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Totally Synthetic by Paul H. Docherty, 4 October 2006

Total Synthesis of Platensimycin


K. C. Nicolaou, A. Li, D. J. Edmonds, Angew. Chem. Int. Ed. 2006, 45, 7086-7090.

DOI: 10.1002/anie.200603892

This target is a novel antibiotic with two distinct regions to its structure. So at least one disconnection is obvious, but the 5,5,6,6-fused tetracyclic unit is less simple.

The group envisaged an interesting SmI2 mediated ketyl radical cyclisation and etherification to complete this unit, allowing sterechemically controlled alkylation of the enone to deliver the acid component of the amide.

One particularly neat transformation in the synthesis uses some Trost chemistry to cyclise the acetylene / alkene unit shown below. The reaction goes in good yield, but to give a mixture of alkene geometries, and with no enantiomeric excess. As indicated towards the end of the paper, should this reaction, or a substitute, yield enantioenriched material, a non-racemic total synthesis of the target could be envisaged.

With this material in hand, a cleavage of the TBS enol ether with HCl delivered the cyclisation precursor, which when treated with SmI2 and HFIP for one minute at -78C promoted radical cyclisation onto the enone to give the preferred six member ring. the alochol product could then be further cyclised to the ether by acidification with TFA, either in situ, or after purification.

With this component complete, double alkylation (always from the bottom-face) completed this fragment, allowing HATU coupling with the aromatic fragment and completion of the natural product.

I think this is an ambitious synthesis, with a few problems, but with an interesting and powerful disconnection strategy. It’s great to see publications where the authors admit where they went wrong, or when reactions just didn’t perform to expectations. Sure, it’s a racemic synthesis for now, but I’m sure that a non-racemic synthesis will follow.