DEFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter free, while others may be from any type o f computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. 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 UMI 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 of 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 UMI directly to order. UMI A Bell & Howell Infbnnation Company 300 North Zed) Road, Ann Arbor MI 48106-1346 USA 313/761-4700 800/521-0600 INDIUM-MEDIATEO ALLYLATIONS OF a-HETEROSUBSTITUTED CYCLOHEXANONES IN AQUEOUS MEDIA DISSERTATION Presented in Partial Fulfillment of tfie Requirements for ttie Degree of Doctor of Ptiilosophy in ttie Graduate Scfwol of Ttie Ofiio State University by Paul Ctiristoptier Lobtien, B.S., M.S. The Ohio State University 1998 Dissertation Committee: Professor Leo A. Paquette, Adviser Approved by Professor David J. Hart Professor Matthew S. Platz Adviser Department of Chemistry UMI Number: 9834022 UMI Microform 9834022 Copyright 1998, 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 With the increasing pressure on the chemical and pharmaceutical industries to reduce their hazardous waste stream has come the demand to develop environmentally benign technologies. This goal has t>een espoused by President Clinton’s Green Chemistry Challenge sponsored by the Environmental Protection Agency. Additionally, the National Research Council has focused on reducing the detrimental effects of chemicals to improve the environment. Effective and efficient carbon-cartwn bond forming reactions are the epitome of organic synthesis. Unfortunately, ttie majority of such transformations are extremely moisture sensitive requiring anhydrous organic solvents and air-sensitive organometallic reagents in an inert atmosphere of Ar or N 2 The reduction of such cumt)ersome protocols would be a welcomed addition to the synthetic and industrial chemist’s arsenal. One attractive method is to replace the traditional organic solvent with water. A water-based technology would have inherently explicit advantages. These include; • reduction of environmental pollution caused by solvent emission and disposal. • lower process and disposal costs, as compared to hydrocaitwn solvents. • significant enhancement of operational safety by eliminating toxic and flammable solvents. • a possOsle increase in stereoselectivity in water. Recently several research groups have shown that the element indium (In) efficiently promotes allylation reactions in water. The ally! group is widely disseminated in organic chemistry and is often used as a key building block in the synthesis of natural and unnatural products. Further investigation of this intriguing water-based chemistry is thus warranted with particular attention to stereoselectivity. Stereoselectivity is a key feature of pharmaceutical synthesis as exemplified by the Federal Drug Administration's mandate requiring companies to produce enantiomerically pure dnjgs. We undertook a comparative study of the allylindium reagent and some of the more traditional allylmetal reagents in reaction with a-oxygenated cydohexanones. We focused on the the diastereoselecthrity obtainable in conjunction with the chelating ability of the neightx)ring oxygen atom. The aqueous indium protocol was found to be highly superior to the traditional techniques with respect to the ease of operation of the chemical reaction and diastereoselectivity. We have further applied this methodoolgy to include a-hydroxycyclohexanones, which otherwise are incompatble with traditional organometallic reagents. We have obtained the highest levels of diastereoselectivity to date with these substrates. The diastereomeric ratio was determined by nuclear magnetic resonance (NMR) techniques and routine chromatographic separation. The experimental procedure simply requires combining in a reaction vessel the a-oxygenated cyclohexanone, allyl bromide, and indium powder in a ratio of 1 ;1.5:1.5, respectively, in water at 0.10 molar concentration. The implications of this research are expected to be significant because of the inherent advantages. It is anticipated that this novel technology will be adopted by chemical and pharmaceutical industries in the near future and thereby drastically reduce environmental pollution and operational costs as well as irwrease workplace safety. To my wife Anne-Marie, whose love and support has made this endurable. To you I owe so very much, for you were too often subjected to my inane episodes. IV ACKNOWLEDGMENTS First. I offer my sincere gratitude to Professor Leo A. Paquette. His patience and trust in me at a turtxjient beginning of my graduate career are gratefully acknowledged. He has senred as a forceful motivator arxl an understanding advisor. By example, he has induced me to strive for excellence arxf has done a great deal to bolster my self-confidence. His constant enthusiasm and meticulous intensity are second to none, and are no doubt contagious. Second, words are not enough the express my overwhelming appreciation of Donna Rothe. She unarguably performs her job with the utmost diligence and precision. It was always my pleasure as Coffee Club President to acknowledge, on behalf of the group, her tremendous contributions. Her insight is unrivaled and greatly appreciated by all. Sincere thanks are offered to Professors T.V. RaJanBabu, David Hart and Matthew Platz for their encouragement, ttioughtful advice, and constructive criticism during the past several years. I am indetited to Kurt L. Loaning for his expertise in nomenclature. There are a few select individuals that deserve to be mentioned by name. The friendship of Scott Edmondson in and out of lab made the first years of graduate school extremely rewarding and productive. His enthusiasm and professional demeanor were infectious and he always encouraged me to fulfill my potential. I am extremely thankful for his friendship. I am also thankful to Jeff Johnston for his gracious assistance in all aspects of my graduate career, most notably during my oral proposal and examination. His thoughtful advice arxf encouragement were always insightful and well appreciated. Also duly acknowledged is the entire indium team, including Roger Rothhaar, Tom Mitzel, and Patrick Bemardelli, who listened as much as they contributed. Their stimulating conversations were central to the success of my endeavors. Todd Heidebaugh’s often humorous antidotes offered a welcomed respite during the busy day. His fanaticism during the inaugural Crew season was a further source of relief from the mundane. I am grateful to Monty Montgomery for reminding me that there are things outside of lab that one can be as passionate about a s chemistry. Finally, I must thank ttie many individuals that tested me on the soccer field by providing a fleeting escape from the everyday frustrations of latxxatory wortc, most notably Fatrrice Gailou and Richard Kryspin. I especially recognize my captains Hans and Mary-Eilen, and express my warm appreciation for their trust in me the keeper of tfieir goal. VI VITA Octobers, 1969 Bom • Cincinnati, Otiio May, 1992 Bachelor of Science, Emory University, Atlanta, Georgia Septemtrer, 1992-September, 1995 Graduate Teactiing Assistant, The Ohio State University, Columbus, Ohio October, 1995 Master of Science The Ohio State University, Columbus, Ohio October, 1995-present Graduate Research Assistant, The Ohio State University, Columbus, Ohio PUBLICATIONS Paquette, L. A.; Lobben, P. C. "n-Facial Diastereoselection in the 1,2 Addition of Allylmetal Reagents to 2-Methoxycydohexanone and Tetrahydrofuranspiro-( 2-cyclohexanone)" J. Am. Chem. Soc. 1996, 118, 1917-1930. Lotiben, P. C.; Paquette, L. A. "Sequenced Reactions with Samarium(ll) Iodide. Tandem Nucleophilic Acyl/Ketyl-Olefin Coupling Reactions* Chemtracts: Organic C/iemsfry 1997, 4, 284. Paquette, L. A.; Lobben, P. C. "Evaluation of Chelation Effects Operative during Diastereoselective Addition of the Allylindium Reagent to 2- and 3-Hydroxycyclohexanones in Aqueous, Organic, and Mixed Solvent Systems” submitted for publication. FIELD OF STUDY Major Field; Chemistry Studies in Organic Chemistry VN TABLE OF CONTENTS Eaa& ABSTRACT.................................................................................................................................................. ii DEDICATION..............................................................................................................................................iv