CATALYTIC, ASYMMETRIC ACYL HALIDE-ALDEHYDE CYCLOCONDENSATIONS IN COMPLEX MOLECULE SYNTHESIS AND APPLICATION TO THE INSTALLATION OF QUATERNARY CARBON STEREOCENTERS by Andrew J. Kassick B. S., The Pennsylvania State University, 1999 Submitted to the Graduate Faculty of the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2004 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES The dissertation of Andrew J. Kassick is approved by: Professor Scott G. Nelson Advisor Date Professor Dennis P. Curran Date Professor Craig S. Wilcox Date Professor Billy W. Day Date University of Pittsburgh November 2004 ii CATALYTIC, ASYMMETRIC ACYL HALIDE-ALDEHYDE CYCLOCONDENSATIONS IN COMPLEX MOLECULE SYNTHESIS AND APPLICATION TO THE INSTALLATION OF QUATERNARY CARBON STEREOCENTERS Andrew J. Kassick, Ph. D. University of Pittsburgh, 2004 The synthetic utility of recently developed catalytic, asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions has been successfully demonstrated in complex molecule total synthesis. Extensive use of the enantiomerically enriched β-lactone products of AAC methodology has led to the enantioselective total synthesis of the potent microtubule-stabilizing agent, (–)-laulimalide (1). Additional highlights of the synthesis include a diastereoselective aldol reaction that united major fragments 85 and 86 and a remarkably high-yielding modified Yamaguchi macrolactonization. Novel methodology was also developed to effect both the one- pot interconversion of β-lactones to dihydropyranones and the Lewis acid-mediated addition of allenylstannane reagents to glycal acetates. OTBS H OH O H O 14 CHO O 27 OPMB 85 Me O 21 O O OH Me Me 1 H H Me Me O H H 5 9 O t (–)-laulimalide (1) BuO2C 86 iii Asymmetric AAC reactions have also been instrumental in recent studies toward the total synthesis of the cytotoxic marine natural product, amphidinolide B1 (133). By exploiting AAC methodology, several key stereochemical relationships present in major fragments 171 and 172 were established. A highly enantioselective installation of the C16 tertiary carbinol stereocenter was acheived through the application of Mukaiyama’s Sn(IV)-allylation protocol, and a rapid synthesis of sulfone subunit 174 was realized from commercially available γ-butyrolactone. Regioselective β-lactone ring opening by phosphonate anions was also documented. TBSO Me OTBSO HO Me OH O Me OTBS 21 OH Me Me 18 I TBSO Me 172 HO Me 13 Me Me OTBS 6 Me 26 O O O 1 B O O Me 171 Amphidinolide B1 (133) Me OtBu O O The enantiomerically enriched β-lactone products of AAC methodology have also been demonstrated to serve as useful templates for the installation of asymmetric quaternary carbon stereocenters. Treatment of β-lactones with NaHMDS in the presence of an in situ electrophile at low temperature resulted in enolization and subsequent alkylation to afford to afford trans-3,4- disubstituted lactones in moderate to good yield with good levels of diastereoselectivity. Resubjecting the monoalkylated products to the reaction conditions and a different electrophile resulted in the efficient production of α,α-disubstituted-β-lactones in high yield with high trans- diastereoselectivity. A more efficient route to α,α-disubstituted β-lactones was realized starting from the cis-3,4-disubstituted β-lactones products of the recently developed second generation iv AAC reaction. Asymmetric quaternary carbon formation was accomplished in two steps affording the desired α,α-disubstituted-β-lactones in high yield with excellent diastereoselectivity. O 10-15 mol% O O Catalyst 36 O NaHMDS O Br Me + O iPr NEt, CH Cl R2–X 2 2 2 R1 R2 R1 –50 °C THF 1 H R –100°C NaHMDS R3–X THF –78°C 10-20 mol% O O O O Catalyst 180 O NaHMDS O 3 + 1 i 3 R Br H R Pr2NEt, BTF 2 1 R –X R R R2 R1 R2 –25 °C THF –78°C Ph CF3 CF3 iPr iPr iPr iPr N N N Al N N Al N F CO S SO CF F C SO CF 3 2 Me 2 3 3 Me 2 3 Catalyst 36 Catalyst 180 v TABLE OF CONTENTS CHAPTER 1. ENANTIOSELECTIVE TOTAL SYNTHESIS OF (–)-LAULIMALIDE............ 1 1.1 BACKGROUND ............................................................................................................ 1 1.1.1 Isolation................................................................................................................... 1 1.1.2 Biological Activity.................................................................................................. 3 1.1.3 Structural Features .................................................................................................. 4 1.1.4 Previous Synthetic Work ........................................................................................ 5 1.2 AAC REACTION TECHNOLOGY IN THE TOTAL SYNTHESIS OF (–)- LAULIMALIDE....................................................................................................................... 