Copyright by Jason Anthony Deck 2007 The Dissertation Committee for Jason Anthony Deck certifies that this is the approved version of the following dissertation: Studies Towards the Total Synthesis of Condylocarpine and Studies Towards the Enantioselective Synthesis of (+)-Methyl Lysergate Committee: Stephen F. Martin, Supervisor Philip D. Magnus Michael J. Krische Richard A. Jones Sean M. Kerwin Studies Towards the Total Synthesis of Condylocarpine and Studies Towards the Enantioselective Synthesis of (+)-Methyl Lysergate by Jason Anthony Deck, B.S.; M.S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin May 2007 Studies Towards the Total Synthesis of Condylocarpine and Studies Towards the Enantioselective Synthesis of (+)-Methyl Lysergate Publication No. _______ Jason Anthony Deck, PhD The University of Texas at Austin, 2007 Supervisor: Stephen F. Martin An iminium ion cascade sequence was designed and its implementation attempted to form the pentacyclic core structure of the natural product condylocarpine. Trapping of the transient Pictet-Spengler-type spiroindolenium ion with a latent nucleophile would form two of the five rings of condylocarpine in a regioselective manner. Progress towards the first fully stereocontrolled synthesis of a lysergic acid derivative has been described. The route utilizes intermediates with the appropriate oxidation state for the target, and the two stereocenters are installed via asymmetric catalysis. The d ring and second stereocenter were simultaneously formed via an unprecedented microwave heated asymmetric ring closing metathesis (ARCM). iv Table of Contents List of Figures...................................................................................................... viii List of Schemes...................................................................................................... ix List of Schemes...................................................................................................... ix Chapter 1: Condylocarpine Alkaloids.....................................................................1 1.1 Introduction...............................................................................................1 1.2 Biogenesis.................................................................................................1 1.3 Synthesis of Condylocarpine Alkaloids – Condyfoline and Tubifoline ...3 1.3.1 Synthesis of Condyfoline and Tubifoline by Harley-Mason ........3 1.3.2 Synthesis of Condyfoline and Tubifoline by Ban.........................5 1.3.3 Formal Synthesis of Condyfoline and Tubifoline by Snieckus ....6 1.3.4 Asymmetric Synthesis of Condyfoline and Tubifoline by Bosch 8 1.3.5 Formal Synthesis of Condyfoline and Tubifoline, and Synthesis of Dehydrotubifoline by Takano.......................................................9 1.3.6 Synthesis of Tubifoline by Bosch...............................................10 1.4 Synthesis of Condylocarpine Alkaloids – Tubotaiwine and Lagunamine12 1.4.1 Synthesis of Tubotaiwine by Harley-Mason ..............................12 1.4.2 Synthesis of Tubotaiwine by Bosch............................................13 1.4.3 Synthesis of Tubotaiwine by Kuehne .........................................14 1.4.4 Synthesis of the (-)-Tubotaiwine Skeleton by Vercauteren........16 1.4.5 Synthesis of the Lagunamine by Vercauteren ............................17 1.5 Synthesis of Condylocarpine Alkaloids – Condylocarpine ....................19 1.5.1 Synthesis of Condylocarpine by Harley-Mason .........................19 1.5.2 Synthesis of Condylocarpine by Kuehne....................................20 1.6 Conclusions....................................................................................23 Chapter 2: Studies Towards the Total Synthesis of Condylocarpine ....................25 2.1 Prior Art from Within the Martin Group ................................................25 2.2 Current Work ..........................................................................................31 v 2.2.1 First Generation Approach..........................................................31 1.6.2 Second Generation Approach .....................................................42 2.3 Outlook and Conclusions........................................................................51 Chapter 3: Methyl Lysergate .................................................................................53 3.1 Introduction.............................................................................................53 3.2 Biogenesis of the Lysergates ..................................................................54 3.3 Synthesis of Lysergates...........................................................................55 3.3.1 Synthesis of Lysergic Acid by Woodward .................................56 3.3.2 Synthesis of (+)-Lysergic Acid by Szántay ................................57 3.3.3 Formal Synthesis of Lysergic Acid by Rebek ............................59 3.3.4 Formal Synthesis of Lysergic Acid by Ninomiya.......................60 3.3.5 Formal Synthesis of Lysergic Acid by Ramage .........................61 3.3.6 Formal Synthesis of Lysergic acid by Kurihara .........................63 3.3.7 Formal Synthesis of Lysergic Acid by Ortar ..............................63 3.3.8 Synthesis of Lysergic Acid by Oppolzer ....................................64 3.3.9 Formal Synthesis of Lysergic Acid by Julia...............................65 3.3.10 Synthesis of Lysergic Acid by Hendrickson.............................66 3.3.11 Synthesis of Lysergic Acid Diethylamide by Vollhardt...........67 3.4 Conclusions.............................................................................................68 Chapter 4: Studies Towards the Stereocontrolled Synthesis of (+)-Methyl Lysergate ..........................................................................................................................70 4.1 Prior Art from Within the Martin Group ................................................70 4.2 Current Work ..........................................................................................73 4.3 Conclusions...........................................................................................125 Chapter 5: Experimental Procedures ..................................................................127 5.1 General methods ...................................................................................127 5.2 Condylocarpine Experimental Procedures............................................129 5.3 Methyl Lysergate Experimental Procedures.........................................145 vi References............................................................................................................160 Vita.......................................................................................................................188 vii List of Figures Figure 1.1 .................................................................................................................1 Figure 1.2 ...............................................................................................................12 Figure 2.1 ...............................................................................................................49 Figure 3.1 ...............................................................................................................54 Figure 4.1 ...............................................................................................................70 Figure 4.3 ...............................................................................................................76 Figure 4.4 ...............................................................................................................89 Figure 4.2 ...............................................................................................................93 Figure 4.5 ...............................................................................................................98 Figure 4.6 .............................................................................................................122 Figure 4.7 .............................................................................................................123 Figure 4.8 .............................................................................................................124 viii List of Schemes Scheme 1.1...............................................................................................................2 Scheme 1.2...............................................................................................................3 Scheme 1.3...............................................................................................................4 Scheme 1.4...............................................................................................................5 Scheme 1.5...............................................................................................................6 Scheme 1.6...............................................................................................................6 Scheme 1.7...............................................................................................................7 Scheme 1.8...............................................................................................................8