University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2015-09-02 The Design, Preparation, and Use of Chiral Organoaluminum dibromide Lewis Acids in Asymetric Reactions Warner, Thomas Warner, T. (2015). The Design, Preparation, and Use of Chiral Organoaluminum dibromide Lewis Acids in Asymetric Reactions (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28049 http://hdl.handle.net/11023/2425 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY The Design, Preparation, and Use of Chiral Organoaluminum dibromide Lewis Acids in Asymmetric Reactions by Thomas G. Warner A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN CHEMISTRY CALGARY, ALBERTA AUGUST, 2015 © Thomas G. Warner 2015 Abstract This dissertation adds to the current knowledge of aluminum-based Lewis acids for use in asymmetric catalysis. A highly regioselective and diastereoselective hydroalumination of olefins was used to generate novel achiral and chiral organoaluminum dibromide compounds in situ. Low-temperature proton NMR binding studies were conducted with several different Lewis bases to prove that the Lewis acids coordinate reversibly to Lewis bases. These Lewis acids were investigated for their ability to promote and catalyze organic reactions including Diels-Alder, intramolecular Diels-Alder, epoxide-opening and Strecker reactions. Allylic O-benzylated dienophiles substituted with chiral oxazolidin-2-one auxiliaries were reacted with the sterically hindered diene 1,3,3-trimethyl-2-vinyl- cyclohexene to access a substituted drimane skeleton for natural product synthesis. The exo adduct was obtained as the major diastereomer in up to 60 % yield. Similar crotonic acid-derivatized dienophiles that were reacted with the same diene produced the endo adduct as the major product in up to 96 % yield. The very first example of a chiral organoaluminum dibromide Lewis acid catalyzing a reaction asymmetrically is also described. The Diels-Alder reaction between methacrolein and cyclopentadiene was catalyzed in 80 % yield and 13.3 % ee, with an exo:endo ratio of 25:1. Additionally, the first example of an R*AlBr(OR*)-type Lewis acid catalyzing a reaction asymmetrically is described. These Lewis acids were shown to undergo a dehydroalumination under the conditions of their formation, but nevertheless generated the Diels-Alder adduct in the reaction between methacrolein and cyclopentadiene in 68 % yield and 16 % ee, with a 29:1 exo:endo ratio. ii Finally, a novel class of 3,3’-disubstituted BINOL-aluminum bromide Lewis acids is also described, generating the same Diels-Alder adduct in up to 77 % yield and 37.5 % ee, with an exo:endo ratio of 14:1. Asymmetric Strecker and epoxide-opening reactions are also described making use of this novel class of BINOL-aluminum bromide Lewis acids. Chiral Strecker adduct was obtained in up to 72 % yield and up to 9.1 % ee with chiral bromohydrins being obtained from the opening of meso-epoxides in up to 65 % yield and 16.8 % ee. iii Preface Aluminum-based Lewis acids are widely used as catalysts, and with numerous chiral ligands commercially available, chiral aluminum-based Lewis acids are very popular for asymmetric synthesis. Three classes of novel aluminum-based Lewis acids are described within this dissertation. The first class includes achiral RAlBr2 and chiral R*AlBr2-type Lewis acids that are used to both promote and catalyze organic reactions. The second class includes R*AlBr(OR*)-type Lewis acids, which unfortunately appear to be prone to dehydroalumination. The final class includes BINOL-aluminum bromide complexes. All three classes of novel aluminum-based Lewis acid are easy to prepare, and are highly efficient Lewis acids for promoting and catalyzing asymmetric reactions. All three classes are shown to be capable of catalyzing several different organic reactions enantioselectively. Chapter one is divided into five sections. The first section provides a brief overview of asymmetric synthesis, including what it is and why it is an important topic to advance through continued research and development. The second section outlines a number of different synthetic philosophies toward the goal of asymmetric synthesis, including the use of chiral templates, classical resolution, chiral auxillaries, and finally chiral catalysts. The third section provides a thorough review of chiral aluminum-based Lewis acids used to asymmetrically catalyze several different organic reactions. The organic reactions reviewed in this