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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Title: First enantioselective oxidative rearrangement of indoles to spirooxindoles, studies toward the total synthesis of IB-00208 and total synthesis of cribrostatin 6
Author: Knueppel, Daniel Isaiah
Abstract: The 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 .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2010 -05 -944
Date: 2010-10-01

Citation

First enantioselective oxidative rearrangement of indoles to spirooxindoles, studies toward the total synthesis of IB-00208 and total synthesis of cribrostatin 6. Doctoral dissertation, University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2010 -05 -944 .

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