Graduation Semester and Year

2010

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Carl Lovely

Abstract

The oroidin family of marine natural products is a growing group of sponge-derived alkaloids which contain 2-aminoimidazole and pyrrolecarboxamide fragments as their signature features. Due to their structural diversity and biological activity, many groups are interested in the total synthesis of these natural products. It has been proposed that many of the alkaloids in this family are produced in nature simply by dimerization and/or cyclization of the simplest member, oroidin. In this dissertation we have attempted to explore these biosynthetic relationships to complete the total synthesis of several oridin-derived natural products. This dissertation consists of two parts. The first part describes the total synthesis of the nominal structure of nagelamide D and the development of approaches towards total synthesis of other congeners with the nagelamide family. The second part of this dissertation describes studies of intramolecular cyclization reactions of imidazolylpropargyl amides as linchpin synthons for the assembly of imidazole-containing natural products. In the first part, a Pd-catalyzed Stille reaction was used as a transformation to construct divinyl imidazole derivatives in convergent fashion. A divergent approach was used to further functionalize intermediates obtained from Stille reaction towards the total synthesis of several nagelamides. The total synthesis of nagelamide D was accomplished by using a double Mitsunobu reaction to install pyrrolecarboxamides. Selective hydrogenation of a trisubstituted olefin or electrocyclization reactions of divinyl intermediates obtained from the Stille reaction provided key frameworks required for the total synthesis of nagelamide A, nagelamide E and ageliferin respectively. Construction of the stereoisomeric Z-vinyl stannane provided access to the divinyl imidazole fragment required for the total synthesis of nagelamide C.In the second part, Pd-catalyzed and/or base promoted intramolecular cyclization reactions of imidazolylpropargyl amides were screened as a part of diversity oriented strategy for the assembly of natural product-like frameworks. Several novel heterocycles including morpholine, pyrazinone, oxazole, pyridinone and azepin derivatives were prepared using intramolecular cyclization. Many of these heterocyclic compounds have potential to serve as intermediates en route to the total synthesis of oroidin-derived alkaloids including stevensine, nagelamide R, nagelamide T, oxocyclostylidol, agelastatin A. The potential of this approach was demonstrated in a formal total synthesis of cyclooroidin

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

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