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1 Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin 1 Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin Through Carbenoid Functionalization A Thesis Presented to the Honors Tutorial College, Ohio University In Partial Fulfillment Of the Requirements for Graduation From the Honors Tutorial College With the degree of Bachelor of Science in Chemistry By: Andrea J. Oliver May 2019 2 This thesis is titled Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin Through Carbenoid Functionalization By: Andrea J. Oliver Has been approved by The Honors Tutorial College And the Department of Chemistry and Biochemistry Dr. Mark C. McMills Associate Professor, Thesis Advisor ______________________________ Dr. Lauren McMills Director of Studies, Chemistry ______________________________ Cary Roberts Frith Interim Dean, Honors Tutorial College ______________________________ 3 ABSTRACT OLIVER, ANDREA J., May 2019, Chemistry Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin Through Carbenoid Functionalization Thesis Advisor: Dr. Mark C. McMills Despite the constant development of new antibiotics, difficulties are encountered almost immediately through the development of antibiotic resistance. Researchers must constantly work to develop new antibiotics, while diversifying old antibiotic structures in order to avoid a global crisis caused by the generation of multidrug resistant organisms. This work described in this thesis attempts to diversify inexpensive, macrolide antibiotic scaffolds such as roxithromycin and spiramycin through the removal of sugar moieties, the functionalization of the existing ring and other structural changes. 4 ACKNOWLEDGEMENTS I would like to thank Dr. Mark McMills and Dr. Lauren McMills for their endless patience and guidance these last four years. I could not have made it this far without the support of two such caring individuals. Thank you for pushing me to try even when I was scared and getting me to the next step. I would like to thank the students in my 1510, 1500, and 1220 labs. It was such a privilege to get to be a part of your learning experience. Thank you for your enthusiasm and giving me opportunities to laugh every week. Thank you to Joe Tysko, you keep the oil changed in the vacuum pump, the N2 tanks filled, and the bin filled with dry ice. Thank you for only making fun of me a little when I ask you stupid questions. To my parents, and everyone else who has loved me along the way, thank you for keeping me sane and giving me the support I needed to keep plugging along. 5 TABLE OF CONTENTS Abstract……………………………………………………………………………………3 Acknowledgements………………………………………………………………………..4 List of Figures & Tables…………………………………………………………………..6 List of Schemes……………………………………………………………………………8 List of Abbreviations……………………………………………………………………...9 Chapter 1: Introduction…………………………………………………………………..10 Chapter 2: Introduction to Macrolides…………………………………………………...13 2.1 Spiramycin…………………………………………………………………...17 2.2 Roxithromycin……………………………………………………………….26 Chapter 3: Carbenoid Functionalization…………………………………………………30 3.1 Synthetic Strategy for the Preparation of Spiramycin Derivatives…………..36 3.2 Synthetic Strategy for the Preparation of Roxithromycin Derivatives………40 3.3 Experimental Determination…………………………………………………42 Chapter 4: General Experimental………………………………………………………...44 4.1 Spiramycin Experimental…………………………………………………….45 4.2 Roxithromycin Experimental………………………………………………...59 Chapter 5: Results………………………………………………………………………..66 Chapter 6: Discussion……………………………………………………………………74 6 List of Figures & Tables Figure 1: The Structure of Penicillin…………………………………………………….10 Figure 2: Tylosin, A 16-Membered Macrolide………………………………………….13 Figure 3: Azithromycin, A 15-Membered Macrolide…………………………………...13 Figure 4: Structure of Roxithromycin’s Aminosugar, which contributes to it’s basicity..14 Figure 5: Tacrolimus: A 23-Membered Macrolide……………………………………....15 Figure 6: Bafilomycin: A 16-Membered Macrolide……………………………………..15 Figure 7: Concanamycin: An 18-Membered Macrolide…………………………………15 Figure 8: Erythromycin: A 14-Membered Macrolide……………………………………16 Figure 9: 2D Structure of Spiramycin……………………………………………………17 Figure 10: Crystal Structure of Spiramycin (1KD1, Protein Data Base, RCSB.org)....... 20 Figure 11: C5 Disaccharide Chain of Spiramycin……………………………………….21 Figure 12: C4-C7 Portion of Spiramycin’s Macrocyclic Lactone Ring (Sans Sugars).....22 Figure 13: Modification of Spiramycin through C5 Triazole Arm with Various R-groups. Derived from (Klich, et. al, 2016)……………………………………………………..…23 Figure 14: Roxithromycin (right) an Oxime Derivative of Erythromycin (left)………...26 Figure 15: Proximity of Roxithromycin groups to Peptidyl Proteins of the Peptidyl Transferase Center. Derived from (Schlunzen, et al., 2001)………………………….