I. LEWIS BASE-CATALYZED ALDOL REACTION IN THE TOTAL SYNTHESIS OF ERYTHRONOLIDE B II. EFFORTS TOWARDS THE TOTAL SYNTHESIS OF AMPHIDINOLIDE H by Dezhi Fu Bachelor of Science, Lanzhou University, 2002 Master of Science, Brown University, 2006 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2011 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Dezhi Fu It was defended on April 8,2011 and approved by Theodore Cohen, Professor, Department of Chemistry Craig S. Wilcox, Professor, Department of Chemistry Billy W. Day, Professor, Department of Pharmaceutical Sciences Dissertation Advisor: Scott G. Nelson, Professor, Department of Chemistry ii Copyright © by Dezhi Fu 2011 iii I. LEWIS BASE-CATALYZED ALDOL REACTION IN THE TOTAL SYNTHESIS OF ERYTHRONOLIDE B II. EFFORTS TOWARDS THE TOTAL SYNTHESIS OF AMPHIDINOLIDE H Dezhi Fu, PhD University of Pittsburgh, 2011 Lewis base (trimethylsilylquinine and trimethylsilylquinidine) catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions have been developed to prepare synthetically important bispropionate units previously by the Nelson group. A new Lewis base-catalyzed diastereoselective Mukaiyama aldol reaction has extended this bispropionate unit preparation methodology to all-syn bispropionates which widely occurred in polypropionate natural products. By using phenoxides as Lewis base catalysts, enol silanes were activated and underwent a Felkin attack on an aldehyde through an antiperiplanar transition state to generate all-syn bispropionate product in high yields and excellent diastereoselectivities. Me Me Me OAr ArO Me Si Si OTMS O Me Me O MeH O OSi OTBS Me ArO– Me O N R N N N H R L Me Me Me OTBS Si = silyl protecting group R = L R All-syn bispropionate prepared from the Lewis base-catalyzed diastereoselective Mukaiyama aldol reaction has been untilized in natural product synthesis of erythronolide B establishing “syn,syn,syn” stereochemical relationships from C -C . 2 5 iv O Me Me 8 Me Me 7 O OH OH OH OH 2 4 Me 13 Me 5 N 1 3 5 OH O 4 Me Me Me O OH 2 "syn, syn, syn" Bispropionate Synthon Me Erythronolide B Studies towards the total synthesis of the cytotoxic marine macrolide amphidinolide H (89) have been disclosed. By exploiting AAC methodology, several key stereochemical relationships present in major fragments 198 and 199 were established. A highly enantioselective synthesis of methyl ketone 200 was realized from commercially available (S)-(−)-glycidol. Iodide 198 was coupled with boronic ester 199 via an efficient Suzuki reaction to form a C -C fragment. 7 20 Aldol coupling Me OH O Me OH O Me OH 18 Me OH 22 14 Me Suzuki HO Me HO Me 196 Me OH Me 11 6 OH + O OH O 1 CHO Julia olefination O Macrolactonization O SO2Ph Me OTMSE Amphidinolide H (89) Me O Me 197 O H O C H OMe-p 198 6 4 I O + Me B(Pin) 2 Me O Me OBn OTBS 200 OTES O 199 v TABLE OF CONTENTS 1.0 LEWIS BASE-CATALYZED DIASTEREOSELECTIVE MUKAIYAMA ALDOL REACTION FOR ALL-SYN BISPROPIONATE UNITS........................................1 1.1 INTRODUCTION.......................................................................................................1 1.1.1 Aldol Reaction...................................................................................................1 1.1.2 Synthesis of Polyketide and Polypropionate Units........................................3 1.1.3 Lewis Base-Catalyzed Mukaiyama Aldol Reaction.......................................8 1.2 LEWIS BASE-CATALYZED DIASTEREOSELECTIVE MUKAIYAMA ALDOL REACTION FOR ALL-SYN BISPROPIONATE UNITS..............................13 1.2.1 Bispropionate Units in the Total Synthesis of Erythronolide B.................13 1.2.2 Design of Enol Silane for Mukaiyama Aldol Reaction................................15 1.2.3 BF -Mediated Mukaiyama Aldol Reaction..................................................17 3 1.2.4 Lewis Base-Catalyzed Mukaiyama Aldol Reaction.....................................20 1.3 CONCLUSION..........................................................................................................36 1.4 EXPERIMENTALS..................................................................................................38 2.0 EFFORTS TOWARDS THE TOTAL SYNTHESIS OF AMPHIDINOLIDE H 54 2.1 INTRODUCTION.....................................................................................................54 2.1.1 The Amphidinolides.......................................................................................54 2.1.1.1 Isolation................................................................................................54 vi 2.1.1.2 Structural Features and Biological Activity.....................................55 2.1.2 Previous Approaches to the Total Synthesis of Amphidinolide H1...........57 2.1.3 Application of AAC Reaction Technology in the Total Synthesis of Amphidinolide H1......................................................................................................66 2.2 EFFORTS TOWARDS THE TOTAL SYNTHESIS OF AMPHIDINOLIDE H69 2.2.1 The Retrosynthesis of Amphidinolide H1....................................................69 2.2.2 The First Generation of Synthesis of the C –C Fragment......................70 14 26 2.2.2.1 Model Study for preparing Fragment C –C .................................70 14 26 2.2.2.2 Synthesis of the C -C Fragment 148..............................................72 14 21 2.2.2.3 Synthesis of the C -C Model Fragment.........................................74 22 26 2.2.2.4 Model Study of Aldol Coupling of C -C Fragment With C -C 76 14 21 22 26 2.2.3 The Second Generation of Synthesis of the C –C Fragment..................77 14 26 2.2.3.1 The Retrosynthesis of the C –C Fragment....................................77 14 26 2.2.3.2 The Synthesis of Fragment 