Total Synthesis of Iejimalides

The iejimalides are naturally occurring 24-membered macrolides possessing a high level of cytotoxicity. Unfortunately these compounds are present in only very low concentrations within their natural sources. Due to the limited amount of substance isolated no detailed investigations concerning the antitumor activities have been undertaken so far. Furthermore no synthetic proof of suggested constitution has been reported as only syntheses of subunits of these interesting compounds have been achieved yet. Due to the unique cytotoxicity of these compounds with IC50 values in the nanomolar region and the very limited availability from natural sources there is great interest in the total syntheses of these macrocycles, especially in iejimalide B which proved to be the most active one among them. Furthermore, there is also a strong demand in investigations concerning the structure- activity relationship (SAR) of this class of macrocyclic lactones. Although syntheses of single fragments were possible in satisfying yields in the past, synthesis of the macrocyclic system via a final Yamaguchi lactonization resulted either in a decomposition of the educt or gave unwanted by- products. Accordingly, there is a strong demand in a modified strategy with an alternative ring closure in a different position to overcome the limited reactivity of this system towards a final lactonization step. Therefore, the main target of this project is the development of a useful synthesis strategy to overcome the final cyclization problems observed in the past. It seems promising to achieve the final ring-closure either via a C6-C7 cross-coupling reaction or via a C5-C6 olefination. Thus it will first be necessary to synthesize useful fragments for this approach. With these synthons available the main focus will be on the final ring-closure and further on the peptide bonding giving the iejimalide skeleton. If this approach succeeds, this methodology shall be used to synthesize a small assembly of differently substituted iejimalide derivatives to get more details about the SAR of these macrocycles. The successful completion of the total synthesis of iejimalides will allow a detailed study of the biological activities with respect to further medicinal applications. Due to the flexibility of the intended strategies, a variety of differently substituted derivatives should be obtainable providing a deeper insight into the SAR of these compounds. The project described herein is designed to build on successful preliminary results and expertise within the host`s research group thus ensuring a firm base from which the chemistry can be developed.