13 1.3 RETROSYNTHETIC ANALYSIS .............................................................................. 15 1.4 THE C1–C14 DIHYDROPYRAN FRAGMENT .......................................................... 16 1.4.1 Retrosynthetic Analysis ........................................................................................ 16 1.4.2 First Generation Synthesis of the C1–C14 Fragment of (–)-Laulimalide............... 17 1.5 FRAGMENT UNION AND MACROLIDE FORMATION ....................................... 30 1.6 REVISED RETROSYNTHETIC ANALYSIS............................................................. 34 1.7 SECOND GENERATION SYNTHESIS OF THE C1–C14 DIHYDROPYRAN FRAGMENT............................................................................................................................. 35 1.8 SYNTHESIS OF THE C15–C20 SUBUNIT .................................................................. 45 1.9 SYNTHESIS OF THE C21–C28 DIHYDROPYRAN SIDECHAIN............................. 47 1.10 COMPLETION OF THE C15–C28 FRAGMENT ......................................................... 48 vi 1.11 FRAGMENT UNION AND MACROLIDE FORMATION ....................................... 50 1.11.1 Asymmetric Aldol Reaction ................................................................................. 50 1.11.2 Seco Acid Formation and Macrolactonization ..................................................... 54 1.12 COMPLETION OF THE TOTAL SYNTHESIS OF (–)-LAULIMALIDE................. 62 1.13 CONCLUSIONS........................................................................................................... 64 1.14 EXPERIMENTAL SECTION...................................................................................... 65 CHAPTER 2. STUDIES TOWARD THE TOTAL SYNTHESIS OF AMPHIDINOLIDE B . 116 2.1 BACKGROUND ........................................................................................................ 116 2.1.1 Isolation............................................................................................................... 116 2.1.2 Structural Features .............................................................................................. 117 2.1.3 Biological Activity.............................................................................................. 118 2.1.4 Previous Synthetic Work .................................................................................... 119 2.2 RETROSYNTHETIC ANALYSIS ............................................................................ 126 2.3 THE C1–C13 FRAGMENT ........................................................................................... 127 2.3.1 Retrosynthesis..................................................................................................... 127 2.3.2 Synthesis of the C1-C6 Subunit ........................................................................... 128 2.3.3 Synthesis of the C7–C13 Subunit ......................................................................... 129 2.4 THE C14–C26 FRAGMENT ........................................................................................ 131 2.4.1 Retrosynthetic Analysis ...................................................................................... 131 2.4.2 Installation of the C16 Tertiary Carbinol Stereocenter ........................................ 132 2.4.3 Synthesis of the C14–C21 Subunit........................................................................ 137 2.4.4 Synthesis of the C22–C26 Subunit........................................................................ 142 2.4.5 Subunit Coupling and Functionalization for Fragment Union ........................... 146 vi i 2.5 FUTURE WORK........................................................................................................ 149 2.6 CONCLUSIONS......................................................................................................... 152 2.7 EXPERIMENTAL SECTION.................................................................................... 153 CHAPTER 3. DIASTEREOSELECTIVE β-LACTONE ENOLATE ALKYLATION IN THE CONSTRUCTION OF QUATERNARY CARBON STEREOCENTERS ............................... 176 3.1 BACKGROUND ........................................................................................................ 176 3.2 ENOLATE ALKYLATION OF AAC-DERIVED β-LACTONES ........................... 180 3.3 SYNTHETIC APPLICATION OF α,α-DISUBSTITUTED β-LACTONES ............ 188 3.4 CONCLUSIONS......................................................................................................... 191 3.5 EXPERIMENTAL SECTION...................................................................................