Applications of ring-closing metathesis in construction of alkaloid natural products : synthetic studies on the immunosuppressant FR901483 and lundurines A-C

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Applications of ring-closing metathesis in construction of alkaloid natural products : synthetic studies on the immunosuppressant FR901483 and lundurines A-C

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dc.contributor.advisor Martin, Stephen F.
dc.creator Simila, Suvi Tuula, 1978-
dc.date.accessioned 2012-10-02T19:14:29Z
dc.date.available 2012-10-02T19:14:29Z
dc.date.created 2008-05
dc.date.issued 2012-10-02
dc.identifier.uri http://hdl.handle.net/2152/18126
dc.description.abstract Ring-closing metathesis (RCM) has proven to be a valuable tool for constructing alkaloid-like, poly-cyclic compounds. The syntheses of alkaloid structures we were interested in developing, could utilize RCM to construct a spirocyclic structure for the immunosuppressant FR901483 and the tetracyclic framework of lundurines A-C asymmetrically. The azaspirane core of FR901483 was obtained via an addition of an allylsilane to an N-acyl iminium ion, and a RCM. Other key functional group manipulations were a stereoselective hydroboration and a subsequent lactonization that provided a precursor for a lactone-lactam rearrangement. This rearrangement provided the azatricyclic core of FR901483. In the enantioselective approach to FR901483 a new mildly cleavable protecting group was developed. Addition of a zinc nucleophile to a chiral N-acyl iminium ion, and a RCM provided the desired precursor for the hydroboration/lactone-lactam rearrangement sequence but without a sufficient stereoselection. A novel approach toward the total synthesis of lundurines A-C has been developed. The key features of the approach involve an intramolecular cyclopropanation of the indole C(2)-C(3) double bond, an enantioselective tandem RCM to construct the tetracyclic core and a concise synthesis to access the RCM precursor. An Ugi reaction was utilized with both cyclic and acyclic ketones, 2-vinyltryptamine derivative, a carboxylic acid and an isocyanide to access diverse compounds, including RCM precursors. An alternative reductive amination route to construct the RCM precursor for the lundurines was found to be more efficient and high yielding than the Ugi approach. An RCM was utilized to affect the closure of the five-and eight-membered rings of the tetracyclic core. This constitutes as the first example of RCM of a 2-vinylindole derivative to give an indole-fused eight-membered ring.
dc.format.medium electronic
dc.language.iso eng
dc.rights Copyright © is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.
dc.subject.lcsh Metathesis (Chemistry)
dc.subject.lcsh Immunosuppressive agents
dc.title Applications of ring-closing metathesis in construction of alkaloid natural products : synthetic studies on the immunosuppressant FR901483 and lundurines A-C
dc.description.department Chemistry
dc.type.genre Thesis
dc.type.material text
thesis.degree.department Chemistry
thesis.degree.discipline Chemistry
thesis.degree.grantor The University of Texas at Austin
thesis.degree.level Doctoral
thesis.degree.name Doctor of Philosophy

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