section include the asymmetric Diels-Alder, Strecker, epoxide opening, sulfide oxidation, and hydrophosphonylation reactions, along with asymmetric aluminum-catalyzed rearrangements. The fourth section includes an introduction of the hydroalumination reaction, along with an introduction of the specific iv hydroalumination reaction proposed as a basis for the chemistry described in this dissertation. The fifth section outlines the tendency of aluminum complexes to form dimers through bridging substituents. Finally, the sixth section outlines several of the project goals. Chapter two is divided into four sections. The first is an overview of the hydroalumination reaction that forms the entire basis for this chemistry, along with in situ 1 13 H and C NMR spectra for several simple hydroaluminated RAlBr2-type Lewis acids. 1 The second section includes low temperature H NMR binding studies wherein RAlBr2- type Lewis acids are investigated for their ability to coordinate and activate simple Lewis base crotonaldehyde reversibly. The third section of this chapter outlines a number of experiments using RAlBr2-type Lewis acid (R = dodecyl) being used to promote the Diels-Alder reaction between chiral oxazolidin-2-one substituted allylic O-benzylated dienophiles and diene 1,3,3-trimethyl-2-vinyl-cyclohexene. Several reaction conditions were tested in an attempt to optimize both the reaction yield as well as the formation of the major exo-adduct. A debenzylation reaction is also described, which pushed this research toward simplified dienophile structures. Finally, the fourth section will highlight the important conclusions from the research conducted in chapter two. Chapter three is divided into six sections. Section one is a brief introduction to the chapter. Section two describes the simplification of the chiral dienophiles into chiral crotonic acid derivatized oxazolidin-2-one substituted dienophiles, along with their use in the Diels-Alder reaction with 1,3,3-trimethyl-2-vinyl-cyclohexene. Each diastereomer is assigned using 1H NMR spectroscopy in conjunction with X-ray crystallography. An elaborate optimization of reaction conditions is described, including optimization of the v amount of Lewis acid, the temperature of the reaction mixture, the reaction time, the solvent, the structure of the dienophile, the R group in the RAlBr2 Lewis acid, among other variables. The optimization of this reaction included the insight that 3.5 equivalents of RAlBr2-type Lewis acid provided the best results. Section three therefore describes numerous efforts to reduce the amount of Lewis acid delivered to the reaction mixture. Section four outlines a proposed binding mechanism to explain the results obtained in sections two and three. Section five introduces two new chemical reactions to study, including a Strecker reaction using TMSCN, an intramolecular Diels-Alder furan reaction, and efforts to catalyze a Diels-Alder reaction using a 1,2-diketone as a dienophile in conjunction with the previously described diene 1,3,3-trimethyl-2-vinyl- cyclohexene. Conclusions for this chapter’s chemistry are presented in section six. Chapter four is divided into seven sections, the first of which simply introduces the chapter. The second section describes the use of simple chiral olefins (+)-camphene and (1R)-(+)--pinene to generate chiral R*AlBr2 Lewis acids to promote and catalyze the three reactions that were successfully optimized in chapter three. The third section describes the synthesis and hydroalumination of several novel chiral olefin derivatives of (1R)-(+)-camphor. The fourth section describes the use of these previously generated novel chiral R*AlBr2 to promote and catalyze the three reactions that were optimized in chapter three. The firth section describes a number of Lewis acid binding studies proving that RAlBr2-type Lewis acids do not disproportionate in solution, and that these Lewis acids are indeed suitable for asymmetric catalysis. The sixth section describes efforts to synthesize dimers of (1R)-(+)-camphor and (+)-camphene with an internal double bond. Conclusions for this chapter’s chemistry are presented in section seven. vi Chapter five is divided into five sections. The first section reiterates the important conclusions from chapter four and introduces the fifth chapter. The second section introduces the novel classes of Lewis acid R*AlBr(OR*) along with R*AlBr(NOR*) by adding either lithiated chiral alcohols or lithiated chiral tertiary