168..........................................................78 2.2.3.3 The Synthesis of Fragment 169..........................................................80 2.2.3.4 Dithiane Addition Trials.....................................................................85 2.2.4 Revised Synthesis of Amphidinolide H1.......................................................87 2.2.4.1 The Revised Retrosynthesis of Amphidinolide H1...........................87 2.2.4.2 Synthesis of the C -C Fragment 199 100..........................................88 7 13 2.2.4.3 Synthesis of the C -C Fragment 211..............................................90 14 18 2.2.4.4 Synthesis of the C -C Fragment 200..............................................92 19 26 2.2.4.5 Fragments Coupling............................................................................93 2.3 CONCLUSIONS........................................................................................................95 vii 2.4 EXPERIMENTALS..................................................................................................96 APPENDIX................................................................................................................................112 BIBLIOGRAPHY.....................................................................................................................161 viii LIST OF TABLES Table 1. Initial trial of Lewis base for Mukaiyama aldol reaction................................................22 Table 2. Screen of counter ions of theLewis base for Mukaiyama aldol reaction.......................23 Table 3. Lithium phenoxide-catalyzed Mukaiyama aldol reaction..............................................25 Table 4. Screen of substituents on phenoxide...............................................................................27 Table 5. Solvents screened for tetrabutylammonium phenoxide-catalyzed Mukaiyama aldol reaction..........................................................................................................................................29 Table 6. Temperature screen of tetrabutylammonium phenoxide-catalyzed Mukaiyama aldol reaction..........................................................................................................................................30 Table 7. Comparison of Lewis base-catalyzed Mukaiyama aldol reaction and Lewis acid- mediated Mukaiyama aldol reaction for all-syn bispropionate synthesis.....................................32 Table 8. Comparison of enol silanes for electronic properties.....................................................34 Table 9. Enol silane comparisons.................................................................................................35 Table 10. Scope of enol silanes.....................................................................................................36 Table 11. Crystal data and structure refinement for 84..............................................................113 Table 12. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 81...................................................................................................................................114 Table 13. Bond lengths [Å] and angles [°] for 84.......................................................................115 Table 14. Anisotropic displacement parameters (Å2x 103) for 84............................................119 ix Table 15. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 84.................................................................................................................................................120 Table 16. Crystal data and structure refinement for 68..............................................................121 Table 17. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 68...................................................................................................................................123 Table 18. lengths [Å] and angles [°] for 68................................................................................124 Table 19. Anisotropic displacement parameters (Å2x 103) for 68............................................128 Table 20. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 68.................................................................................................................................................129 Table 21. Crystal data and structure refinement for 81..............................................................130 Table 22. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 81...................................................................................................................................132 Table 23. Bond lengths [Å] and angles [°] for 81.......................................................................133 Table 24. Anisotropic displacement parameters (Å2x 103) for 81............................................137 Table 25. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 81.................................................................................................................................................138 Table 26. Crystal data and structure refinement for 78..............................................................139 Table 27. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)for 78....................................................................................................................................141 Table 28. Bond lengths [Å] and angles [°] for 78.......................................................................143 Table 29. Anisotropic displacement parameters (Å2x 103) for 78............................................150 x
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