SYNTHESIS, CHARACTERIZATION, AND APPLICATIONS OF CHIRAL AMINO ACID DERIVED PYRROLINES A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Daniel P. Jackson May, 2015 SYNTHESIS, CHARACTERIZATION, AND APPLICATIONS OF CHIRAL AMINO ACID DERIVED PYRROLINES Daniel P. Jackson Dissertation Approved: Accepted: _______________________ _______________________ Advisor Department Chair Dr. Michael J. Taschner Dr. Kim C. Calvo _______________________ _______________________ Committee Member Dean of the College Dr. Claire A. Tessier Dr. Chand Midha _______________________ _______________________ Committee Member Interim Dean of the Graduate Dr. Wiley J. Youngs School Dr. Rex D. Ramsier _______________________ _______________________ Committee Member Date Dr. David A. Modarelli _______________________ Committee Member Dr. Bi-min Zhang Newby ii ABSTRACT Many alkaloids, those usually containing a pyrroldiine ring, exist in many natural products and are often used in organocatalysis. Synthetic chemists have thus taken advantage of various pyrroline intermediates in order to achieve target molecules. This dissertation will describe a logical approach to the syntheses of tropane alkaloid analogues and polyhydroxylated pyrrolidines. The latter poises an interesting model for developing chiral auxiliaries for enantioselective reactions. Chapter I of this work provides a brief overview into the pyrrolidine alkaloids and explains the significance of various pyrroline intermediates. The 3- pyrroline system is appealing because the placement of the π-bond allows for further functionilzation to a meso pyrrolidine diol, which will be useful in catalysis later. Chapter II then describes the progression of organocatalysis with a focus on carbon-carbon bonding forming reactions with allylsilanes and carbonyl reductions with boranes. The former reaction is a modification of the Hosomi- Sakurai reaction and utilizes the alkaloids derived in chapter I to make silacycles, where coordination of the electrophile causes a conformational change to allow selective allylation to occur. The latter reaction also utilizes the previous iii alkaloids to generate the corresponding boracyle to transfer a hydride towards electrophiles. Chapter III highlights the attempts of utilizting amino acid derived 3- pyrroline intermediates towards the syntheses of several natural product analogues. A foundation was laid for these target molecules, which would then be further investigated for biological activity and potentially serve as useful chiral auxiliaries in asymmetric synthesis. iv DEDICATION I would like to dedicate this dissertation to my family, as you all are the most important people in my life. My parents, Stanley and Gail Jackson, have sacrificed everything to allow me to grow into the man I am today. I could not thank you both more than anything in the world and I will do my best to be as good of a parent to my children. My siblings, Heather, Meredith, Claudia, and David, you all were always there as role models in helping me interpret what is right from wrong. My in-laws, James and Renee Jones, you have been very supportive and an inspiration to me during my graduate career. I cannot thank you enough for the opportunities you have provided for my continued success. My brothers that have stuck with me for eight long years through college, may we continue an everlasting bond that will never break. Our pillars wiil continue to define my character and everything that I embody. My children, Daylen and Ariel, have made me develop an unbelievable level of efficiency. I would never sacrifice our time and I love you both more than anything. You are my motivation. Last but not least, my wife Lindsey, I could write a book about how much I love you and what you mean to me. You have helped keep me on track, been a perfect mother to our children, and set aside your career so that I could v accomplish my dream. Your smile is as bright as a million suns and I thank you for pole vaulting into my life! vi ACKNOWLEDGEMENTS I would like to acknowledge Dr. Taschner first and foremost for being an outstanding mentor over the course of my graduate career. His guidance has enabled me to gain a whole new appreciation of all areas chemistry through analyzing problems from multiple perspectives. Dr. Taschner was faced with the option of retiring, yet, chose to stay for another five years to continue his passion of teaching to mentor one last student. He was always there when I needed him and always had an answer to help calm me down when I was unsure of myself. In his role as interim department chair, he provided the opportunity to begin teaching laboratory sections as the instructor of record to provide the necessary experience for further teaching opportunities. I will truly never forget what he has done for my family and I wish him the best in his new journey ahead. I would also like to acknowledge my committee members, Dr. Claire Tessier, Dr. Wiley Youngs, Dr. David Modarelli, and Dr. Bi-min Zhang Newby for their assistance in the prepartion of this dissertation. I would like to thank the University of Akron Chemistry department faculty and staff for their guidance. A special thanks to the NMR staff for helping me gain a better understanding of the vii various instrumentation. Lastly, I would like to thank the front office administration, Nancy and Jean, for their help and support over the years. viii TABLE OF CONTENTS Page LIST OF TABLES ................................................................................................. xi LIST OF FIGURES .............................................................................................. xii LIST OF SCHEMES ........................................................................................... xiv TABLE OF ABBREVIATIONS ...........................................................................xviii CHAPTER I. INTRODUCTION TO PYRROLIDINE ALKALOIDS...........................................1 1.1 Alkaloids ..............................................................................................1 1.2 Pharmacology of PAs .........................................................................5 1.3 Tropane Alkaloids ................................................................................8 1.4 Polyhydroxylated Pyrrolidines............................................................13 1.5 Pyrroline Intermediates......................................................................21 II. ALKALOIDS IN ORGANOCATALYSIS ..........................................................32 2.1 Early Organocatalysis........................................................................32 2.2 Impact of Proline in Modern Organocatalysis ....................................34 2.3 Asymmetric Allylic Alkylation..............................................................40 2.4 Hosomi-Sakurai Reaction ...................................................................45 2.5 Boron Hydride Donor Reagents..........................................................50 III. SYNTHESES OF 3-PYRROLINES AND DERIVATIVES ..............................57 3.1 Direct Addition of Amino Ester to Ditosyl Acetonide ..........................57 ix 3.2 Alkene Metathesis of N,N-Diallylamino Ester ....................................62 3.3 Direct Addition of Dihaloalkene..........................................................63 3.4 Mosher Ester Analysis .......................................................................67 3.5 Syntheses of TA analogues...............................................................70 3.6 Syntheses of PHP analogues ............................................................74 3.7 Syntheses of Silacycles ......................................................................75 3.8 Syntheses of Boracycles.....................................................................78 IV. CONCLUSIONS ............................................................................................80 V. EXPERIMENTAL SECTION...........................................................................83 5.1 General Experimental Methods ..........................................................83 5.2 Syntheses of Amino Acid Methyl Ester Hydrochlorides......................84 5.3 3-Pyrroline synthesis via direct addition to ditosylacetonide...............88 5.4 3-Pyrroline synthesis via alkene metathesis.......................................91 5.5 3-Pyrroline synthesis via direct addition of cis-1,4-dichloro-2-butene.92 5.6 Mosher Ester Analysis ........................................................................96 5.7 Syntheses of amino acid derived PHPs from 3-pyrrolines..................98 5.8 Synthesis of amino acid derived silacycle from 3-pyrrolines.............102 5.9 Synthesis of amino acid derived boracycle from 3-pyrrolines...........103 REFERENCES ..................................................................................................104 APPENDIX.........................................................................................................111 x LIST OF TABLES Table Page 1. Amino acid methyl ester synthesis with thionyl chloride/methanol ..........58 2. Amino acid methyl ester synthesis with chlorotrimethylsilane/methanol...59 3. Direct addition of amino ester and dihaloalkene to form 3-pyrroline.........64 4. Syntheses of amino acid methyl ester pyrrolines via direct addition to a dihaloalkene in the presence