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Totally Synthetic by Paul H. Docherty, 27 September 2007

Total Synthesis of Platensimycin


K. Tiefenbacher, J. Mulzer, Angew. Chem. Int. Ed. 2007, 46, 8074-8075.

DOI: 10.1002/anie.200702852

This total synthesis of platensimycin is some smart work by Johann Mulzer at the University of Vienna. Rather than complete a full synthesis, they’ve done the same as a few other groups and taken an intermediate from Nicolaou’s work and completed a synthesis of that structure. This is the same intermediate present in Snider’s synthesis, so I guess the consensus is that this is a good disconnection.

The synthesis starts with the literature three-step synthesis of the acid shown in the scheme below. This compound is then converted to the acid chloride followed by an Arndt-Eistert homologation. This is a cool piece of classical rearrangement chemistry which goes via formation of an α-diazo ketone, which then perfoms a Wolff rearrangement to give the ketene. This is then trapped by any nucleophile present - in this case the electron-rich arene. The reaction forms the five member ring, and a lot of the complexity is introduced in this step. However, the synthesis is racemic, which is quite a drawback. Mulzer states that if one performed this chemistry on an enantiomerically enriched acid starting material, the reaction should be controlled by that centre. This asymmetry could be introduced in the final step in the creation of the acid by doing an asymmetric hydrodgenation or a resolution.

Anyway, the racemic chemistry is cool, so it’s time to complete the formal synthesis with a further hydrodenation. However, they have a selectivity issue in that there are two similar olefins (but one is clearly less accessible). They didn’t get the selectivity required, so simply reduced both moieties, and then reoxidised. I hadn’t seen this reaction before, but they restore the required enone using iodic acid dimethyl sulfoxide complex. Nice! Hypervalent iodine reagents are useful!