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A Synthesis of Erythronolide B Catalytic Asymmetric Synthesis of Complex Polypropionates: A Synthesis of Erythronolide B by Binita Chandra MS, Indian Institute of Technology Kharagpur, 2001 MS, North Dakota State University, 2004 Submitted to the Graduate Faculty of University of Pittsburgh in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 0 2009i UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Binita Chandra It was defended on December 8th, 2009 and approved by Craig S. Wilcox, PhD, Professor Tara Meyer, PhD, Associate Professor Alexander S. Doemling, PhD, Associate Professor Dissertation Advisor: Scott G. Nelson, PhD, Professor, Department of Chemistry ii Catalytic Asymmetric Synthesis of Complex Polypropionates: A Synthesis of Erythronolide B Binita Chandra, PhD University of Pittsburgh, 2009 Studies towards the total synthesis of the polypropionate macrolide agycone Erythronolide B have been presented. Catalytic asymmetric AAC methodology has been applied to efficiently generate the C10-C13 and the C4-C5 stereocenters in the polypropionate fragments 105 and 209 through β-lactones 76, 80, and 86 respectively. An efficient installation of the C2 and C3- stereocenters in 193 was realized through a Lewis-base catalyzed Mukaiyama aldol reaction. Finally, a highly stereoselective aldol coupling of fragments 105 and 209 was used to join the fragments together. O PMB Me 8 Me Aldol TBSO O O Me Me 7 Me Me OH OH 13 8 Me 13 Me + Me Me OH O Me Me 105 O 1 OH O O O O Me 6 H 7 1 OMe 3 O Me Me Me TES O 191 O OTBS Me Me Me O OH OH 80 "syn, anti, syn" N Me Me Me O O O O 176 "syn, syn, syn" Me Me Me Me 76 86 iii TABLE OF CONTENTS LIST OF ABBREVIATIONS ................................................................................................. XIV PREFACE ................................................................................................................................. XVI 1.0 INTRODUCTION ........................................................................................................ 1 1.1 POLYPROPIONATE NATURAL PRODUCTS .............................................. 1 1.2 THE ERYTHROMYCINS ................................................................................. 2 1.2.1 Occurrence, Biological Activity and Biosynthesis ........................................ 2 1.2.2 Previous Syntheses of Erythronolide B ......................................................... 8 1.3 SYNTHESIS OF POLYPROPIONATE UNITS ............................................ 15 1.3.1 Iterative Strategies for Polypropionate Synthesis ...................................... 18 1.3.2 The Cinchona Alkaloid-Catalyzed AAC Reaction for the Efficient Formation of Polypropionate Units .......................................................................... 25 2.0 APPLICATION OF AAC TO THE SYNTHESIS OF ERYTHRONOLIDE B: THE FIRST GENERATION APPROACH ............................................................................. 34 2.1.1 Retrosynthetic Analysis ................................................................................. 34 2.1.2 Synthesis of Ketone Fragment 84 ................................................................. 36 2.1.3 Synthesis of Epoxide 99 ................................................................................. 39 2.1.4 Coupling Studies on Fragments 84 and 99 .................................................. 44 3.0 THE SECOND GENERATION APPROACH ........................................................ 47 iv 3.1.1 Revised Aldol Strategy .................................................................................. 47 3.1.2 Introduction of the O11-PMB Protecting Group in the Ketone Fragment 48 3.1.3 Synthesis of Aldehyde 110 ............................................................................. 49 3.1.4 The Problem of Diastereoselectivity in the Aldol Coupling ....................... 51 3.1.5 Enolization of Ketone 105 ............................................................................. 60 3.1.6 Strategy for Assigning Stereochemistries in the Aldol Products .............. 62 3.1.7 Aldol Coupling of Fragments 105 and 110 .................................................. 63 3.1.8 Change in Protecting Group on Aldehyde 110 ........................................... 67 3.1.8.1 Synthesis of α-Benzyloxy Aldehyde 146 and the Aldol Coupling of Fragments 105 and 146 ..................................................................................... 68 3.1.8.2 Stereochemistry Determination of the Aldol Product ..................... 70 3.1.9 The Aldolate-Ketalization Problem Revisited: Use of TBS Group ........... 72 3.1.10 On the Way to Erythronolide B from Aldol Adduct 145: An Unexpected Problem ....................................................................................................................... 76 3.1.11 Dihydroxylation of 147 Using AD-mix β .................................................... 81 3.1.12 Stereochemical Reassignment of C6-OH Containing Structures ............. 83 3.1.13 Conclusion ..................................................................................................... 86 4.0 CORRECTION OF C6-STEREOCHEMISTRY AND SYNTHESIS OF SYN, SYN, SYN POLYPROPIONATE UNIT .................................................................................... 87 4.1 SYNTHESIS OF THE SYN, SYN, SYN-POLYPROPIONATE UNIT ......... 88 4.1.1 Lewis Base-Catalyzed Mukaiyama Aldol Reaction: Contributions of the Nelson Group .............................................................................................................. 91 4.1.2 Synthesis of the All Syn C2-C5 Bispropionate of Erythronolide B............. 95 v 4.2 INSTALLATION OF THE C6-STEREOCENTER ....................................... 96 4.2.1 Correction of C6 Stereochemistry ................................................................ 96 5.0 COMPLETING THE SYNTHESIS OF ERYTHRONOLIDE B ........................ 102 5.1 ALDOL COUPLING OF FRAGMENTS 105 AND 191 .............................. 102 5.2 SYNTHESIS OF MACROLACTONE 198 ................................................... 103 5.3 CONCLUSION ................................................................................................ 108 5.4 EXPERIMENTAL ........................................................................................... 109 6.0 DEVELOPMENT OF A TWO STEP PROTOCOL FOR CONVERSION OF LACTONE TO ALDEHYDE .................................................................................................. 156 6.1 REACTION DESIGN AND RESULTS ......................................................... 156 6.2 EXPERIMENTAL ........................................................................................... 160 APPENDIX A ............................................................................................................................ 168 BIBLIOGRAPHY ..................................................................................................................... 174 vi LIST OF TABLES Table 1. Selected examples of Lewis base-catalyzed Mukaiyama aldol reaction on chiral aldehydes....................................................................................................................................... 93 Table 2. Conversion of lactones to β-silyloxy aldehydes ........................................................... 159 Table 3. Crystal data for 99′ ....................................................................................................... 168 Table 4. Crystal data for 147a..................................................................................................... 170 Table 5. Crystal data for 176...................................................................................................... 172 vii LIST OF FIGURES Figure 1. Classification of polyketides. .......................................................................................... 1 Figure 2. The catalytic cycle of chain elongation ........................................................................... 5 Figure 3. Second phase in the biosynthetic pathway of erythromycins .......................................... 7 Figure 4. Macrolactonization studies by Woodward .................................................................... 14 Figure 5. General structure of polypropionate natural products ................................................... 15 Figure 6. Possible number of stereoisomers for polypropionates ................................................. 16 Figure 7. Stereotetrads .................................................................................................................. 18 Figure 8. Iterative Lewis acid catalyzed Diene aldehyde cyclocondensation sequence for the synthesis of 6-deoxyerythronolide B ............................................................................................ 20 Figure 9. Iterative crotyboration (Roush). .................................................................................... 21 Figure 10. Iterative Wittig methodology ...................................................................................... 22 Figure 11. Iterative aldol condensation with Paterson’s chiral ketone (R)-12 .............................. 23 Figure 12. Iterative auxiliary based aldol sequence in Crimmins’ synthesis of 6- deoxyerythronolide B.................................................................................................................... 25 Figure 13. Iterative application
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