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Totally Synthetic by Paul H. Docherty, 17 October 2009

Total Synthesis of Platensimycin


N A. McGrath, E. S. Bartlett, S. Sittihan, J. T. Njardarson, Angew. Chem. Int. Ed. 2009, 48, 8543-8546.

DOI: 10.1002/anie.200903347

Compared to Nicolaou's syntheses which are published in a full paper in JACS, this synthesis by Jon Njardarson of Cornell does maybe not represents the best route. However, some very smart chemistry has been used, so it’s a pleasure to examine this synthesis too.

In the first interesting chemical reaction, Molander’s potassium tetrafluoroborates were used, which are a lot nicer to work with than boronic acids.

This sp3-aryl coupling is one of the more impressive implementations of this chemistry I’ve seen. And Njardarson has achieved a decent yield here. However, the coupling was not developed in his labs, but the following reaction was.

What we’ve got here is a neat, selective epoxidation of an alkene and rearrangement of the allylic system to give a dihydropyran ring More on this methodology can be found here. The use of the trityl hydroperoxide was key to the regioselectivity of the nucleophilic epoxidation - more about that in a paper in JACS by John Porco.

With that tricyclic system in place, a reduction installed a further stereocenter, and left the group ready to perform a radical reaction to close the final ring yielding the core. However, in an earlier work no product could be found. They have even tried a few simple structural modifications to bring the prospective partners closer together, but to no avail. This is an unfortunate problem with radical chemistry - if the reaction decides not to work, switching reagents rarely works. Often the only solution is to change the substrate...

Luckily, the group had a further idea and switched to an ionic reaction. First they had to prepare the desired functionality, requiring silyl protection on the phenol. Using triethyl silane and tris(pentafluorophenyl)borane, they achieved both removal of the methyl ether and reprotection. Very interesting chemistry. A deprotection at high temperature produced a nucleophilic centre that reacted with the primary tosylate to give the desired ring.