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SYNTHESIS and CHARACTERIZATION of NOVEL BIOLOGICALLY ACTIVE BORON-CONTAINING ANALOGUES of CAPSAICIN by Maxim F. Landry a Thesis

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SYNTHESIS and CHARACTERIZATION of NOVEL BIOLOGICALLY ACTIVE BORON-CONTAINING ANALOGUES of CAPSAICIN by Maxim F. Landry a Thesis SYNTHESIS AND CHARACTERIZATION OF NOVEL BIOLOGICALLY ACTIVE BORON-CONTAINING ANALOGUES OF CAPSAICIN By Maxim F. Landry A thesis submitted to the Department of Chemistry & Biochemistry Mount Allison University in partial fulfillment of the requirements for the Bachelor of Science degree with Honours in Chemistry Thesis Committee Supervisor Dr. Stephen Westcott Professor of Chemistry Reviewer Dr. Glen Briand Professor of Chemistry ii ACknowledgements Firstly, I would like to thank my parents for their unconditional love and support. I could never have had success that I did throughout this project without the lessons on hard work and perseverance you taught me growing up. To Chris Vogels, the Toads lab runs as smoothly as it does because of you. Because of the work you put in every day, us students can focus on doing research and having fun. Thank you for your lab guidance, Friday afternoon challenges, and our chats about sports. To Jen Melanson and Steve Geier, you’ve both set excellent examples on what it looks like to work effectively and efficiently in the lab. Thank you also to Danny Durant for your expert technical assistance and for eating lunch with me in the lounge most days, and to Dr. Glen Briand, my second reader. I also want to extend thanks to the great friends I’ve made as a Wild Toad. To Shortbread, G-Dawg, MKV, DR., Actor, Wigboys #1 and #2, JJ, and Skinny Boy, it has been a pleasure working with you all. A special thanks goes out to Cletus Gump for keeping the lab safe. To Steve Westcott, I can’t thank you enough for everything you’ve done for me. You have been my biggest mentor over the past two years. I have learned so much from you, but most of it has little to do with chemistry. Thank you making me think critically about what I want in life, for encouraging me to take pride in everything I do, and for challenging me to constantly improve. Thank you especially for all that you have invested in my future. I am eternally grateful for your support and guidance. iii Abstract The anti-microbial and anti-cancer activities of the natural product capsaicin and related amides are of growing interest to medicinal chemists. Similarly, boron-containing compounds have been shown to have potent biological properties, with four boron-containing pharmaceuticals currently available on the market. As such, a number of boron-containing capsaicin analogues were generated for future biological testing and are discussed herein. Imines were generated from the facile reactions of 3,4-dimethoxybenzaldehyde with Bpin-functionalized aniline derivatives. These imines were subsequently reduced to the corresponding amines using HBcat as a reducing agent. Finally, the amines were reacted with aliphatic acyl chlorides, readily affording the desired amides in moderate yields. All amides were characterized using 1H NMR, 13C{1H} NMR, and FT- IR spectroscopy, as well as 11B NMR spectroscopy where applicable. iv Table of Contents Thesis Committee ........................................................................................................................... ii Acknowledgements ........................................................................................................................ iii Abstract .......................................................................................................................................... iv Table of Contents ............................................................................................................................ v List of Abbreviations .................................................................................................................... vii List of Tables ................................................................................................................................. ix List of Schemes ............................................................................................................................... x List of Figures ................................................................................................................................ xi Introduction ..................................................................................................................................... 1 1.1 Chemotherapy ..................................................................................................................... 1 1.2 Capsaicinoids as Anti-Cancer Agents ................................................................................. 3 1.3 Organoboron Chemistry ...................................................................................................... 6 1.3.1 Boronic Acids and Boronate Esters ............................................................................. 6 1.3.2 Organoboron Compounds as Therapeutics .................................................................. 7 1.3.3 Boron-Containing Capsaicin Derivatives .................................................................. 12 Results and Discussion ................................................................................................................. 15 2.1 Imine Formation ................................................................................................................ 15 2.2 Reductive Amination ....................................................................................................... 19 v 2.3 Amidation ......................................................................................................................... 21 2.4 Characterization ................................................................................................................ 22 Conclusions and Future Directions ............................................................................................... 23 Experimental ................................................................................................................................. 24 4.1 General Procedures ........................................................................................................... 24 4.2 Imine Synthesis ................................................................................................................. 24 4.3 Reductive Amination ........................................................................................................ 32 4.4 Amidation ......................................................................................................................... 42 References ..................................................................................................................................... 51 Appendices .................................................................................................................................... 56 A. Select NMR Spectra ......................................................................................................... 56 B. Curriculum Vitae .............................................................................................................. 63 vi List of Abbreviations � chemical shift ℃ degrees Celsius 13C{1H} proton-decoupled 13C ACS American Chemical Society Ar aryl br broad (spectral) CDCl3 deuterated chloroform CH2Cl2 dichloromethane d doublet (spectral) eq equivalents FDA US Food and Drug Administration g grams h hour(s) HBpin pinacolborane HBcat catecholborane HCOOH formic acid Hz Hertz IR infrared J coupling constant m multiplet (spectral) m moderate (spectral) vii MeOH methanol min minutes mL milliliters mmol millimoles NaBH4 sodium borohydride NMR nuclear magnetic resonance ov overlapping (spectral) PBA phenylboronic acid q quartet (spectral) quint quintet (spectral) ROS reactive oxygen species rt room temperature s singlet (spectral) s strong (spectral) t triplet (spectral) TRPV1 transient receptor potential cation channel subfamily V member 1 w weak (spectral) viii List of Tables Table 1.1: Anti-microbial activity of select compounds reported by Ramsaywack et al. ............ 13 ix List of SChemes Scheme 1.1: Amide resonance forms. ............................................................................................. 5 Scheme 1.2: sp2 Hybridized boron atom acting as a Lewis acid. ................................................... 7 Scheme 2.1: Generation of imines in this study. .......................................................................... 15 Scheme 2.2: Imine formation reaction mechanism. ...................................................................... 16 Scheme 2.3: Deactivation of amino group through resonance of 2- and 4-aminophenylboronic acid pinacol ester. .......................................................................................................................... 18 Scheme 2.4: Protodeboronation of phenylboronic acid pinacol ester. .......................................... 18 Scheme 2.5: Generation of amines in this study. .......................................................................... 19 Scheme 2.6: Reduction by hydroboration reaction mechanism. ................................................... 20 Scheme 2.7: Generation of amides in this study. .......................................................................... 21 Scheme 2.8: Amidation reaction mechanism. ............................................................................... 22 x List of Figures Figure 1.1: Chemical structures of select chemotherapeutic agents. 2 Figure 1.2: Chemical structures of vanillin and capsaicin. 4 Figure 1.3: Chemical structures of boronic acids
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