UC Riverside UC Riverside Electronic Theses and Dissertations Title Synthesis of Small Molecule Candidate Insulin Mimics by the Claisen Rearrangement Permalink https://escholarship.org/uc/item/4tf6m10c Author Nalbandian, Jenifer N. Publication Date 2013 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA RIVERSIDE Synthesis of Small Molecule Candidate Insulin Mimics by the Claisen Rearrangement A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry by Jenifer Natée Nalbandian August 2013 Dissertation Committee: Dr. Michael C. Pirrung, Chairperson Dr. Michael J. Marsella Dr. Richard J. Hooley Copyright by Jenifer Natée Nalbandian 2013 The Dissertation of Jenifer Natée Nalbandian is approved: Committee Chairperson University of California, Riverside Acknowledgements First, I would like to thank God for calling me to be a chemist and for choosing to love and use foolish things like me to shame the wise. All I do is by Your grace and for Your glory. Through all the storms and trials of grad school, You have been my Comforter and Deliverer. Even when I was faithless, You remained faithful, patiently revealing Your character to me. I thank Christ Jesus my Lord, who has given me strength, that He considered me trustworthy and faithful, appointing me to His service. Through You, I have a hope and a future. I would like to also thank my husband for being there for me through all of the victories, failures, and freak-outs of my graduate career. You have been my best friend, boyfriend, fiancé, husband, chef, leader, personal assistant, chauffeur, garbage collector, counselor, graphic designer, protector, nurse, walking buddy, pastor, handyman, mover, massage therapist, computer programmer, deliveryman, partner, co-host, supporter, and more. I truly would not have made it through grad school without you by my side. I love you so much and I cannot wait to see what God has planned for us after grad school. Thank you to my family for always believing that God had great things in store for me. Mom and Dad, you were there for every science fair, test, project, presentation, and paper that led to this point. Every time I wanted to quit, you both were there, encouraging me, loving me, and reminding me who I am in Christ. I would not be where I am today without your love, prayers, and money (hahaha). To my younger siblings, Nathan, Madelynne, Ethan, and Elijah: you four are my favorite people in the whole world and I would do anything for you. Thank you for all the Thanksgivings and iv Christmases where I was able to forget about the stress of school and just have a great time, hanging out with my hilarious siblings. Thank you to my Nalbandian family for loving and accepting me. I am thankful God allowed me to marry into such a great family. Thank you to my best friends, Mattie and Melissa, for putting up with having a best friend that did not have time to call or visit often. Thank you to my Vegas friends, Erin, Erin, Tanya, and Hayley for always making me laugh whenever we get together. Thank you to my Pepperdine friends, especially Jan Bello and Malia, for those great dinners we had where we laughed, complained, and reminisced. Thank you to Tiffany and Theresa for the fun times we had while working together in the lab. Thank you to Nisana and Renee for the breakfasts, lunches, and dinners. Hanging out with you ladies was always the highlight of my day. Thank you to Angie for allowing me to force you to move in with me and for always being so hilarious. Thank you to Dr. Debbie Smith for being my friend. Having a Spirit-filled woman of God with a PhD as my friend has been a real blessing. Thank you to my family at The Rock for loving me and Michael and helping us grow into the people we are today. Finally, thank you to Prof. Pirrung for your support and guidance. Thank you to the past and present members of the Pirrung group for your help with everything, especially with getting my reactions to work, figuring out the problem sets, changing the gas cylinders, refilling the acetone dispenser, doing the inventories. You all made the time I spent in lab so much more interesting. Also, fellowship support from NIH (GM086130) is greatly appreciated. v Copyright Acknowledgement The text and figures in Chapter 4, in part or in full, are a reprint of the material as it appears in Tetrahedron Lett. 2013, 54, 3752-3754, with permission from Elsevier. The co-author, Prof. Michael C. Pirrung, listed in that publication directed and supervised the research, which forms the basis for this chapter. vi Dedication This dissertation is dedicated to Jesus Christ, “For in Him all things were created: things in Heaven and on earth, visible and invisible…all things have been created through Him and for Him.” Colossians 1:16 This dissertation is also dedicated to my husband, Michael, for his support, patience, and love. vii ABSTRACT OF THE DISSERTATION Synthesis of Small Molecule Candidate Insulin Mimics By the Claisen Rearrangement by Jenifer Natée Nalbandian Doctor of Philosophy, Graduate Program in Chemistry University of California, Riverside, August 2013 Dr. Michael C. Pirrung, Chairperson The aim of this dissertation is the discovery of novel small molecule insulin mimics. Natural product demethylasterriquinone B1 (DAQ B1) is an orally active insulin mimic, but this small molecule contains a quinone moiety that hindered further development of this drug class. The Pirrung lab has successfully replaced the offensive quinone with a pyrone ring derived from the natural product kojic acid, while maintaining the promising biological activity of DAQ B1. The first part of the dissertation describes work toward the synthesis of a diverse library of potential activators of the insulin receptor, indolylkojates. Past work in the Pirrung lab developed a synthetic route to candidate kojate-based insulin mimics that relies on the Claisen rearrangement as a key step. This route employs iodoanilines as a starting point in a Sonogashira reaction with an O-propargylated kojate to make the target indolylkojates, but the use of iodoanilines is limited by the low commercial availability of iodoarenes. In the present study, various functionalized arenes were examined as replacements for iodoaniline, but all failed to be productive coupling partners with our viii functionalized kojate. Finally, success was achieved through the use of a benzyloxy- substituted iodoaniline. The second part discloses results from the examination of our indolylkojate target compounds for signs of axial chirality. We hypothesized that a large group in the 4- position of the indole would provide sufficient steric bulk that rotation about the indole- kojate bond would be restricted. The synthesis of a (4-bromo)indolylkojate disproved this theory, as chiral chromatography failed to indicate the presence of discreet atropisomers. The third part details work done to develop a catalyst that would allow the Claisen rearrangement step to be conducted at lower temperatures than those typically required under thermal conditions (160-190 °C). Literature surrounding the catalyzed Claisen rearrangement of O-allyl kojates is scarce, but, using catalysts known to efficiently mediate the rearrangement of (allyloxy)acrylates and allyl aryl ethers, a catalyst screen was developed. Lewis acid Zn(OTf)2 was determined to be the best catalyst for the rearrangement of O-allyl kojates at low temperatures, with the best yield arising from the use of trans-cinnamyl kojate as the substrate. ix Table of Contents Acknowledgments.............................................................................................................. iv Dedication......................................................................................................................... vii Abstract............................................................................................................................ viii Table of Contents.................................................................................................................x List of Figures .................................................................................................................. xiii List of Schemes..................................................................................................................xv List of Tables .....................................................................................................................xx List of Abbreviations ....................................................................................................... xxi Chapter 1: Introduction ........................................................................................................1 1.1 Diabetes Overview...................................................................................................1 1.2 Insulin ......................................................................................................................2 1.3 Diabetes: Causes and Symptoms .............................................................................8 1.4 Diabetes Treatments...............................................................................................10 1.5 The First Orally-Active Insulin Mimic: DAQ B1..................................................14 1.6 Total Syntheses and SAR Studies of DAQ B1 by Other Groups ..........................19 1.7 Total Syntheses