Information to Users

INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. U M I films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter 6ce, while others may be from any type o f computer printer. The quality of this reproduction is dependent upon the quality of the copy suhmitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send U M I a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back o f the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6” x 9” black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact U M I directly to order. UMI A Bell & Howell Infonnadon Company 300 North Zeeb Road, Ann Arbor MI 48106-1346 USA 313/761-4700 800/521-0600 TANDEM REACTIONS OF FUNCTIONALIZED SOUARATE ESTERS AND OTHER CYCLOBUTENEDIONES. METHODOLOGY AND APPLICATIONS TO THE SYNTHESIS OF POLYQUINANE NATURAL PRODUCTS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University by Tina M. Morwick, B.A. The Ohio State University 1996 Dissertation Committee: Professor Leo A. Paquette, Advisor Approved by Professor David J. Hart Professor John S. Swenton Adviser Department of Chemistry UMI Number: 9639312 UMI Microform 9639312 Copyright 1996, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT A novel cascade rearrangement generating poiyquinane structures on addition of two unsaturated anions to squarate esters has been investigated. Utilizing a single laboratory operation, the electrocyclic^/aldol reaction is capable of the installation of up to five new chiral centers in a stereocontrolled fashion. It will accommodate both carbocyclic and heterocyclic nucleophiles, with either sp2 or sp hybridization. Relief of strain and possible anionic acceleration initiate the process under relatively mild conditions. Initial mechanism studies focusing on the isolation and characterization of reaction intermediates have revealed the mode of bond reorganization for both major and minor products. The major products occur as a result of initial trans addition of two vinyl anions, followed by 4 k electrocyclic ring opening of the highly strained cyclobutene dioxolate. This process necessarily occurs with the appropriate torquoselectivity to deliver an acyclic tetraene whose intemal double bonds have a cis configuration. The tetraene undergoes a second 8 tc electrocyclic event, establishing a cyclooctatriene dienolate. On protonation, transannular aldolization ensues providing the poiyquinane substrates. Other pathways include cis addition followed by [3,3] sigmatropy and aldol reaction, as well as second-stage conjugate addition, pericyclic bond reorganization and vinylogous transannular aldol reaction. The particular pathway is orchestrated by the mode of second-stage addition. Structure-reactivity studies have revealed that both electrocyclic events fall under substituent control, and the effects of a variety of functionality have been investigated. Several methods for controlling regio and stereoselectivity have also been developed. Incorporation of an allene into the current methodology has provided a means for investigating the "allene effect" with respect to periselectivity for the second electrocyclic event. The allene is apparently capable of significant transition state stabilization for the 6 k disrotatory option, leading exclusively to hexadienone substrates. Finally, attempts to utilize the newly discovered process as a key step for synthesis of the natural product crinipellin B have been carried out. Model studies addressing both the feasibility of a particular reaction sequence, as well as the reactivity of the y-hydroxy-a,p-bisalkoxy enone products derived from the electrocyclic^ aldol reaction were pursued to a successful conclusion. It was found that the trimethylsilyl group provides excellent diastereoselectivity and promotes reaction efficiency to a significant degree. Ill To my husband, Ken, our children, Chrissy, Greg, Joe and Matt, and in memory of our parents, Oscar and Julia Pickard and Lloyd and Orpha Morwick IV ACKNOWLEDGMENTS I would like to thank the many individuals whose contributions have made this work possible. I must first thank my family for their patience and encouragement, and especially my husband, Ken, for all the extra responsibilities he has assumed over the last few years. His constant support has made this impossible task a reality. I must also thank my advisor. Dr. Leo Paquette, for giving me the opportunity to work in his research group. Contributing his blend of wisdom and practical experience, he has both guided and encouraged me throughout this study. The substance