FÃ¼rstner, Nevado, Tremblay, Chevrier, TeplÃ½, AÃ¯ssa, and Waser. ACIEE, 2006, Early View. DOI: 10.1002/anie.200601860.
An interesting read by FÃ¼rstner, into the synthesis of this cytotoic and anticancer polyene macrolide. 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 campaign had to be revised. They decided, then, to complete the macrocyclisation using a RCM strategy. (Two other papers by the authors are referenced as being connected to this decision, but the papers are not available yet… I’ll add them when I can. Update: Heres one…Â )
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 . Although this seems rather remote from the amine, FÃ¼rstner 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.
 My spies in Germany say that certain “issues” have been had with Angewandte…
 A badge and a balloon to anyone who can tell me what a tigelate group is.
Update: NoName and Movies tie on this one, both post around the same time that the tiglate group is the tiglic acid ester: