Totally Synthetic by Paul H. Docherty, 4 February 2007
Total Synthesis of Discodermolide
E. de Lemos, F.-H. Porée, A. Commerçon, J.-F. Betzer, A. Pancrazi, J. Ardisson, Angew. Chem. Int. Ed. 2007, 46, 1917-1921.
This is a very popular target, and the routes towards this potent molecule have been optimised to process-level perfection by Novartis, but it's still a great way to show off new technology. This is pretty much the approach taken by Ardisson’s group at Université de Cergy-Pontoise, where they have used a unique aldol reation-type methodology to build this very aldol-friendly target.
For ill-prepared and initiated, disco(dermolide) is one hell of a microtubule stabilising compound; even more potent than Taxol and its derivatives. It went to trials with Novartis, but was pulled in the end, after they made a rather impressive 60g. Their route was considered to be an hydrid of the Paterson and Smith routes, themselves reliant on an elegant aldol reaction based strategy. Ardisson’s route recognises several aldol disconnections, but also considers that there is a common syn-anti stereotriad motif present:
So now you’re rightly wondering what chemistry they used to build those triads, and the answer is in the prior publications by the group. They’ve been working on a very interesting crotyltitanation reaction, developed by Dieter Hoppe, but used extensively by the group in other syntheses. This involves formation of a chiral organo-titanium compound, which is then added to the aldehyde, as shown in this example from the start of their synthesis.
They used this chemistry three times in this synthesis, achieving yields between 66-84% with pretty complex and sensitive substrates. The other disconnections in the synthesis were completed very nicely, though using fairly well-known chemistry. However, an example of Phil Kocienski’s work turned up, using his methodology to make the stannane shown below in one step.