77 2.3. Kanosamine modified kanamycin derivatives and their MIC activity 78 2.4. Mono and di alkylations of diacetonide substrate 81 2.5. Mixed alkylations of diacetonide substrate 83 2.6. Glycosylations of dimethyl kanosamine anomeric bromide 90 3.1. Rhodium catalyzed asymmetric hydrogenation route to 1,4-benzodioxanes 163 3.2. Iridium catalyzed asymmetric hydrogenation route to 1,4-benzodioxanes 164 3.3. Ligand screen on 2-cycloproply test substrate 167 3.4. Screen
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