Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2013)

Abstract

Development of Gold-Catalyzed Oxidative Alkene Heteroarylation and of Enantioselective Reactions Enabled by Phase Separation

by

Aaron Daniel Lackner

Doctor of Philosophy in Chemistry

University of California, Berkeley

Prof. F. Dean Toste, Chair

As with many bodies of research compiled through the course of a graduate career, this thesis reflects an uneven progression of aim based on the accumulation of unexpected results. Three main topics will be discussed in this thesis' chapters that may appear somewhat disparate. In particular, a significant conceptual gap exists between the first topic, oxidative gold catalysis, and the second topic, chiral anion phase-transfer catalysis. However, these fields are united by the realization that the characteristics of a reagent integral to the former might also be uniquely suitable for implementation in the latter.

Chapter 1 discusses the development of a redox-active Au(I)-Au(III) catalytic system for the functionalization of alkenes. Based on early precedent, we hoped to show that the strong dicationic oxidant Selectfluor could generate a catalytically active cationic Au(III) center that enables reactivity that cannot be achieved through Au(I) catalysis, terminating in an arylation rather than protonation to return the catalyst. Methods for the intra- and intermolecular heteroarylation of alkenes were developed and experiments were performed suggesting an unusual reaction mechanism. Attempts to expand the types of transformations that could be accomplished under this mode of reactivity unexpectedly led us to consider instead the properties of Selectfluor and how it could be effectively employed as a reagent in enantioselective transformations.

Chapter 2 addresses this very topic. The dicationic nature of the electrophilic fluorination reagent Selectfluor imparts on it many favorable qualities, but solubility in organic solvents is not one of them. Using a concept developed earlier within our laboratories, we hoped to show that this insolubility could be used to suppress racemic background reaction in enantioselective fluorination reactions, a class of transformation that remains largely underdeveloped in the literature. Lipophilic chiral phosphate anions, which can undergo anion exchange with the reagent salt, serve to solubilize the cationic fluorinating agent, rendering it both chiral and available for reaction with a suitable substrate. This mode of reactivity, chiral anion phase-transfer catalysis, was used to develop the enantioselective fluorocyclization of alkenes. Studies in the use of another type of cationic electrophile for the enantioselective oxidation of alcohols will also be discussed.

An extension of the concept of phase-separation for suppression of unwanted reactivity was applied to the deracemization of chiral amines, which is presented in Chapter 3. Single-operation deracemization, in which a racemic substrate is dynamically resolved to its enantioenriched form, generally employs an oxidant to destroy a stereocenter and a reductant to reform it, as well as a chiral element to impart enantioselectivity on at least one of these steps. The highly reactive nature of oxidants and reductants towards one another has thus far precluded the development of such a deracemization by purely chemical means. We hypothesized that by separating the oxidant, substrate, and reductant into different phases, we could use a single catalyst to promote both the oxidation and subsequent enantioselective reduction of chiral substrates. This concept was used in the development of a deracemization protocol for 3H indolines and other chiral amine substrates.

    Cover page: Development of Gold-Catalyzed Oxidative Alkene Heteroarylation and of Enantioselective Reactions Enabled by Phase Separation
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2014)
    During the past decade, the use of Au(I) complexes for the catalytic activation of C-C π-bonds has been investigated intensely. Over this time period, the development of homogeneous gold catalysis has been extraordinarily rapid and has yielded a host of mild and selective methods for the formation of carbon-carbon and carbon-heteroatom bonds. The facile formation of new bonds facilitated by gold naturally led to efforts toward rendering these transformations enantioselective. In this Account, we survey the development of catalysts and ligands for enantioselective gold catalysis by our research group as well as related work by others. We also discuss some of our strategies to address the challenges of enantioselective gold(I) catalysis. Early on, our work with enantioselective gold-catalyzed transformations focused on bis(phosphinegold) complexes derived from axially chiral scaffolds. Although these complexes were highly successful in some reactions like cyclopropanation, the careful choice of the weakly coordinating ligand (or counterion) was necessary to obtain high levels of enantioselectivity for the case of allene hydroamination. These counterion effects led us to use the anion itself as a source of chirality, which was successful in the case of allene hydroalkoxylation. In general, these tactics enhance the steric influence around the reactive gold center beyond the two-coordinate ligand environment. The use of binuclear complexes allowed us to use the second gold center and its associated ligand (or counterion) to exert a further steric influence. In a similar vein, we employed a chiral anion (in place of or in addition to a chiral ligand) to move the chiral information closer to the reactive center. In order to expand the scope of reactions amenable to enantioselective gold catalysis to cycloadditions and other carbocyclization processes, we also developed a new class of mononuclear phosphite and phosphoramidite ligands to supplement the previously widely utilized phosphines. However, we needed to judiciously design the steric environment to create "walls" that enclose the gold center. We also successfully applied these same considerations to the development of binuclear carbene ligands for gold. Finally, we describe the design of bifunctional urea-monophosphine ligands used in a gold-catalyzed three-component coupling.
      Cover page: Development of Catalysts and Ligands for Enantioselective Gold Catalysis
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2013)
      The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant, and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation and resulted in the isolation of highly enantioenriched starting materials in high yields.
        Cover page: Single-Operation Deracemization of 3H-Indolines and Tetrahydroquinolines Enabled by Phase Separation
        Top