I. INTRAMOLECULAR [4+2] CYCLOADDITIONS OF CONJUGATED YNONES AND RELATED SPECIES. II. STUDIES DIRECTED TOWARD THE TOTAL SYNTHESIS OF GLYCINOECLEPIN A. By JASON MICHAEL DIFFENDAL B.S., Chemistry Villanova University, 1997 SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY September 2002 © 2002 Massachusetts Institute of Technology All Rights Reserved Signature of Author................................................................................................................ Department of Chemistry July 25, 2002 Certified by ............................................................................................................................ Rick L. Danheiser Thesis Supervisor Accepted by ........................................................................................................................... Robert W. Field Departmental Committee on Graduate Studies This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Timothy F. Jamison ............................................................................................... Chairman Professor Rick L. Danheiser .................................................................................................. Thesis Supervisor Professor Daniel S. Kemp...................................................................................................... 2 Acknowledgments First and foremost, I would like to thank my research advisor, Rick L. Danheiser for everything he has done for me these past five years. Rick has been an excellent mentor and I am grateful for the opportunity to have worked in his laboratory. Rick is also a superb teacher and I learned an enormous amount of chemistry from him. I also owe Rick a big (very big) thank-you for his time and effort spent proofreading and editing this thesis. The rest of the thanks will start from the beginning. I thank my parents for their unwavering love and support in all of my endeavors. Without them I could never even dream to be where I am today. I also thank my fiancée, Angel. She has been with me every step of the way, to Boston and back again. She has been a source of unending support and love throughout these past ten years. I have been blessed with some of the best chemistry teachers a student could ask for. For my introduction to chemistry, I thank Mr. Jim Ferris. His enthralling chemistry course at Pius led me down the path to an exciting career. Dr. Saul Shupack’s unique teaching style and constant guidance during my first year at Villanova made it clear to me I made the right choice. His was the first laboratory in which I worked. I also thank Dr. Barry Selinski and Dr. Joe Bausch for the opportunities to have worked in their laboratories. I also thank Grant Spoors for the opportunity to work with him as a summer intern at SmithKline Beecham for two summers. That experience is what prompted my desire to return to the pharmaceutical industry. I also wish to thank the members of the Danheiser Group at MIT for the camaraderie these past years. They made MIT a fun place to be and I owe much to all of them. I thank Chris Mellon who was my first baymate for the leadership during my first year at MIT. Also I thank Kevin Shea, Greg Dudley, Matt Martin, Rob Niger, Dawn Bennett, Yoshi Ikeura, and Hiro Shinokubo for their friendship and for looking after me in the lab. 3 I also thank the current Danheiser Group members for their support and friendship: Dave Amos, Aimee Crombie, Martin Hayes, Charnsak Thongsornkleeb, Chris Davie, Graham Wright, Josh Dunetz, Christian Peschko, and Y. J. Zhang. I also thank all of my MIT colleagues for the fun we’ve had. Dana Buske, Michele Harris, Luis Melean, Tim Long, J. D. Tovar, Brian Hodous, and everyone else: it’s been a great time. I also extend thanks to everyone who helped me with this thesis, whether proofreading the text or discussing the chemistry. I wish you all the best of luck in your future endeavors. I will always remember you as I think fondly of my MIT years. 4 To the three most important people in my life: Mom, Dad, and Angel 5 I. INTRAMOLECULAR [4+2] CYCLOADDITIONS OF CONJUGATED YNONES AND RELATED SPECIES. II. STUDIES DIRECTED TOWARD THE TOTAL SYNTHESIS OF GLYCINOECLEPIN A. by Jason Michael Diffendal Submitted to the Department of Chemistry on July 25, 2002 in partial fulfillment of the requirements for the degree of Doctor of Philosophy ABSTRACT The intramolecular [4 + 2] cycloaddition reactions of α,β-alkynyl carbonyl compounds are described. This reaction, the first heterocyclic variant of the enyne cycloaddition reaction, affords a product with a dihydroisobenzofuran ring system. For this reaction, we propose a mechanism in which a highly strained heterocyclic