UC Berkeley

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.