The Allenic Carbocyclization Reaction of Allene-ynes: Progress towards the Syntheses of Fumagillol and Ovalicin by Jolie Elaine DeForrest B.S. Chemistry, Pennsylvania State University, 2003 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 2009 d UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES DEPARTMENT OF CHEMISTRY This dissertation was presented by Jolie Elaine DeForrest It was defended on April 14, 2009 and approved by Professor Dennis P. Curran, Department of Chemistry Professor Paul E. Floreancig, Department of Chemistry Professor Billy W. Day, Department of Pharmaceutical Sciences Thesis Director: Professor Kay M. Brummond, Department of Chemistry ii Copyright © by Jolie Elaine DeForrest 2009 iii The Allenic Carbocyclization Reaction of Allene-ynes: Progress towards the Syntheses of Fumagillol and Ovalicin Jolie E. DeForrest, Ph.D. University of Pittsburgh, 2009 The Rh(I)-catalyzed allenic carbocyclization reaction is a powerful strategy for the assembly of densely functionalized cyclic cross-conjugated trienes. This methodology exhibits excellent functional group compatibility, and allows for the construction of five-, six-, and seven- membered rings in high yields from allene-yne precursors. In this thesis, progress towards the total synthesis of (–)-fumagillol and (–)-ovalicin is reported. The entire carbocyclic skeleton of both structurally related natural products has been synthesized in a single synthetic transformation via an allenic carbocyclization reaction. It is anticipated that the allylic hydroxyl group of the functionalized cross-conjugated can be used for the chemo- and stereoselective installation of epoxides and hydroxyl groups incorporated in both sesquiterpenes. The constitutional group selectivity of the β-hydride elimination step in the allenic carbocyclization reaction has been investigated. We found that TMS-alkynyl allenes with an appending isobutylene group can be reacted under Rh(I)-catalyzed allenic carbocyclization reaction conditions to afford regioisomerically pure cross-conjugated trienes in good yields. The examples within, indicate that a coordinating alkene can be incorporated into the allene-yne substrate to control the β-hydride elimination step of the cyclization reaction to yield trienes with a 1,1-disubstituted alkene side chain. iv TABLE OF CONTENTS LIST OF SCHEMES ............................................................................................................... XIII ACKNOWLEDGEMENTS .................................................................................................. XVII LIST OF ABBREVIATIONS .............................................................................................. XVIII 1.0 THE ALLENIC CARBOCYCLIZATION REACTION OF ALLENE-YNES: PROGRESS TOWARDS THE SYNTHESES OF FUMAGILLOL AND OVALICIN ......... 1 1.1 INTRODUCTION: THE ALDER-ENE REACTION ..................................... 1 1.2 THE TRANSITION METAL-CATALYZED ENYNE CARBOCYCLIZATION REACTION .............................................................................. 2 1.3 THE RHODIUM-CATALYZED ALLENIC CARBOCYCLIZATION REACTION: THE CONSTRUCTION OF CYCLIC CROSS-CONJUGATED TRIENES ............................................................................................................................... 5 1.4 CROSS-CONJUGATED TRIENES IN LIBRARY DEVELOPMENT AND NATURAL PRODUCT SYNTHESIS ................................................................................ 8 1.5 BIOLOGICAL ACTIVTY OF FUMAGILLOL, OVALICIN, AND RELATED SESQUITERPENES ...................................................................................... 12 1.6 SYNTHETIC STRATEGIES TO FUMAGILLOL AND OVALICIN......... 15 1.6.1 Previous Syntheses of Fumagillol .............................................................. 15 1.6.2 Previous Syntheses of Ovalicin .................................................................. 19 v 1.6.3 Brummond and Coworkers’ Previous Approach to Ovalicin ................ 21 1.6.4 Retrosynthetic Analysis: Brummond / DeForrest Approach to Fumagillol / Ovalicin via an Allenic Carbocyclization Reaction ........................... 23 1.7 RESULTS AND DISCUSSION: SYNTHESIS AND FUNCTIONALIZATION OF A CROSS-CONJUGATED TRIENE PRECURSOR FOR THE SYNTHESES OF FUMAGILLOL AND OVALICIN ................................. 24 1.7.1 Synthesis of Cross-conjugated Triene 109 ................................................ 24 1.7.2 Alcohol-Directed Epoxidation of Triene 109: Formation of a Pivotal Intermediate for the Syntheses of Ovalicin and Fumagillol ................................... 