VIRIDIOFUNGINS AND XENIOLIDE F: TARGET ORIENTED SYNTHESIS USING DIFFERENT REARRANGEMENT REACTIONS OF A COMMON SUBSTRATE CLASS DISSERTATION zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von Diplom-Chemikerin ANNETT POLLEX geboren am 14.01.1978 in Dresden Gutachter: 1) 2) 3) Eingereicht am: Tag der Verteidigung: Dresden 2006 The present Ph.D. thesis work was realized based upon a suggestion and under the guidance of Prof. M. Hiersemann between September 2003 and September 2006 at the Technische Universität Dresden. I thank Prof. M. Hiersemann for giving me the opportunity to work on this interesting project and for his constant support and advice. To My Parents & Patrick Table of Contents Table of Contents 1 The Task............................................................................................................................. 1 Part 1: Viridiofungins................................................................................................................. 5 2 Introduction........................................................................................................................ 7 2.1 Fungi: Versatile Multi-Purpose Organism with Fundamental Importance................ 7 2.2 Trichoderma Viride.................................................................................................... 9 2.3 Viridiofungins .......................................................................................................... 11 2.3.1 Viridiofungin A – an Alkyl Citrate ...................................................................... 11 2.3.2 Viridiofungins – Biological Activity.................................................................... 14 2.3.3 Proposed Biosynthesis of Viridiofungins............................................................. 18 2.3.4 Published Total Syntheses of Viridiofungins....................................................... 19 3 Retrosynthetic Analysis of Viridiofungin A .................................................................... 27 4 Ester Dienolate [2,3]-Wittig Rearrangement ................................................................... 30 4.1 Historical Development, Main Characteristics and Heteroatom Analogues............ 30 4.1.1 The Carbanion Stabilizing Group G..................................................................... 32 4.1.2 Formation of the Carbanion ................................................................................. 34 4.2 Mechanism and Simple Diastereoselectivity ........................................................... 36 4.3 Induced Diastereo- and Enantioselectivity during [2,3]-Wittig Rearrangements .... 41 4.3.1 Substrate-Induced Diastereo- and Enantioselectivity: 1,3-Chirality Transfer and Remote Stereocontrol........................................................................................... 41 4.3.2 Auxiliary-Induced Diastereoselectivity................................................................44 4.3.3 Reagent-Induced Enantioselectivity..................................................................... 46 4.3.4 Catalyst-Induced Enantioselectivity..................................................................... 47 4.4 Ester Enolate [2,3]-Wittig Rearrangement............................................................... 49 4.5 Ester Dienolate [2,3]-Wittig Rearrangement ........................................................... 50 5 Synthesis of the Eastern Half ........................................................................................... 56 6 Synthesis of the Western Half.......................................................................................... 60 7 Synthesis of the Viridiofungin A, A2 and A4 Triesters .................................................... 66 8 Verification of the Proposed Structure of Viridiofungin A Triester (−)-65a ................... 75 Table of Contents Part 2: (+)-Xeniolide F............................................................................................................. 81 9 Introduction...................................................................................................................... 83 9.1 Xenias: Soft Corals of the Genus Anthozoa – their Biology and the Resulting Potential as Sources of Pharmaceutical Interesting Natural Products...................... 83 9.2 Xenicane Diterpenes................................................................................................ 88 9.2.1 Xeniolide F – One Bioactive Representative of the Xenicane Diterpenes .......... 88 9.2.2 Proposed Biosynthesis of (+)-Xeniolide F........................................................... 91 9.2.3 Published Total Synthesis of Xenicane Diterpenes.............................................. 93 10 Retrosynthetic Analysis of Xeniolide F ........................................................................... 96 11 The Catalytic Asymmetric Claisen Rearrangement (CAC) ........................................... 102 11.1 Historical Development and Important Variations ................................................ 102 11.2 Mechanism and Simple Diastereoselectivity ......................................................... 105 11.2.1 Mechanism ......................................................................................................... 105 11.2.2 Simple Diastereoselectivity (Syn-/Anti-Selectivity).......................................... 107 11.2.3 Strategies for the Diastereoselective Formation of the Vinyl Ether Double Bond . ............................................................................................................................ 109 11.3 Induced Diastereo- and Enantioselectivity during Claisen Rearrangements ........ 112 11.3.1 Substrate-Induced Diastereo- and Enantioselectivity: 1,3-Chirality Transfer and Remote Stereocontrol......................................................................................... 112 11.3.2 Auxiliary-Induced Diastereoselectivity..............................................................113 11.3.3 Reagent-Induced Enantioselectivity................................................................... 116 11.3.4 Catalyst-Induced Enantioselectivity................................................................... 119 12 Copper(II) Bis(oxazoline) Complexes ........................................................................... 136 13 Stereoselective Synthesis of the Allylic Alcohol........................................................... 144 13.1 Butyrolactone Route............................................................................................... 144 13.2 Cross-Coupling Approach...................................................................................... 147 13.2.1 Stille Cross-Coupling......................................................................................... 149 13.2.2 Negishi and Suzuki-Miyaura Cross-Coupling ................................................... 152 14 Stereoselective Synthesis of Allyl Vinyl Ethers via Horner-Wadsworth-Emmons ............ Olefination...................................................................................................................... 160 14.1 Rhodium-Catalyzed OH-Insertion......................................................................... 161 14.1.1 Synthesis of the Phosphonates ........................................................................... 166 14.1.2 Application of the Rhodium-Catalyzed OH-Insertion ....................................... 167 14.2 Horner-Wadsworth-Emmons Olefination.............................................................. 168 15 Catalytic Asymmetric Claisen Rearrangement (CAC) .................................................. 172 16 Side Chain Synthesis and Introduction .......................................................................... 185 17 Preliminary Experiments for the Envisaged Nozaki-Hiyama-Kishi Reaction............... 195 18 Summary and Future Prospects...................................................................................... 197 Table of Contents 19 Verification of the Proposed Structure........................................................................... 200 Part 3: Experimental Section.................................................................................................. 207 20 Experimental Section..................................................................................................... 209 20.1 General Experimental Methods.............................................................................. 209 20.2 Viridiofungins ........................................................................................................ 214 20.2.1 Synthesis of the Eastern Half ............................................................................. 214 20.2.2 Synthesis of the Western Half............................................................................ 224 20.2.3 Synthesis of the Viridiofungin A, A4, A2 Triesters............................................ 234 20.3 (−)-Xeniolide F....................................................................................................... 251 20.3.1 Stereoselective Synthesis of the Allylic Alcohol ............................................... 251 20.3.2 Synthesis of the Allyl Vinyl Ether, Synthesis of the Catalyst, Claisen Rearrangement and Further Steps toward (−)-Xeniolide F..............................