Total synthesis of the marine macrolide leiodolide A

• Research unit: COST
• Project number: C11.0143

Key words (English)

Leiodolides; anticancer; macrolides; marine natural products; oxazole; total synthesis; ring-closing metathesis; structure-activity relationship

Research programs (English)

COST-Action CM0804 - Chemical Biology with Natural Products

Short description (English)

Leiodolide A (1) is a 19-membered marine macrolide that was isolated in 2006 by Fenical and co-workers from the deep-water marine sponge Leiodermatium. Leiodolide A (1) exhibits several unique structural features, including a conjugated oxazole ring and a carboxylic acid side chain that also incorporates a tertiary alcohol moiety. The compound has shown significant in vitro antiproliferative activity against a range of human cancer cell lines, in particular those of myeloid lineage. This project aims at the total synthesis of 1, in order to provide sufficient material for more extensive biological studies (including the elucidation of the mechanism of action); at the same time, the chemistry established in the course of the total synthesis work will establish the basis for the synthesis of analogs and structure-activity relationship (SAR) studies. In addition, the successful total synthesis of 1 will establish the configuration at C13, which has remained undetermined so far.

Further information (English)

Full name of research-institution/enterprise: ETH Zürich Dep.Chemie und Angewandte Biowissenschaften Institut für Pharmazeutische Wissenschaften, HCI H 405

Partners and International Organizations (English)

BE; CZ; DK; FI; FR; DE; EL; HU; IE; IT; LV; LT; NO; PT; RO; RS; ES; SE; TR; UK

Abstract (English)

Leiodolide A is a 19-membered marine macrolide that was isolated in 2006 by Fenical and co-workers from the deep-water marine sponge Leiodermatium, ogether with the related macrolactone leiodolide B. Leiodolides A/B exhibit several unique structural features, including a conjugated oxazole ring, a bromine substituent (in the case of leiodolide B), and a carboxylic acid side chain that also incorporates a tertiary alcohol moiety. Leiodolide A has shown significant cytotoxicity in the NCI's 60 cell panel (average Gl50 of 2.0 _M). However, the absolute configuration of leiodolides was not fully assigned in the isolation work and subsequent synthetic studies have even cast doubt on the structural assignment of leidolides as a whole. In this project we have explored several strategies towards the synthesis of the nominal macrolactone core structure of leiodolide A with its embedded oxazole ring. In particular, we have prepared model dienes that served to study the possibility of macrocyclization by ring closing olefin metathesis (RCM) between C6 and C7. An efficient syntheses for these dienes was developed that could have been easily adapted to provide a macrocycle suitable for elaboration into leiodolide A. Unfortunately, and in spite of extensive experimentation, the model dienes could not be induced to undergo macrocyclization. As a consequence, we are currently pursuing alternative strategies towards the construction of the macrocyclic core of leiodolide A and ultimately towards the natural product itself.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C11.0143