Synthesis of Four Diastereomeric Linoleic Triols and Development of a Large Scale Convergent Approach to Apoptolidinone C

Abstract

CHEMISTRY

Synthesis of Four Diastereomeric Linoleic Triols and Development of a Large Scale Convergent Approach to Apoptolidinone C

Robert Woods Davis

Dissertation under the direction of Professor Gary A. Sulikowski The mammalian epidermal water barrier is essential for life to exist on dry land. While a number of gene products are implicated in this process, mutation in a single gene is lethal in mice, and leads to the hallmark symptoms of congenital ichthyosis in humans. Human and mouse genetic studies have identified an enzymatic pathway initiated by 12R-lipoxygenase as critical to the formation of an intact epidermal barrier. Oxidation of linoleate by 12R-lipoxygenase, followed by epidermal lipoxygenase-3 and hydrolytic epoxide opening affords trihydroxy-linoleates. The identification and quantification of these trihydroxy-isomers is complicated by their chromatographic and spectroscopic similarities. Further study will indeed be aided by isomerically pure synthetic standards. Efforts toward four such isomers are described in Chapter I. In Chapter II, our efforts toward a large-scale synthesis of the macrolide polyketide apoptolidinone C are described. It is our hope that large scale synthetic access to apoptolidinone C will facilitate further biological studies.

Approved: ___________________________________________________Date______________ Gary Sulikowski, Ph.D.