Discodermolide
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:
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.
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.
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Feels good to see my Boss’s name reaction in this synthesis.
question for totsynth: are you going to run this website forever or untill the end of your grad school?
totsynth: what are your plans after the graduation?
and what are your plans after you will finish your post-doc? Or what are you goiong to do after the first 3 years of your job in industry?
I’m certainly planning to keep blogging after my DPhil, but that does depend on access to journals. I’m hoping to finish up my DPhil by the year-end, and then onto more chemistry. I’ve applied for both post-docs and jobs with pharma, and I’ll take whatever I consider to be the right offer at the end of the day. I don’t want to through all my eggs in one basket – funding is a bit suboptimal for post-docs just now, and the job market in the UK isn’t ace after the Pfizer/AZ decisions… Basically, I just want to keep doing chemistry!
You chaps?
I think your disco structure is wrong, on the right hand end is it not a carbamate rather than an acetate?
Sir, you are quite correct; I’ll change it later (tomorrow…)
Apparently, the stereotriad was recognised by one of Amos Smith’s graduate students; that’s what Smith himself told us in a talk. And of course, the real value of disco is that it is also potent against Taxol resistant cells.
did you guys notice tough reaction mechanisms on fukuyama’s website? I mean they are really tough
like this for example:
http://www.f.u-tokyo.ac.jp/~fukuyama/problems/p0612.pdf
Actually, if you easily want to access the list of problem sets, use this link:
http://www.f.u-tokyo.ac.jp/~fukuyama/index-e.htm
Interesting problems with solution keys!!
Actually, are there other non-North American organic chemistry research websites worthy of a visit? I never thought about looking them out: there for sure has to be a wealth of interesting things!
Schrieber’s group was the first to publish a total synthesis of discodermolide. They used Roush crotylboration methodology in order to make the stereotriad. Any chemist that put some thought into making this molecule would notice the repeating stereotriad.
cool blog, I wish one of these wasgoing while I was in graduate school.
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