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Totally Synthetic by Paul H. Docherty, 30 July 2006

Total Synthesis of Iejimalide B


A. Fürstner, C. Nevado, M. Tremblay, C. Chevrier, F. Temlý, C. Aïssa, M. Waser, Angew. Chem. Int. Ed. 2006, 45, 5837-5842.

DOI: 10.1002/anie.200601860

An interesting read by Fürstner, into the total synthesis of this cytotoyic and anticancer polyene macrolide. As the most active member of the family, it’s certainly a useful target, but one would think that the disconnections for the retrosynthetic analysis would be relatively straight-forward. However, that tempting macrolactonisation failed, so their approach to this compound had to be revised. They decided, then, to complete the macrocyclisation using a RCM strategy. Their fragment synthesis involved a notable palladium mediated alkylation, working with a propargyl mesylate (R= H, TIPS) and an aldehyde. This transformation uses diethyl zinc, and returned a better d.r. (unsurprisingly) with the TIPS-bearing acetylene.

Other fragments were built using more traditional means, leading them to the assembly stage. The ester was returned using Yonemitsu methods, and RCM with Grubbs II completed the macrocycle to give the desired product in a quantitative transformation. This is no mean feat; RCM of polyolefins is a difficult process to say the least. However, at this point, their luck ran out; cleavage of the BOC group proved impossible without decomposition of the macrocycle! Examining this process further using a suitable model system, certain subtleties became apparent, namely the choice of alcohol protecting group [1]. Although this seems rather remote from the amine, Fürstner proposed a very interesting and plausible reason for this anomaly.

A replanned assembly strategy then allowed them to complete the molecule; peptide coupling at an earlier stage, Suzuki, esterification and RCM completed the skeleton, with only deprotection required to finish. Again, a great read; I have great respect for those authors who discuss their problems and setbacks, as it brings the achievement of the synthesis into greater focus.

[1] A tiglate group (tiglic acid ester):

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