Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Total synthesis of dictyostatin analogs for anticancer agents

Jung, Won-Hyuk (2008) Total synthesis of dictyostatin analogs for anticancer agents. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (3MB) | Preview


(-)-Dictyostatin, isolated from a marine sponge, shows potent cancer cell antiproliferative activity by stabilizing microtubules. Following the structure proof of dictyostatin, efforts have focused on the design and synthesis of analogs on the basis of the structural similarities between dictyostatin and discodermolide. To this end, the C15 Z-alkene was introduced in dictyostatin and the C16 methyl group was removed to simplify the structure, which gave 16-normethyl-15,16-dehydrodictyostatin. The macrolactone was disconnected into three main fragments, each of which had a full carbon skeleton. The C1-C9 fragment was synthesized via Brown crotylation and cross metathesis as key reactions. The C10-C15 fragment was synthesized via Roush crotylation of the (S)-Roche ester and diimide reduction. The C16-C26 fragment was synthesized via Evans aldol reaction of the (S)-Roche ester, syn 1,3-reduction and Nozaki-Hiyama reaction. The C10-C15 and C16-C26 fragments were coupled via a Wittig reaction, and the C1-C9 fragment was coupled with the lithium reagent derived from the C10-C26 vinyliodide. Yamaguchi macrolactonization and global deprotection produced 16-normethyl-15,16-dehydrodictyostatin, along with C2E-, C9 isomers and an isomeric lactone. 16-Normethyl-15,16-dehydrodictyostatin showed a low nanomolar cancer cell antiproliferative activity and effectively competed with paclitaxel for binding to tubulin polymer.6-epi-Dictyostatin showed potent cancer cell antiproliferative activity in preliminary results. Further biological evaluation of 6-epi-dictyostatin required the preparation of a large quantity. A common intermediate was made to reduce the number of reaction steps for constructing both the C11′-C17 and C18-C26 fragments. The C1-C10′ and C11′-C17 fragments were coupled via a silicon-tethered ring-closing metathesis reaction. The C1-C17 and C18-C26 fragments were united via a HWE reaction. The Stryker and syn 1,3-reductions converted the C19 enone into the saturated alcohol regio- and diastereoselectively. A Shiina reagent used for macrolactonization suppressed the isomerization of the C2 Z-unsaturated ester. A mild grobal deprotection method was developed to complete the synthesis. As an effort to validate the routes for the large-scale synthesis, 33 mg of 6-epi-dictyostatin was synthesized.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jung,, wonhyuk_jung@hotmail.comWOJ2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCurran, Dennis Pcurran@pitt.eduCURRAN
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberKoide, Kazunorikoide@pitt.eduKOIDE
Committee MemberFloreancig, Paul Eflorean@pitt.eduFLOREAN
Date: 13 June 2008
Date Type: Completion
Defense Date: 20 March 2008
Approval Date: 13 June 2008
Submission Date: 25 March 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: total synthesis; anticancer agent; dictyostatin
Other ID:, etd-03252008-125826
Date Deposited: 10 Nov 2011 19:32
Last Modified: 15 Nov 2016 13:37


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item