University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Fall 2013 I The tandem chain extension-acylation reaction II Synthesis of papyracillic acid A: Application of the tandem homologation- acylation reaction III Synthesis of tetrahydrofuran-based peptidomimetics Carley Meredith Spencer Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Spencer, Carley Meredith, "I The tandem chain extension-acylation reaction II Synthesis of papyracillic acid A: Application of the tandem homologation-acylation reaction III Synthesis of tetrahydrofuran-based peptidomimetics" (2013). Doctoral Dissertations. 749. https://scholars.unh.edu/dissertation/749 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. I. THE TANDEM CHAIN EXTEN SION - AC YL ATION REACTION II. SYNTHESIS OF PAPYRACILLIC ACID A: APPLICATION OF THE TANDEM HOMOLOGATION-ACYLATION REACTION III. SYNTHESIS OF TETRAHYDROFURAN-BASED PEPTIDOMIMETICS BY Carley Meredith Spencer B.A., Connecticut College, 2008 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry September 2013 UMI Number: 3575989 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Di!ss0?t&iori Piiblist’Mlg UMI 3575989 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 This Dissertation has been examined and approved. Dissertation Director, Charles K. Zercher Professor of Chemistry 0 Gary Weisman Professor of Chemistry Howard Mayne Professor of Chemistry Roy Planalp Associate Professor of Chemistry Nivedita Gupta Associate Professor of Chemical Engineering Date DEDICATION This dissertation is dedicated to my parents, John and Lisa Spencer. Without their endless support and encouragment I would not have gotten to where I today. ACKNOWLEDGMENTS I would like to thank the entire Department of Chemistry at the University of New Hampshire for helping me through my graduate studies. I am grateful to my advisor and P.I. Professor Charles Zercher for accepting me into his research group. His guidance and patience as I worked my way to an understanding of chemistry has been invaluable. All that Professor Zercher has taught me both in the classroom and the laboratory is greatly valued and will continue to to be used in my future endeavors. I had the pleasure of taking classes with Professor Weisman, Professor Planalp, Professor Johnson, Professor Greenberg, Professor Miller, and Professor Mayne. Their enthusiasm and knowledge of chemistry made learning exciting. Thank you to all of my fellow Zercher group members. Tim Henderson, Jenn Mazzone, Alex Jacobine, and Ian Tashner were there at the beginning to welcome me to the department. They were always willing to offer their support and advice. More recent group members Deepthi Bhogadhi, Peter Moran, Rekha Chhetri, Matt Mower, Kim Drew, Amanda St. Jean, and Lindsay Daniels have all offered encouragment and a lot of entertainment while in lab. I have truly enjoyed discussing chemistry and life in general with every one of them. Kate Cahill, Justin Massing, and all of the other friends I have made during my time here have all greatly influenced my graduate school experience. I would like to thank Pat Wilkinson, John Wilderman, Kristen McFarlane, Jane Austin, Rebecca Thompson, Susan Small, and Bob Constantine for all of their help. Finally, I have to thank Cindi Rohwer and Peg Torch, without whom the department would cease to function. TABLE OF CONTENTS DEDICATION......................................................................................................................... iii ACKNOWLEDGMENTS.......................................................................................................iv LIST OF SCHEMES............................................................................................................ xiii LIST OF FIGURES..............................................................................................................xvii LIST OF TABLES...............................................................................................................xviii LIST OF ABBREVIATIONS............................................................................................... xix ABSTRACT........................................................................................................................... xx CHAPTER........................................................................................................................PAGE I. INTRODUCTION........................................ 1 Zinc Carbenoid-Mediated Chain Extension Reaction .................................. 1 Functionalization of the P-Position of the y-Keto Backbone ....................... 9 Functionalization of the a-Position of the y-Keto Backbone .....................13 II. THE TANDEM CHAIN EXTENSION-ACYL ATI ON REACTION.................... 26 Discovery of the Tandem Homologation-Acylation Reaction ..................26 Tandem Chain Extension-Acylation with Cyclic Anhydrides ..................28 Expansion of Methodology ........................................................................... 31 III. SYNTHESIS OF PAPYRACILLIC ACID A: APPLICATION OF THE TANDEM HOMOLOGATION-ACYLATION REACTION...................................................... 40 Papyracillic Acid Famil of Natural Products ...............................................40 Previous Synthesis of Papyracillic Acids .................................................... 42 Synthesis of Papyracillic Acid A ..................................................................45 2-(Trimethylsilyl)ethyl Protecting Group .................................................... 57 IV. SYNTHESIS OF TETRAHYDROFURAN-BASED PEPTIDOMIMETICS 59 Introduction to Peptide Mimetics ..................................................................59 Previous Syntheses of Substituted Tetrahydrofurans .................................64 Utility of/>-Methoxybenzyl Protecting Group .............................................70 Model P-Keto Imide ......................................................................................72 Amino Acid-Derived P-Keto Imides ............................................................74 Alternate Aldehydes and Ketones as Electrophiles .................................... 85 Conclusion ......................................................................................................89 V. EXPERIMENTAL SECTION.......................................................................................91 General Experimental Section ............................................................................91 Detailed Experimental Section ...........................................................................93 Compound 93. Methyl 2-acetyl-5,5-dimethyl-4-oxohexanoate .................. 93 Compound 95. 2-(Methoxycarbonyl)-5,5-dimethyl-1 -phenyl-1,4- hexanedione ...........................................................................94 Compound 112. Methyl 2-acetyl-4-oxo-4-phenylbutanate ............................95 Compound 120. l-((5)-4-Isopropyl-2-oxooxazolidin-3-yl)-3-((5)-l- tosylpyrrolidin-2-yl)propane-l,3-dione ..............................96 Compound 121. Methyl 2-(isobutyryl)-5,5-dimethyl-4-oxohexanoate .........97 Compound 122. tert-Butyl 2-acetyl-4-oxopentanoate .................................... 98 Compound 123. tert-Butyl 2-benzoyl-4-oxopentanoate .................................99 vi Compound 124. Allyl 2-acetyl-4-oxopentanoate .........................................100 Compound 125. 2-(Allyloxycarbonyl)-l-phenyl-l,4-pentanedione ........... 101 Compound 126. Methyl 2-benzoyl-4-oxo-4-phenylbutanote ......................102 Compound 127. 2-Benzoyl-i^^V-dimethy 1-4-oxopentanamide ....................103 Compound 128. 2-Benzoyl-l-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-4- ((S)-1 -tosylpyrrolidin-2-yl)butane-1,4-dione ....................104 Compound 131. l-(l//-Benzo[<5f|[l,2,3]triazol-l-yl)ethanone 106 Compound 132. tert-Butyl 2-oxopyrrolidine-1 -carboxylate .......................106 Compound 133. 6-terr-Butyl-4-methyl-2-(tert-butyl)-2-hydroxy-1 - oxa-6-azaspiro[4.4]nonane-4,6-dicarboxylate... .107 Compound 145. 3-Methoxyfuran-2,5-dione (3-methoxymaleic anhydride) ............................................................................108 Compound 146. Allyl (3S,4S)-2-hydroxy-9-methoxy-2,3-dimethyl- 7-oxo-l,6-dioxaspiro[4.4]non-8-ene-4- carboxylate .............................................................. 110 Compound 147. (2R,3S,4S,5R)-Allyl 9-methoxy-2,3-dimethyl-7-oxo-2- (2,2,2-trichloroethoxy)-1,6-dioxaspiro[4.4]non-8ene-4- carboxylate ...........................................................................111