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Discodermolide   

4 February 2007 6,231 views 14 Comments

discodermolide_1.jpg
Ardisson, Lemos, Porée, Commerçon, Betzer and Pancrazi. ACIEE, 2006, EarlyView. DOI: 10.1002/anie.200604629.

Okay, so it’s been a pretty popular target, and the routes towards this potent beastie have been optimised to process-level perfection by Novartis, but its 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 (which google maps informs me is just north-west of Paris), where they have used a unique aldol-type methodology to build this very aldol-friendly target.

For ill-prepared and initiated, disco(dermolide) is one hell of a microtubule stabilising mo-fo; even more potent that Taxol and it’s 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-tastic strategy. Ardisson’s route recognises several aldol disconnections, but also considers that there is a common syn–anti stereotriad motif present:

discodermolide_2.jpg
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 rather tasty 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 into the aldehyde, as shown in this example from the start of their synthesis.
discodermolide_3.jpg

They used this chemistry three times in this synthesis, achieving yields between 66-84%, and with pretty complex and sensitive substrates. The other disconnections in the synthesis were completed very nicely, though using fairly well-known chemistry. However, another example (I’ve blogged it before) of Phil Kocienski’s work turned up, using his methodology to make the stannane shown below in one step.

discodermolide_4.jpg

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14 Comments