…27 Figure 16: Crystal Structure of Spiramycin (1KD1, Protein Data Base, RCSB.org)…....28 Figure 17: Carbene (left) and Metal Stabilized Carbene (right)…………………………31 Figure 18: The Structure of Cyclopropane……………………………………………....33 Figure 19: p-ABSA, a Diazo-Transfer Reagent. (Davies et. al, 1992)……………..…....34 Figure 20: Proposed Product Structure with C10 -C12 Alkene Intact…………………..…48 7 Figure 21: Methyl Malonyl Chloride (ChemDraw, 2019)……………………………….50 Figure 22: Structure of Roxithromycin…………………………………………………..66 Figure 23: Figure 23: H1 NMR of Roxithromycin…...…………………………………..67 Figure 24: H1 NMR of Spiramycin ………………………..…………………………….69 Figure 25: Structure of Roxithromycin w/o Cladinose…………………………………..70 Figure 26: H1 NMR of AO13-BF (Cladinose-Free Roxithromycin).……………………71 Figure 27: IR of AO13-BF (Cladinose-Free Roxithromycin)………………..………….72 Figure 28: Acetal Formation of Spiramycin’s C6 Aldehyde…………………………….73 Table 1: Establishing Solvent System for Spiramycin…………………………………..46 Table 2: Solvent System Determined for AO-06A……………………………………....51 Table 3: Establishing Solvent System for AO-06B……………………………...………52 Table 4: Establishing Solvent System for AO-07B Post Ethyl Acetate/Methanol (9:1) Column…………………………………………………………………………………...54 Table 5: Establishing Solvent System for AO-08 Crude………………………………...59 Table 6: Establishing Solvent System for AO-08C……………………………………...60 8 List of Schemes Scheme 1: Enzymatic Peptide Bond Formation, (forming peptide bond shown in red). Derived from (Berg et. al, 2015)…..…………………………………………………..…19 Scheme 2: Intramolecular Ketal Formation of Anhydroerythromycin in an Acidic Environment. (Al-Qattan, 2019)…………………………………………………………26 Scheme 3: Intermolecular Insertion into a Carbon-Hydrogen Bond. (Doyle, 1998)…….32 Scheme 4: Intermolecular Carbon Insertion into an Oxygen-Hydrogen Bond. (Doyle, 1998)……………………………………………………………………………………..32 Scheme 5: Cyclopropanation of an Alkene using Diazomethane and Palladium (II) Catalyst. (Doyle, 1998)…………………………………………………………………..34 Scheme 6: Mechanism of Diazo-Transfer Using p-ABSA. (Davies et. al, 1992)……….35 Scheme 7: A 1,3 dipolar cycloaddition. (McMills Group, 2019)………………………..36 Scheme 8: The Acylation of Unmodified Spiramycin using Ethyl Malonyl Chloride…..36 Scheme 9: Diazotization of β -Diester Derivative of Spiramycin……….………………37 Scheme 10: The Removal of Sugar, Mycarose from Spiramycin……………………….38 Scheme 11: The Acylation of Mycarose-Free Spiramycin using Methyl Malonyl Chloride…………………………………………………………………………………..39 Scheme 12: Diazotization of Acetylated Mycarose-Free Spiramycin Derivative……….39 Scheme 13: Tandem Ylide Formation/Cycloaddition Strategy………………………….40 Scheme 14: Removal of Cladinose from Roxithromycin………………………………..40 Scheme 15: Acylation of Cladinose-Free Roxithromycin Using Methyl Malonyl Chloride…………………………………………………………………………………..41 Scheme 16: Diazotization of Acetylated Cladinose-Free Roxithromycin Derivative…...41 9 Scheme 17: Projected OH Insertion Products from Diazotized Roxithromycin………...42 Scheme 18: Acetal Formation of C6 Aldehyde Before Attempted Sugar Removal……..58 List of Abbreviations MIC: Minimum Inhibitory Concentration MPC: Mutant Prevention Concentration MSW: Mutant Selection Window PAMS: Periodic Antibiotic Monitoring and Supervision A Site: Amino Site P Site: Peptidyl Site E Site: Exit Site p-ABSA: para-aminobenzenesulfonyl azide HCl: Hydrochloric Acid NaOH: Sodium Hydroxide NaCl: Sodium Chloride TLC: Thin Layer Chromatography dd: Doublet of Doublets ddq: Doublet of Doublets of Quartets m: Multiplet s: Singlet CDCl3: Chloroform-D Et3N: Triethylamine NMR: Nuclear Magnetic Resonance 10 Chapter 1: Introduction H H R N S CH3 O N CH3 O OH O Figure 1: The Structure of Penicillin. Since the discovery of penicillin in 1928 by Alexander Fleming, antibiotics have become an indispensable tool of our healthcare system. Whether it is treating routine bacterial infections in the general population, helping immune-compromised cancer patients avoid infection, or keeping recently transplanted organs viable in the bodies of transplant patients who are often susceptible to bacterial infections, antibiotics are an essential part of today’s healthcare system.1 Fleming’s insight into the trajectory of antibiotic use is far beyond his serendipitous discovery. In his Nobel Peace Prize acceptance speech, he warned those who would listen, that antibiotics under constant use are quickly plagued by antibiotic resistance. Resistance is inevitable as bacteria thrive in the most adverse conditions due to their ability to evolve so quickly. Bacteria utilize methods such as horizontal gene transfer within and between species, as well as selective pressure for beneficial random mutation, to thrive at a rate that the immune system cannot always match. In order to preserve antibiotics as
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