Totally Synthetic by Paul H. Docherty, 11 July 2007
Total Synthesis of Reidispongiolide A
I. Paterson, K. Ashton, R. Britton, G. Cecere, G. Chouraqui, G. J. Florence, J. Stafford, Angew. Chem. Int. Ed. 2007, 46, 6167-6171.
I think we’re going to do a bit of a macrolide spectacular this week, as there’s been quite a few publications of late. Reidispongiolide A has some interesting activity, as it interacts with Actin, promoting microfilament destabilisation and antiproliferation. As is quite common for this type of target, much can be taken from the retrosynthesis, so lets get to grips with it:.
As can clearly be seen, this synthesis is heavily reliant on Aldol reactions, a discipline which the group has excelled in. Indeed, this synthesis utilises that reaction six times, deriving much of the stereochemistry. The variants they use include their lactate aldol, Mukaiyama and of course the boron aldol. Anyone familiar with Paterson’s work will be aware of the power of this reaction, but a highlight in this paper is the example below, where they were able to overturn the substrate induced selectivity in close to 2:1 preference for reagent control. The vinyl iodide moiety must have required some care, as they tend to decompose on exposure to light; I’m astonished they managed to carry it through so many steps!
A second impressive example is the final aldol reaction (not shown), appending the C-30 to C-36 fragment. This was completed as the third-to-last step, working with elaborate fragments, and must have been quite a scary step to complete.
Once again, well done folks!