University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2015 I. A New Route To Azomethine Ylides: Shifting The Reliance On Amino Ester Precursors II. Applications In Total Synthesis Natalie Kay Machamer University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Organic Chemistry Commons Recommended Citation Machamer, Natalie Kay, "I. A New Route To Azomethine Ylides: Shifting The Reliance On Amino Ester Precursors II. Applications In Total Synthesis" (2015). Graduate College Dissertations and Theses. 407. https://scholarworks.uvm.edu/graddis/407 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. I. A NEW ROUTE TO AZOMETHINE YLIDES: SHIFTING THE RELIANCE ON AMINO ESTER PRECURSORS II. APPLICATIONS IN TOTAL SYNTHESIS A Dissertation Presented by Natalie Kay Machamer to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Chemistry October, 2015 Defense Date: May 26, 2015 Dissertation Examination Committee: Stephen P. Waters, Ph. D., Advisor Darren L. Hitt, Ph. D., Chairperson Matthias Brewer, Ph. D. Rory Waterman, Ph. D. Cynthia J. Forehand, Ph. D., Dean of the Graduate College ABSTRACT Nitrogen-containing heterocycles have great utility in the biomedical and medicinal fields and one such heterocycle is the 5-membered pyrrolidine ring. The synthesis of pyrrolidine rings has been studied extensively with the routes relying on anodic oxidation, transition metals and dipolar cycloadditions with azomethine ylides. Previous work in the Waters group has been focused on new routes to azomethine ylides through a domino sequence. Through a thermal aza-Cope rearrangement followed by [3+2] dipolar cycloaddition the synthesis of a library of 2-allyl pyrrolidines was accomplished. It was discovered that by using allylic amines and glyoxals at room temperature a cycloadduct was isolated bearing a 5-vinyl moiety. The results were promising and the first part of the project was to optimize the reaction followed by substrate scope expansion to build a library of compounds. The new cycloadducts could not have been synthesized under traditional methods due to side reactivity difficulties and therefore this work circumvents the problems associated with the classical routes. This is the first report of azomethine ylides derived from allylic amines and glyoxals to date. Many cycloadducts were synthesized and they all contained the 5-alkenyl group with many of them closely matching pyrrolidine containing natural products. The natural product, spirotryprostatin B, is an ideal target for featuring the developed methodology in total synthesis. Spirotryprostatin B was found to inhibit the G2/M phase in the cell replication pathway, suggesting a possible anti-cancer treatment. Using allylamine, ethyl glyoxylate, and appropriate dipolarophile under the optimized reaction conditions would afford a highly substituted cycloadduct that could be transformed into the final target. The core of the structure was synthesized in just three steps with only two steps requiring purification. The regio- and stereochemistry of the cycloadducts were analyzed using NOE enhancement and DFT studies to conclude that the [3+2] dipolar cycloaddition proceeded through the exo transition state. The total synthesis of the anti-cancer compound peducularine was also studied. Many different dipolarophiles were tested, but the ideal dipolarophile was not identified. The results of these experiments were important in defining the scope of the methodology. CITATIONS Material from this dissertation has been published in the following form: Machamer, N. K.; Liu, X.; Waters, S. P.. (2014). A New Entry to Azomethine Ylides from Allylic Amines and Glyoxals: Shifting the Reliance on Amino Ester Precursors. Organic Letters, 16, 4996-4999. ! ii! DEDICATION This work is dedicated to my parents. Without their love and support this would not have been possible. I love you. ! iii! ACKNOWLEDGEMENTS My six years in graduate school has not been without its ups and downs, but there are many people who have helped me along the way. I would first like to thank my advisor, Professor Stephen Waters, for allowing me to work in his lab. I have had the privilege of working on exciting project and have learned so much as a result. I appreciate your willingness to stop what you’re doing when I came to your office with a question. I would like to thank my committee members, Professors Matthias Brewer and Rory Waterman, for their help from the beginning of my graduate school career. Matthias has always offered helpful research advice and has been someone I could go to with even the smallest question. Rory has always been supportive, in and out of the research lab, and for that I am grateful. I would also like to thank Professor Darren Hitt for being the chairperson of my committee. In the very first meeting we had he offered valuable career advice that I very much appreciated. I want to give my sincere thanks to Dr. Alexander Wurthmann. His passion for teaching is contagious and over the last five years I have learned so much. With his help I have become more confident in my teaching abilities and has helped me realize that teaching was something I wanted to do after graduate school. There is no doubt in my mind that any success that comes from teaching in the future is a direct result of the training Sandy has given to me. There is not enough room to adequately thank Drs. Xiaoxi Liu and Corinne Sadlowski. You guys were the best group mates and friends I could ever ask for. Xiaoxi, what started ! iv! out as just sharing a desk has grown into one of my closest friendships in graduate school. I consider myself fortunate that I was able to work so closely with you on our project. Corinne, you are one of the most caring people I know and I appreciate being able to talk to you about anything. I cannot wait to go to Barre class with you again. I wish you both the most success in your future. I can vividly remember being terrified to take organic chemistry at Juniata College (I was a business major!), but after only a few classes I knew this was what I wanted to do and I have Professor Richard Hark to thank for that. I will never forget when I approached him after class one day and told him I wanted to change my major to chemistry and how he offered to be my advisor on the spot. I cannot thank him enough for his support and encouragement over the past ten years. I would also like to thank two of my closest friends in graduate school, Joel Walker and Neil Mucha for their continuous support and encouragement. Joel, you are the person I turn to when I need advice and regardless of what is going on. I know I can always count on you to be understanding, helpful, and reassuring. Neil, I am so lucky to be able to call you a friend. Pennsylvania forever! This would not be complete if I did not thank my family. None of this would be possible with out the unconditional love and support from them. My parents have always put education first and for this I am forever grateful. I am so lucky to be able to call my sister, Amanda, and brother, Cheston, my best friends. I love when we can all get together – times like those really helped with the stress of graduate school. ! v! TABLE OF CONTENTS Citation ................................................................................................................................ ii Dedication .......................................................................................................................... iii Acknowledgements ............................................................................................................ iv List of Tables .................................................................................................................... vii List of Figures .................................................................................................................. viii List of Schemes .................................................................................................................. ix Chapter 1: DEVELOPMENT OF A NEW ROUTE TO AZOMETHINE YLIDES TO YIELD 5-ALKENYL SUBSTITUTED PYRROLIDINES .................................................1 1.1 Background ........................................................................................................1 1.2 Previous Methods for the Synthesis of 5-Vinyl Pyrrolidines ............................4 1.2.1 Anodic Oxidation .............................................................................4 1.2.2 Transition Metal Catalysis ...............................................................8 1.2.3 Other Methods ...............................................................................15 1.3 Azomethine Ylide Generation: Classical Method ...........................................17 1.4 Previous Pyrrolidine Work in the Waters Group .............................................22 1.5 Optimization of Methodology ..........................................................................25 1.6 Substrate Scope Expansion ..............................................................................34 1.6.1 Amines