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Studies Directed Toward Enantioselective Catalysis Brian E University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Open-Access* Master's Theses from the University Libraries at University of Nebraska-Lincoln of Nebraska-Lincoln 5-1995 Studies Directed toward Enantioselective Catalysis Brian E. Jones University of Nebraska-Lincoln Follow this and additional works at: http://digitalcommons.unl.edu/opentheses Part of the Chemistry Commons Jones, Brian E., "Studies Directed toward Enantioselective Catalysis" (1995). Open-Access* Master's Theses from the University of Nebraska-Lincoln. 53. http://digitalcommons.unl.edu/opentheses/53 This Thesis is brought to you for free and open access by the Libraries at University of Nebraska-Lincoln at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Open-Access* Master's Theses from the University of Nebraska-Lincoln by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. STUDIES DIRECTED TOW ARD ENANTIOSELECTIVE CATALYSIS by Brian E. Jones A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of the Requirements For the Degree of Master of Science Major: Chemistry Under the Supervision of Professor James M. Takacs Lincoln, Nebraska May, 1995 STUDIES DIRECTED TOW ARD ENANTIOSELECTIVE CATALYSIS Brian Edward Jones, M.S. University of Nebraska, 1995 Adviser: James M. Takacs Many organic molecules of modest size and complexity have chirality. That is, these molecules can exist in more than one stereoisomeric form. There is a strong desire to synthesize chiral compounds that exist in the form of a single stereoisomer. The method of synthesizing chiral compounds that was studied in our research employed a less than stoichiometric amount of chiral catalyst to both catalyze and control the stereochemical outcome of the reactions attempted. A new chiral ligand was developed to be used as part of the chiral catalyst. This new ligand was used in the enantioselective Diels-Alder cycloaddition reaction and the enantioselective allylation reaction in the attempt to synthesize products of high enantiomeric purity. Acknowledeements To Dr. James M. Takacs and his research group members that I've worked next to past (Dr. Sithamalli "Mouli" V. Chandramouli, Dr. John J. Weidner) and present (Lei Zhang, Francis Clement, Scott C. Boito, Ed C. Lawson, Rajan V. Athalye, Steve J. Mehrman, Dave A. Quincy), including the undergraduates (John "Chad" Byrd, Greg S. Timm, Mark A. Youngman, Kevin L. Reiman), the post-doctoral fellows (Dr. Bill R. Shay, Dr. Adrian "Sam" Vellekoop, Dr. Kevin J. Koeller), and the new members (Carol L. Walters, John A. Dickmeyer) for freely giving advice and giving my research results even more meaning. I also gratefully acknowledge Dr. Charles Ross for determining the structure of ligand 6, via xray crystallography using the facilities in the UNL laboratory of Professor John J. Stezowski, which is shown in Figure 4 of the text. For helping me to cope with problems seemingly on a daily basis, I wish to thank these fine ladies: Jasmine R. Mayhew, for reading very rough drafts of this thesis and for telling me that when I least expect it ... ; Terry Schneider, for being there, listening, and giving me something good to look at; Marijean Nelson Eggen, for giving great professional advice and being fun to work with; Laura Elizabeth "Bess" Ingalls Wilder, I am very proud to have met you and your world through the "Little House" books. 11 Dedications To Elissa W. Johnson, whose support for me to "go back to" and "stay in" school may have cost her a mate. Words are not enough, but thanks for everything. To Dr. Leo A. Paquette of The Ohio State University, who lit the fire of desire to enjoy chemistry within me, thanks for getting me started. To Edward W. and Martha J. Jones, alias Dad and Mom, thanks for saying this education was possible while supporting me throughout. And to James E. Davis and family, for the friendship from afar, always being there for me, and most of all for making me an uncle to his children. 111 Table of Contents Acknowledgements ······································································· Dedications ················································································· 11 Table of Contents ········································································· Ill List of Equations ·········································································· iv List of Figures ············································································ v List of Schemes ·········································································· VI List of Tables ············································································· viii Text I. Introduction ············································································ II. Results and Discussion ······························································ 6 III. Conclusions and Future Directions ··············································· 39 IV. Experimental Procedures ·························································· 45 v. References ··········································································· 61 IV List of Equations Equation# Page# Equation l. The Diets-Alder cycloaddition reaction and its potential sites for stcreochemical control. 