Lee, Kim, An, Shin, Yu, Woo and Jung. ACIEE, 2006, Early View. DOI: 10.1002/anie.200603363.
Another amphidinolide in the bag, this time Amphidinolide E, completed by Eun Lee’s group at Seoul National University. Their approach is very convergent, with an interesting choice of disconnections, some which are obvious, others less so.
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.) goes to re-enforce 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 free alcohol was then free for functionalisation with an olefin and the tosylate converted to an iodide via a Finklestein 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 NHK, 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.
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.
I’ll be honest and say that whilst this is all well done, this paper didn’t grab me, generally because it’s lacking in novel methodology. However, it’s a complex target, and the first total synthesis, so I guess it’s still worthy…