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Synthesis of novel simplified sarcodictyin/eleutherobin analogs with potent microtubule-stabilizing activity, using ring closing metathesis as the key-step

Beumer, R, Bayon, P, Bugada, P, Ducki, S, Mongelli, N, Sirtori, FR, Telser, J and Gennari, C 2003, 'Synthesis of novel simplified sarcodictyin/eleutherobin analogs with potent microtubule-stabilizing activity, using ring closing metathesis as the key-step' , Tetrahedron, 59 (44) , pp. 8803-8820.

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Abstract

The synthesis of a number of novel simplified eleutheside analogs with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in 6 steps on a multigram scale from R-( - )-carvone in 30% overall yield] via multiple stereoselective Brown allylations. Second generation RCM catalyst 13 gave the desired ring closed 10-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) likely reflects thermodynamic control. The crucial role of the protecting groups of the homoallylic and allylic substituents for the efficiency of the RCM reactions is discussed. These simplified analogs of the natural product (lacking inter alia the C-4/C-7 ether bridge) retain potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma and human colon carcinoma cell lines, IC[5][0] in the μM range given in Table 2), three orders of magnitude less than paclitaxel (IC[5][0] in the nM range).

Item Type: Article
Uncontrolled Keywords: Allylation, antitumor compounds, metathesis, stereocontrol
Themes: Subjects / Themes > Q Science > Q Science (General)
Subjects outside of the University Themes
Schools: Colleges and Schools > College of Science & Technology
Colleges and Schools > College of Science & Technology > School of Environment and Life Sciences
Journal or Publication Title: Tetrahedron
Publisher: Elsevier
Refereed: Yes
ISSN: 00404020
Depositing User: H Kenna
Date Deposited: 07 Aug 2007 13:55
Last Modified: 20 Aug 2013 16:45
URI: http://usir.salford.ac.uk/id/eprint/140

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