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Development and Mechanistic Investigations of Gold-Catalyzed Reactions

  • Author(s): Shapiro, Nathan David
  • Advisor(s): Toste, F. Dean
  • et al.
Abstract

Historically, chemists have been motivated by problems in total synthesis or by a desire to develop reactions of broad utility. In answer to these challenges, several approaches to fundamental research have been developed. In chapter 1, we describe how our reactivity-driven approach has led to the discovery of numerous synthetic tools.

The development of new synthetically useful methodology often rests on an understanding of the mechanistic underpinnings of the desired transformation. This is particularly true when this knowledge forms the basis for subsequent mechanistic proposals. The coordination of an alkyne to a cationic Au(I) complex represents the prototypical mechanistic starting place for many Au(I)-catalyzed reactions. In chapter two, we describe the isolation and characterization of a gold(I)-coordinated alkyne. The crystal structure of this compound is compared to related Ag(I) and Cu(I) compounds. With these structures in hand, we can begin to understand the unique ability of Au(I) complexes to serve as effective %pi;-activation catalysts, especially in understanding why gold is often more effective than copper or silver.

In addition to being able to activate %pi;-bonds toward nucleophilic attack, it has been proposed that gold is also capable of stabilizing adjacent carbocations. Such species (i.e. [L-Au-CR2]+) have been referred to as gold-carbenoids or gold-stabilized carbocations. In chapter 3, we describe a bonding model for these intermediates that suggests that while the gold-carbon bond order is generally less than or equal to one, this bond includes both %sigma;- and %pi;-type bonding. Furthermore, the position of a given Au-stabilized intermediate on a continuum ranging from gold-stabilized singlet carbene to gold-coordinated carbocation is dictated by both the carbene substituents and the ancillary ligand. This model provides an explanation for observed ancillary ligand effects and should enable more efficient reaction optimization.

In chapter 4, a series of gold(I)-catalyzed rearrangement reactions of alkynyl sulfoxides, sulfimides and sulfur ylides are reported. Homopropargyl sulfoxides are rearranged to benzothiepinones or benzothiopines, while %alpha;-thioenones are formed in the reaction of propargyl sulfoxides. It is proposed that these reactions proceed via an %alpha;-carbonyl gold-carbenoid intermediate formed through gold-promoted oxygen atom transfer from sulfoxide to alkyne.

In chapter 5, the development of a convenient gold(III)-catalyzed synthesis of azepines from the intermolecular annulation of propargyl esters and %alpha;,%beta;-unsaturated imines is discussed. Mechanistic experiments suggest that this formal [4 + 3]-cycloaddition reaction proceeds via a stepwise process involving intermolecular trapping of a gold-carbenoid intermediate and subsequent intramolecular trapping of the resulting allyl-gold intermediate.

In chapter 6, we discuss the gold(III)-catalyzed [3+3]-cycloaddition reaction of propargyl esters and azomethine imines. This reaction provides a rapid entry into a wide range of substituted tetrahydropyridazine derivatives from simple starting materials. A mechanism similar to that proposed in chapter 5 is discussed, along with a detailed description of the consequences of this mechanism on the diastereoselectivity of the annulation reaction. In addition, a strategy for rendering this reaction asymmetric is presented.

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