allene intermediate undergoes an unusual rearrangement leading to a 3-furfuryl carbene. A 1,2-C-H insertion then produces the polycyclic furan product. A detailed analysis of the scope and mechanism of this reaction is presented. The synthetic utility of the method for the synthesis of complex organic molecules is illustrated by two sequences demonstraing further transformations of the dihydroisobenzofuran products. A two-step formal benzannulation process generates a tetrahydroanthracene derivative. Ozonolysis of a 7-oxabicycloheptene derivative prepared from a dihydroisobenzofuran affords a product that contains the core oxabicyclo[6.2.1]undecane ring system of eleutherobin and the sarcodictyin family of natural products. Glycinoeclepin A is the natural hatching stimulus agent of the soybean cyst nematode. A new strategy for the synthesis of an advanced A-ring intermediate in the total synthesis of this important compound is presented. This strategy provides the key A-ring enyne intermediate in seven steps from 2,2-dimethylcyclohexanedione, utilizing a novel acid-catalyzed cyclization reaction of a hydroxy enedione. Thesis Supervisor: Rick L. Danheiser Title: Professor of Chemistry 6 Table of Contents Part I: Intramolecular [4 + 2] Cycloadditions of Conjugated Ynones and Related Species Chapter 1: Introduction and Background: Intramolecular [4 + 2] Cycloadditions of Enynes and Arenynes Importance of Cycloadditions in Organic Synthesis.......................................11 Intramolecular [4 + 2] Cycloadditions of Enynes: Early Studies...................13 Cyclic Allenes and Isoaromatic Species..........................................................20 Arenyne Cycloadditions..................................................................................30 Intramolecular [4 + 2] Cycloadditions of Enynes: Recent Work...................47 Summary .........................................................................................................54 Chapter 2: Introduction and Background: Intramolecular [4 + 2] Cycloadditions of Heteroenynes Importance of Heterocyclic Compounds.........................................................55 Significance of Furans in Organic Synthesis ..................................................56 Diels-Alder Reactions of 1-Oxabutadienes.....................................................58 The Heteroenyne [4 + 2] Cycloaddition of Ynones and Related Species.......61 Mechanism of the Heteroenyne Cycloaddition ...............................................68 Goals for Further Studies ................................................................................74 Chapter 3: Scope, Mechanism, and Synthetic Utility of [4 + 2] Cycloadditions of Conjugated Ynones and Related Species Strategies for the Synthesis of α,β-Alkynyl Carbonyl Compounds ................78 Cycloaddition of a Heteroenyne with a Substituted Tether ............................83 Cycloaddition of a Heteroenyne with an Aldehyde Activating the Heteroenynophile.....................................................................91 7 Cycloaddition of an Alkynyl Aldehyde as the Heteroenyne...........................97 Heteroenyne Cycloaddition with Further Transformation of the Carbene Intermediate...............................................................................101 Cycloaddition of a Heteroenyne with a Tether Containing an Aromatic Ring ..........................................................................................108 Experiments Probing the Reactivity of Alkynyl Esters as Heteroenynes .....126 Cycloadditions of a Compound with the Activating Group Contained in the Tether .................................................................................129 Synthetic Utility of the Dihydroisobenzofuran Products of the Heteroenyne Cycloaddition...........................................................................132 Mechanism of the [4 + 2] Cycloaddition of Conjugated Oxaenynes ............137 Summary .......................................................................................................140 Part II: Studies Directed Toward the Total Synthesis of Glycinoeclepin A Chapter 1: Background and Significance Heterodera glycines: The Soybean Cyst Nematode......................................143 Alternative Approaches to Pest Control........................................................145 Isolation and Biological Activity of Glycinoeclepin A.................................146 Potential Use of Glycinoeclepin A as a Pest-Control Agent.........................148 Summary .......................................................................................................149 Chapter 2: The