7 Equation 2. Endo and exo product formation in the Diets-Alder reaction. 7 Equation 3. The possible products of this Diets-Alder reaction. 8 Equation 4. The asymmetric allylation reaction catalyzed by (Rj-binaphthol-titanium tetraisopropoxide using the Keck system. 35 v List of Fieures Figure# Page# Figure 1. Prochirality and chelation. 3 Figure 2. A C2-symmetric ligand, the bis-phosphine DIOP. 3 Figure 3. Target C2-symmetric chiral bisoxazolines used in this research. 19 Figure 4. Crystal structure and fractional coordinates for the homochiral ligand 6. 22 Figure 5. Chiral bisoxazoline ligands investigated in our research. 26 Figure 6. Conformations of a seven member ring. 31 Figure 7. Determining the enantiomer ratio of l-phenyl-3-buten-l-ol catalyzed by ligand 6 via NMR shift reagents. 36 Vl List of Schemes Scheme# Page# Scheme 1. The asymmetric effect of DIOP (1) and other C2-symmetric chiral ligands. 4 Scheme 2. The enantioselective Diels-Alder reactions catalyzed by chiral Lewis acids using: a) the Corey system; and b) the Evans system. IO Scheme 3. Models for the origin of the stereoinduction observed in: a) the the Corey catalyst system; and b) the Evans catalyst system. 12 Scheme 4. The Carsten Bolm C2-symmetry bisoxazoline ligand and its non-Cj-symrnetric zinc chloride complex. 15 Scheme 5. Molecular modeling of a ( 1,3)-bisoxazoline-zinc chloride complex. 17 Scheme 6. Molecular modeling of a ( 1,4 )-bisoxazoline-zinc chloride complex. 18 Scheme 7. Synthesis of the C2-symmetric homochiral bisoxazoline 6. 21 Scheme 8. Synthesis of the C2-symmctric heterochiral bisoxazoline 7. 25 Vll Scheme 9. Model for the origin of the (2R) product stereoselectivity observed with the ligand 6-zinc catalytic complex. 32 Scheme I 0. The aysmmctric allylation reaction and possible transformations subsequent to the allylation. 34 Scheme 11. (1,4 )-B isoxazolines worthy of being synthesized and attempted to be used as chirality inducing ligands. 42 Scheme 12. Synthesis of C2-symmetric compounds 10 and 11. 43 Vlll List of Tables Table# Page# Table 1. The effect of (R)-phcnyl bisoxazolines and certain metal triflates on the asymmetric Diels-Alder reaction. 28 Table 2. The effect of (R)-phenyl bisoxazolincs plus zinc triflate chiral catalytic complex on the asymmetric allylation reaction. 37 1 I. Introduction As a consequence of the tetrahedral nature of carbon, most organic molecules of even modest complexity are chiral; that is, they can exist in two mirror image ( enantiomeric) forms. In the case of pharmaceuticals and agrochemicals, one enantiomer of the compound is often largely responsible for the desired biological activity of the substance. Furthermore, harmful side-effects arc sometimes associated with the "wrong" enantiomer.L? It is now recognized that in most cases single enantiomer drugs and agrochemicals will be the standard for the industry. Therefore, efficient, reliable, general synthetic methods for the synthesis of enantiomerically pure compounds are needed. A number of approaches toward asymmetric synthesis have been defined.3.4 Among these, methods to synthesize compounds in high yield and high enantiopurity from achiral starting materials have long attracted interest.5,6,7,8,9 Two general approaches have been defined. One employs a chiral reagent in stoichiometric amounts to control the stereochemical course of the reaction. The second approach, the one that is commonly exploited in nature through the use of enzymes, employs a sub-stoichiometric amount of a chiral catalyst to both catalyze and control the stereochemical course of the organic reaction. The latter approach, termed enantioselective or asymmetric catalysis, is a rapidly growing field of research. The advantages of the enantioselective catalysis approach are clear. Catalytic versus stoichiometric amounts of chiral reagent lowers the cost. In theory, it is possible to recover and reuse the chiral catalyst. Fewer side products should be formed compared to stoichiometric reagents thus reducing the amount of waste generated by the reaction. The 2 only disadvantage of asymmetric catalysis is that it proves difficult to design efficient catalysts and predict the stereochemical
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