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Totally Synthetic by Paul H. Docherty, 14 November 2006

Total Synthesis of Amphidinolide E


C. H. Kim, H. J. An, W. K. Shin, S. K. Woo, S. K. Jung, E. Lee, Angew. Chem. Int. Ed. 2007, 45, 8019-8021.

DOI: 10.1002/anie.200603363

Eun Lee’s approach for the total synthesis of Amphidinolide E is very convergent, with an interesting choice of disconnections. Some are obvious, others less.

So, to the forward synthesis; starting with a known chiral triol, protection with a PMP acetal and reduction of a an ester to the aldehyde gave the starting material for the first interesting transformation, a Roush crotylation. Many of you will have seen this before, but the result (86%, 16:1 d.r.) illustrates the utility of this transformation.

Transformation of this product into the starting material shown below was accomplished easily, firstly by protection of the free alcohol, deprotection of the acetal and selective tosylation of the primary alcohol. The freed alcohol was then ready for functionalisation with an olefin and the tosylate converted to an iodide via a Finkelstein reaction. Cyclisation onto the alkene via radical generation ((TMS)3SiH) returned the THF in rather decent 92%. However, they had a problem, in that they required homologation of the olefin to the acetylene shown. The tried using an Nozaki-Hiyama-Kishi Coupling/Wittig sequence, but this gave them rather low yields, so they resorted to using diazophosphonate on the aldehyde. Again, not novel chemistry, but a nice implementation in 83% overall yield.

Metathesis of the acetylene with 1,4-pentadiene completed most of the top-half, requiring functional group transformation to deliver the Julia-Kocienski substrate. Coupling with the lower fragment (produced relatively quickly), deprotection and macrolactonisation then completed the target.