Zirconocene-Mediated Carbonylative Coupling of Grignard Reagents and Cancer Prevention via Compounds that Modulate 15-PGDH

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2016-08-26

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Moss, Melissa Christine

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Abstract

This manuscript consists of two chapters. The first chapter describes the carbonylative coupling of Grignard reagents using organozirconocene intermediates. Organozirconocenes are versatile synthetic intermediates that can undergo carbonylation to yield acyl anion equivalents. Zirconocene hydrochloride is often the reagent of choice for accessing these intermediates but generates organozirconocenes only from alkenes and alkynes. This requirement eliminates a broad range of substrates. For example, organozirconocenes in which the zirconium center is bonded to an aromatic ring, a benzylic group, or an alkyl group that possesses a tertiary or quaternary carbon atom α to the carbon-zirconium bond can not be formed in this way. Therefore, the methodology presented in this chapter provides more generalized access to acyl zirconium reagents through transmetalation of Grignard reagents with zirconocene dichloride under a CO atmosphere. This protocol generates acyl zirconium(IV) complexes that are inaccessible with the Schwartz reagent, including those derived from secondary and tertiary alkyl and aryl Grignard reagents. The second chapter describes a medicinal chemistry campaign that was aimed at the discovery of small molecules that increase the expression of the cancer-suppressor gene 15-Prostaglandin Dehydrogenase (15-PGDH) for treatment of colon cancer. Presented within this chapter is the identification of a 15-PGDH activator, synthesis and structure-activity relationship (SAR) of analogs, and conclusions from our explorations.

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