of the project has provided many avenues for growth, and I have thoroughly enjoyed developing the various aspects involved. His shared enthusiasm and his very accessible nature has aided the work immeasurably. I would also like to thank the other members of my Dissertation Committee; Dr. John Swenton, not only for serving on the committee, but for his many helpful discussions, and Dr. David Hart, who also served as my temporary advisor when I first came to Ohio State. Additionally, I would like to thank Dr. Gideon Fraenkel for the opportunity to work in his laboratory my first summer, and Dr. Kevin Martin for his help in getting started. My former supervisor from Eli Lilly & Co., Dr. Charles Paget, has given me a great deal of practical advice and help over the years, and I acknowledge him for his assistance in a variety of situations. There is one group member, whether she considers herself as such or not, that I must single out as someone who has unselfishly contributed a great deal of her time and talent to making it all work. Donna Rothe has helped in ways too numerous to express. I have truly enjoyed her friendship and support over the past five years. In similar vein, I would also like to thank Barbara Cassity for her help in a variety of areas. I would like to acknowledge Dr. Robin Rogers and Dr. Judith Gallucci for solving several crystal structures, and Dr. Kurt Loaning for his timely assistance in deriving names for the various structures. Finally, one of the distinct advantages to working in a group of this size is the exposure one has to a vast array of unique backgrounds and experiences. Many people have shared with me their particular wisdom and expertise, as well as their friendship, making my time at Ohio State a very enjoyable and rewarding experience. I would like to especially thank Dr. Dirk Friedrich who was responsible for the NMR studies and initial structural assignments, and who taught me how to run and interpret many of the special experiments required for the success of this project, and also Jeff Johnston for his contributions to the NMR work, as well as many helpful discussions and ideas. Dr. Gene Hickey was a willing mentor in many areas. He taught me how to use the relevant computer software programs, day to day operations in the laboratory, and shared his unique chemistry expertise and creativity as well as his friendship. Gene, along with Scott Edmondson and Jim Lanter were also responsible for the computational chemistry involved in this study. Dr. Tim Lowinger shared his experience and many of his skills soon after I began working in the laboratory. I would like to thank Stephana Borrelly, Todd Heidelbaugh, Zhong-Li Gao and Ralf Braun for helpful discussions and the use of many of their reagents as I vi embarked on the natural product work. Finally, I would like to thank Steven Paget and Ashton Hamme, whose friendships I have profited from immeasurably. Always willing to help and always good listeners, I wish both of them success in their future endeavors. VII VITA June 16, 1950 Bom-lndianapolis, IN. June, 1972 Bachelor of Arts The University of Indianapolis Indianapolis, IN January, 1973-November, 1979 Organic Chemist, Eli Lilly & Co. September, 1990-August 1996 Graduate Fellow, The Ohio State University PUBLICATIONS 1. Morwick, T.; Paquette, L. “Preparation of Polyquinanes by Double Addition of Vinyl Anions to Squarate Esters: 4,5,6,6a-Tetrahydro-3a-Hydroxy- 2,3-Diisopropoxy-4,6a-1(3aH)-Pentalenone”, Org.Synth., ^996, 74, 169. 2. Morwick, T.; Paquette, L. "Mapping the Chemical Reactivity of Polyquinanes Produced by Twofold Addition of Vinyl Anions to Squarate Esters. A Bicyclic Case Study", J. Org. Chem., 1996, 61, 146. 3. Paquette, L.; Monwick, T.; Negri, J. "Addition of 2,3-Dihydro-5- furanyllithium to Diisopropyl Squarate as a Means for the Rapid Generation of Structurally Complex Oxygen-Containing Tetraquinane Networks", Tetrahedron 1998, 52, 3075. 4. Paquette, L; Morwick, T. "The Squarate Ester -1 ,3,5,7-Octatetraene - Poiyquinane Cascade: Reaction Efficiency is Intimately Linked to the Locus of Substitution Within the Vinyl Anion", J. Am. Chem. Sac., 1995, 117, 1451-1452. VIII 5. Morwick, T.; Doyen, J.; Paquette, L. "Acetylide Anions Exert Complete Control Over Aldolization During the Direct Conversion of Squarate Esters Into Polyquinanes", Tetrahedron Lett., 1995, 36, 2369-2372. 6. Negri, J.; Monwick, T.; Doyon, J.; Wilson, P.; Hickey, E.; Paquette, L "Direct Elaboration of Complex Polyquinanes through 2-Fold Addition of Vinyl Anions to Squarate Esters", J.

Load more