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Strategies for Enantioselective Carbon-Heteroatom Bond Formation

  • Author(s): Miles, Dillon Harding
  • Advisor(s): Toste, F. Dean
  • et al.
Abstract

Although the topics discussed in this dissertation each stand as unique areas of research in their respective fields, they are united under the common approach of using catalyst structure to control the selectivity of a particular reaction. For the majority of these transformations, use of a chiral counterion-based catalyst, a relatively new strategy in the field of asymmetric synthesis, proved essential for successful enantioinduction. An additional subtheme, design and application of electrophilic reaction components, provided an added dimension of control to the reaction outcome.

Chapter 1 presents a brief perspective on the gold-catalyzed synthesis of heterocycles with an emphasis on previously published hydrofunctionalizations of allene substrates containing tethered nucleophiles, thus providing context for Chapter 2.

Chapter 2 describes efforts toward the gold(I)-catalyzed enantioselective bromocyclization of allenes. The primary goal of this project was the synthesis of enantioenriched vinyl halide-containing products containing enantioenriched allylic stereocenters within a heterocyclic ring moiety. Efforts to synthesize these molecules were initially hindered if more traditional electrophilic halogen sources such as N-bromosuccinimide were used; however, employment of the relatively unexplored N-bromolactams resulted in high yields and selectivities of the desired products. Additionally, this methodology partially utilized chiral phosphate-based molecules as counterions as an additional source of chiral information.

Chapter 3 takes inspiration from the previous use of chiral phosphate counterions to accomplish an enantioselective intermolecular α-amination reaction utilizing nucleophilic nitrogen sources. This project sought a reaction complementary to previously existing versions which utilized electrophilic sources of nitrogen. Choice of chiral phosphoric acid in addition to an appropriately activated azoalkene substrate was critical for the high levels of yield and enantioselectivity observed. While expanding the substrate scope, a serendipitous kinetic resolution was observed, which revealed an interesting mode of reactivity associated with α-arylamino hydrazones.

Chapter 4, the final installment, is intended to be an initial survey of explorations into Pummerer-like reactivity again utilizing chiral phosphoric acids or phosphates as a source of chirality. Still in its infancy, this project has explored various carbon-heteroatom bond-forming reactions utilizing either sulfoxide or fluorosulfonium moieties as a source of oxidized sulfur to enable an enantioselective cross-dehydrogenative coupling using a Pummerer-like reaction mechanism. One eventual goal would be to expand the space of enantioenriched sulfur-containing heterocycles.

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