First enantioselective oxidative rearrangement of indoles to spirooxindoles, studies toward the total synthesis of IB-00208 and total synthesis of cribrostatin 6

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dc.contributor.advisorMartin, Stephen F.en
dc.contributor.committeeMemberBielawski, Christopher W.en
dc.contributor.committeeMemberKrische, Michael J.en
dc.contributor.committeeMemberJones, Richard A.en
dc.contributor.committeeMemberWhitman, Christian P.en
dc.creatorKnueppel, Daniel Isaiahen
dc.date.accessioned2010-10-01T16:42:45Zen
dc.date.accessioned2010-10-01T16:42:53Zen
dc.date.accessioned2017-05-11T22:20:18Z
dc.date.available2010-10-01T16:42:45Zen
dc.date.available2010-10-01T16:42:53Zen
dc.date.available2017-05-11T22:20:18Z
dc.date.issued2010-05en
dc.date.submittedMay 2010en
dc.date.updated2010-10-01T16:42:53Zen
dc.descriptiontexten
dc.description.abstractThe first enantioselective oxidative rearrangement of indoles to spirooxindoles was developed. A 2,3-disubstituted indole was stereoselectively epoxidized using an in situ-generated chiral dioxirane catalyst. Rearrangement of the transient epoxide intermediate afforded the antipode of the tricyclic spirooxindole present in the marine alkaloid citrinadin A. A mild and rapid entry to 1,4-dioxygenated xanthones from benzocyclobutenones was developed. This method was applied to the construction of the highly aromatic pentacyclic core of IB-00208, a promising antitumor agent with reported nanomolar activity. The requisite angularly-fused benzocyclobutenone was accessed via a novel ring-closing metathesis approach. Lack of success in synthesizing the final ring of IB-00208 from the pentacycle led us to revise our approach and incorporate an extra ring earlier in the synthesis. After constructing a modified benzocyclobutenone, the hexacyclic core of IB-00208 was efficiently accessed using the same key chemistry. An oxidation, deprotection and glycosylation remain to complete the synthesis of the natural product. A total synthesis of antimicrobial and antineoplastic cribrostatin 6 was accomplished in only four steps in the longest linear sequence from commercially available starting materials. The key step employed a tandem 4π-electrocyclic ring opening, radical cyclization, and homolytic aromatic substitution sequence to afford the tricyclic core of the natural product, which was converted to cribrostatin 6 via a subsequent oxidation in one pot. The versatility of this reaction sequence was demonstrated by preparation of analogs of the natural product, which were tested for their anticancer activity.en
dc.format.mimetypeapplication/pdfen
dc.identifier.urihttp://hdl.handle.net/2152/ETD-UT-2010-05-944en
dc.language.isoengen
dc.subjectSynthesisen
dc.subjectSpirooxindolesen
dc.subjectIB-00208en
dc.subjectCribrostatin 6en
dc.titleFirst enantioselective oxidative rearrangement of indoles to spirooxindoles, studies toward the total synthesis of IB-00208 and total synthesis of cribrostatin 6en
dc.type.genrethesisen

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