Date of Completion

8-24-2016

Embargo Period

2-20-2017

Keywords

heterocycles, transition metals, oxetane, lactone, beta-lactones, platinum, platinacyclobutane, palladium, rhodium, conjugate addition

Major Advisor

Amy R. Howell

Associate Advisor

Christian Brueckner

Associate Advisor

Mark Peczuh

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Heterocycles are present in more than half of organic compounds. For organic chemists, they are valued as synthetic targets or scaffolds to construct valuable products. For the past two decades, the Howell group has made contributions towards the synthesis and applications of 4-membered heterocyclic compounds, such as oxetanes and beta-lactones. Most of the previously reported transformations that involve strained heterocyclic compounds rely on traditional methods in which rendering the reaction with good and predictable selectivity (regio-, chemo- and stereoselectivity) is challenging.

The works described took advantage of the intrinsic reactivity of strained heterocycles and combined that with the highly selective transformations promoted by transition metal (TM) catalysts. Three successful methodologies were developed. Chapter 1 describes the discovery and scope of a novel Pt-catalyzed expansion of spirocyclopropyl oxetanes to synthetically useful 3-methylenetetrahydrofurans. This unprecedented oxetane expansion was realized via cyclopropane activation under platinum catalysis. Mechanistic studies, through 13C-labelling and 13C-DEPT NMR analyses, suggested that the oxetane expansion was promoted by a regioselective carbon-carbon bond activation of cyclopropane with platinum.

Chapter 2 describes two transition metal catalyzed transformations of alpha-methylene-beta-lactones. First is a Rh-catalyzed conjugate addition with aryl boronic acids to access various beta-lactones. beta-Lactones are highly privileged synthetic products and intermediates. They have been shown to elicit serine hydrolase inhibition. They are also used as intermediates to obtain difunctionalized acyclic compounds, and this was the goal in the next method. The second method developed involves a chemoselective opening of beta-lactones to form beta-hydroxy amides. Ring opening of beta-lactones with several nucleophiles typically provide a mixture of two major products; opening via the (a) alkyl C–O bond, or (b) the acyl C–O bond. The selective ring-opening was realized via activation of acyl carbon-oxygen bond under palladium catalysis. Under the developed conditions, several beta-lactones were selectively opened with various amine nucleophiles and gave beta-hydroxy amides as sole product. This method was also translated to a Pd-catalyzed asymmetric kinetic resolution of racemic to enantioenriched beta-lactones.

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