Development of Amino Acid-Derived Ligands for Enantioselective Synthesis of Amines and Alcohols

Abstract

Chapter One Development of Simple Organic Molecules as Catalysts for Enantioselective Allyl Additions to N-Phosphinoylaldimines and Isatins A new catalytic protocol for the enantioselective addition of organoborates to imines and carbonyls is described. This novel method, which does not require transition metals utilizes a modular and easily accessed aminophenol to dictate the stereochemistry of the products. Allyl-additions to N-phosphinoylaldimines and isatins, as well as allenyl-additions to isatins are studied and literature relevant to these transformations is discussed. Additionally, two separate methods for obtaining "crotyl-type" addition products to aldimines; one requiring α-chiral allylboronates and the other requiring a zinc-alkoxide, are discussed. Studies to elucidate the mechanism of this catalytic protocol are also contained in this chapter. Chapter Two Enantioselective Additions to Fluorinated Ketones: A Platform for Studying the Interaction Between Organofluorine and a Small Molecule Utilizing the new protocol discussed in Chapter One, allyl- and allenyl-groups are added enantioselectively to ketones containing a fluorinated substituent. Myriad tertiary alcohols are synthesized, demonstrating the value of this method. This study also allows for examining how organofluorine containing compounds bind to other organic molecules, which is a current topic of intense interest in the field of medicinal chemistry. Mechanistic studies support the idea that, in many cases, the fluorine of the substrate is electrostatically attracted to the ammonium-ion in the catalyst. Chapter Three Enantioselective Additions of Organoboronates to Ketones and Alphaketoesters Promoted by an Aminophenol Containing Catalyst Modification of the aminophenol disclosed in Chapter One allows for increased enantioselectivity for the allyl-addition to both simple ketones (such as acetophenone) and alphaketoesters. For simple ketones, a critical component of the optimal catalyst is replacing the tert-butyl group ortho to the phenol with the sterically large triphenylsilyl group. For alphaketoesters, this tert-butyl group was replaced with the sterically smaller metyl group. Rationale for why these contradictory changes in the catalyst structure lead to higher enantioselectivity for reactions with these two classes of ketones is discussed. Chapter Four Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of γ-Substituted Siloxyfurans with Aldimines A previously disclosed Ag-catalyzed enantioselective vinylogous Mannich reaction (EVM) with α-, β-, and unsubstituted siloxyfurans is extended to include γ-substituted siloxyfurans. This method, which generates a tertiary stereogenic center concurrent with an adjacent to a quaternary stereogenic center, requires a rarely used 2-thiomethylaniline N-protecting group for the aldimines.