UC San Diego UC San Diego Electronic Theses and Dissertations Title Advancements in isocyanide based multicomponent reactions Permalink https://escholarship.org/uc/item/6mn0r6n2 Author Isaacson, Jerry Calhoun Publication Date 2009 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Advancements in Isocyanide Based Multicomponent Reactions A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Jerry Calhoun Isaacson Committee in charge: Professor Yoshihisa Kobayashi, Chair Professor William Gerwick Professor Judy Kim Professor Ted Molinski Professor James Whitesell 2009 Copyright Jerry Calhoun Isaacson, 2009 All rights reserved. The Dissertation of Jerry Calhoun Isaacson is approved, and it is acceptable in quality and form for publication on microfilm and electronically: _____________________________________________________________________ _____________________________________________________________________ _____________________________________________________________________ _____________________________________________________________________ _____________________________________________________________________ Chair University of California, San Diego 2009 iii Dedicated to my loving, beautiful wife, Deborah. I also wish to acknowledge Mrs. Shutey, Mr. McElroy, Professor Eric Jacobsen, Professor Gary Procter, Professor Jim Davis, Professor Yoshi Kobayashi, and my Mom and Dad, all of whom inspired and encouraged me to be a scientist. iv Almost all commercially available isocyanides are volatile and carry this repulsive odor… The more long-term inhalation of isocyanides is also said to increase the intensity of dreams at night. Alexander Dömling and Ivar Ugi v Table of Contents Signature Page....................................................................................................................iii Dedication...........................................................................................................................iv Epigraph...............................................................................................................................v Table of Contents................................................................................................................vi List of Abbreviations..........................................................................................................xi List of Figures...................................................................................................................xiv List of Schemes................................................................................................................xxv List of Tables.................................................................................................................xxxii Acknowledgements......................................................................................................xxxiii Vita.................................................................................................................................xxxv Abstract of the Dissertation..........................................................................................xxxvi Chapter One Expeditious Access to Various Pyroglutamic Acid Analogues…..................1 A. Introduction.........................................................................................................1 B. Convertible Isocyanides and the Ugi 4-Center 3-Component Reaction...................................................................................................................5 1. Known Convertible Isocyanides for the Ugi Reaction............................5 2. The Ugi 4-Center 3-Component Cyclization Reaction............................8 3. Introduction of Indole Isocyanide............................................................9 C. Synthesis of a Series of Pyroglutamic Acids....................................................11 1. Searching for an Ammonia Equivalent for the Ugi Reaction................12 2. Synthesis of Linear Starting Materials...................................................15 vi 3. Elaboration of the Ugi Products to Pyroglutamic Acids........................16 D. Study of Diastereoselectivity in the U4C-3CR.................................................20 1. Synthesis of Linear Starting Materials – Chiral γ-Ketoacid..................21 2. Substrate-Controlled Diastereoselectivity in the U4C-3CR..................22 E. Conclusions.......................................................................................................24 G. Acknowledgements...........................................................................................25 F. Experimental Section.........................................................................................26 1. Materials and Methods...........................................................................26 2. Procedures and Spectral Data................................................................27 H. References and Notes........................................................................................44 Chapter Two Racemic Total Synthesis of Dysibetaine featuring Ugi 4-Center 3- Component Condensation Reaction...................................................................................47 A. Introduction.......................................................................................................47 B. History of Dysibetaine......................................................................................48 C. Retrosynthetic Plan...........................................................................................51 D. Synthesis of Linear Ugi Precursors and Study of Diastereoselectivity............53 1. Synthesis of Linear Precursors for the Ugi Reaction.............................53 2. Testing the U4C-3CR of γ-Ketoacid and Studies of Diastereoselectivity....................................................................................54 3. Good Diastereoselectivity in the Passerini Reaction of γ-Ketoacid..................................................................................................57 E. Completion of the Racemic Total Synthesis of Dysibetaine.............................58 1. Separation and Determination of Diastereomers...................................58 2. Completion of the Total Synthesis of (±)-Dysibetaine .........................60 vii F. Conclusion.........................................................................................................63 G. Acknowledgements...........................................................................................66 H. Experimental Section........................................................................................66 1. Materials and Methods...........................................................................66 2. Procedures and Spectral Data................................................................67 I. References and Notes.........................................................................................85 Chapter Three Enantioselective Total Synthesis of (–)-Dysibetaine.................................87 A. Introduction and Retrosynthesis........................................................................87 B. Initial Studies into Chiral γ-Ketoacid Synthesis..............................................89 1. Attempts Towards Chiral γ-Ketoacid via Carbon-Carbon Bond Forming Reaction.............................................................................89 2. Initial Attempts Towards Chiral γ-Ketoacid from L-Malic Acid..........92 3. Testing Chiral γ-Ketoacids Derived from L-Malic Acid in the U4C-3CR.........................................................................................95 C. Unique Ugi Reaction of an Activated Ester.....................................................98 1. Initial Discovery.....................................................................................98 2. Optimization of Reaction Conditions..................................................101 3. Mechanistic Hypothesis.......................................................................105 D. Completion of the Total Synthesis of (–)-Dysibetaine..................................108 E. Summary..........................................................................................................111 F. Conclusion.......................................................................................................113 G. Acknowledgements.........................................................................................116 H. Experimental Section......................................................................................116 1. Materials and Methods.........................................................................116 viii 2. Procedures and Spectral Data..............................................................117 H. References and Notes......................................................................................129 Chapter Four Extended Use of Indole Isocyanide in Multicomponent Reactions...........132 A. Introduction.....................................................................................................132 B. Scope and Mechanism of Indole Isocyanide in Isocyanide Based MCRs........................................................................................................133