30 1.7.2.1 Diverging Palladium-Catalyzed Transformations of Epoxide 115 31 1.7.2.2 Palladium-Catalyzed Hydrogenolysis of Epoxide 115: Synthesis of Diol 117a/b .......................................................................................................... 32 1.7.2.3 Palladium-Catalyzed CO2-Insertion of Epoxide 115: Formation of Carbonate 118 .................................................................................................... 36 1.8 INVESTIGATING THE REACTIVITY OF THE CROSS-CONJUGATED TRIENE MOIETY AND DERIVATIVES TOWARDS CROSS-METATHESIS: APPENDING THE ISOBUTYLENE SIDE CHAIN OF OVALICIN AND FUMAGILLOL TO THE TRIENE .................................................................................. 39 1.9 REVISED RETROSYNTHETIC ANALYSIS: INSTALLATION OF THE SIDE CHAIN OF OVALICIN THOUGH AN OLEFINATION REACTION ............. 43 1.9.1 Synthesis of Epoxy Ketone 131: Construction of the Oxygenated Carbocyclic Framework of Ovalicin ........................................................................ 43 vi 1.9.2 Olefination of Methyl Ketone 131: Installation of the Masked Skipped Diene Side of Ovalicin ................................................................................................ 46 1.9.3 Investigation of the Julia and Wittig Olefination Reactions for the Installation of the Side Chain in Ovalicin ................................................................ 50 1.10 THIRD GENERATION APPROACH TO OVALICIN: INSTALLATION OF THE SIDE CHAIN OF OVALICIN VIA A [3,3]-SIGMATROPIC REARRANGEMENT ........................................................................................................ 52 1.10.1 Synthesis of and Claisen Rearrangement of Allylic Acetate 144 ............ 52 1.10.2 Projected End-game of Ovalicin from Diene 151 ..................................... 56 1.10.3 Summary and Conclusions for the Synthesis and Functionalization of Cross-conjugated Triene 109 .................................................................................... 57 1.11 THE CARBOCYCLIZATION REACTION OF ALLENE-YNES: INVESTIGATING THE CONSTITUTIONAL SITE SELECTIVITY OF DIFFERENTIALLY FUNCTIONALIZED 1,1-DISUBSTITUTED ALLENES AND ITS APPLICATION TO OVALICIN AND FUMAGILLOL ........................................ 58 1.11.1 Trost’s Constitutional Site Selectivity Study of 1,6-Enynes Appended to an Isobutylene Group ................................................................................................ 58 1.11.2 Previous Studies Regarding the Constitutional Site Selectivity in the Allenic Carbocyclization Reaction ........................................................................... 59 1.11.3 Retrosynthetic Analysis of Ovalicin and Fumagillol from α-Hydroxy Allene-yne 162 ............................................................................................................ 60 1.11.4 Synthesis of Allene-ynes Tethered to an Isobutylene Group .................. 61 1.11.4.1 Substrate Design of α-Hydroxy Allene-ynes................................... 61 vii 1.11.4.2 Synthesis of Malonate and Heteroatom Tethered Allene-ynes ..... 67 1.11.5 The Constitutional Site Selectivity of Allene-ynes Tethered to an Isobutylene Group ...................................................................................................... 72 1.11.5.1 Investigating the Role of the Allene-yne Functional Groups on the Selectivity of the Allenic Carbocyclization Reaction ...................................... 72 1.11.5.2 Explanation for the Constitutional Site Selectivity of the Allenic Carbocyclization Reaction of Allene-ynes containing an Isobutylene group 82 1.11.5.3 Examining the Effect of Coordinating Solvents on the Regioselectivity of the Rh(I)-Catalyzed Allenic Carbocyclization Reaction 82 1.11.5.4 Exploring Rhodium and Ruthenium Catalysts for the Carbocyclization of Allene-yne 162 .................................................................. 86 1.11.5.5 Assignment of the Stereochemistry of Cross-Conjugated Trienes E-161 and Z-161 through nOe Analysis ........................................................... 88 1.11.5.6 The Iridium-Catalyzed Allenic Carbocyclization of Allene-ynes Containing Tethered Alkenes ........................................................................... 90 1.11.5.7 The Thermally Induced Ene Cyclization of Allene-yne 162 ......... 92 1.11.5.8 Summary and Conclusions for the Allenic Carbocyclization Reaction of Allene-ynes with an Appending Isobutylene Group .................. 95 1.12 INVESTIGATING THE REACTIVITY OF CROSS-CONJUGATED TRIENE E-161 TOWARDS SELECTIVE OXIDATION REACTIONS ..................... 97 1.12.1 Application of Alcohol-Directed Oxidation Reactions to Cross- Conjugated Triene E-161 .......................................................................................... 97 viii 1.12.1.1 Application of Alcohol-Directed