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

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.available2010-10-01T16:42:45Zen
dc.date.available2010-10-01T16:42:53Zen
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.description.departmentChemistry and Biochemistry
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
thesis.degree.departmentChemistry and Biochemistryen
thesis.degree.disciplineChemistryen
thesis.degree.grantorUniversity of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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