Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Marisa C. Kozlowski

Abstract

Part I. The first asymmetric synthesis of a-allyl-a-aryl a-amino acids by means of a three component coupling of a-iminoesters, Grignard reagents, and cinnamyl acetate is reported. Notably, the enolate from the tandem process provides a much higher level of reactivity and selectivity than the same enolate generated via direct deprotonation, presumably due to differences in the solvation/aggregation state.

A novel method for removal of a homoallylic amine protecting group delivers the free amine congeners. The a-allyl moiety offers a means to generate further valuable a-amino acid structures. Cross-metathesis of the tandem product provided allylic diversity not afforded in the parent reaction. Cyclic a-amino acid derivatives could be accessed by ring closing metathesis presenting a viable strategy to higher ring homologues of enantioenriched a-substituted proline. The 8-member proline analog was successfully converted to the pyrrolizidine natural product backbone.

Part II. The asymmetric spirocyclization of allenyl ketones is reported. High-throughput experimentation by means of a chiral Lewis acid library enabled the determination of a suitable catalyst system. Protecting group manipulation provides an orthogonal route to enantioenriched para-quinone and ortho-quinone spirocycles. This novel technology provides access to the spirocyclic core that is prevalent in many natural products.

Part III. Palladium has been identified as a suitable catalyst for the chemoselective activation of C(sp3)-H bond over C(sp2)-H bond of toluene and tolyl analogs. This technology has been combined with the C(sp3)-H activation of acidic C-H bonds to form new C-C bonds. High-throughput experimentation was used for identifying conditions that reduced toluene loading and engendered catalyst turnover via a suitable oxidant.

The parent reaction has been extended to include the Pd catalyzed alkylation of phenylglycine azlactones with ethylbenzene, 2-ethylnaphthalene, propylbenzene and butylbenzene. Mechanistic studies were initiated to determine whether the process occurs via free radicals or via Pd mediated C(sp3)-H activation. Our studies support a Pd mediated process in which the C(sp3)-H activation of the tolyl analog is the rate determining step. This finding represents a paradigm shift in our understanding of Pd and its selectivity for arene activation vs benzylic activation.

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