Bengazole A
Ley, Bull, Balskus, Horan and Langner. ACIEE, 2006, Early View. DOI: 10.1002/anie.200602050.
A sweet and ultimately, short synthesis of this interesting target. I won’t bore you with a list of biological activity – suffice to say that it’s a very potent anti-fungal agent, and also anthelminthic. Their strategy was based around a unifying and diastereoselective [3+2] nitrile oxide cyclisation. This was used to impart the stereochemistry on one of the “down” via the inside alkoxy effect. The other could then be derived from the reduction of a ketone with Et2BOMe.
This is a thoroughly creative method of generating a 1,3 diol in a stereochemically defined manner, and is well exemplified in this synthesis. They also show two methods of generating a oxazole, one from a amide/aldehyde intramolecular cyclisation which I found particularly interesting.
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What does the NCS do in the first step?
Mitch
I had thought Carreira showed the generation of 1,3-diols from nitrile-oxide cycloadducts….where’s the ref?
Org Lett. 2004, 2485.
It’s used to chlorinate the oxime; they then eliminate with the base and make the nitrile oxide, which is the reactive species for the [3+2]. There’s a good introduction to this stuff here. I love Dave Evans’s website.
NCS gives you a chloro-oxime: R-CH=N-OH -> R-CCl=N-OH, which then breaks to nitrile oxide R-N(+)#O(-) which is of course the actual compound reacting with the double bond. # stands for a triple bond.
Somebody correct if I lied too much
And by the way I like this synthesis.
I’m not sure about your formula/structures, yepyep, but that’s the gist of it. You lost a carbon between the R and N…
Well, lost to the admin himself by 2 mins… And that nitrile oxide should be R-CN(+)#O(-). I’m just so environmentally-friendly that I automatically got rid of some carbon.
Nice and succint synthesis. The nitrile oxide cycloaddition has been known for some time as a good alternative to the aldol reaction. I believe Scott Denmark had done some good syntheses with it (some bridgehead N alkaloids)
Was the sterochemistry of the [3+2] product predicted or hoped for do we think?
Biotech,
You can predict it…the olefin has a preferred conformation (perpendicular to the oxygen), the dipole then approaches from the less hindered side. Of course, if that gives the wrong sterochem, it’s another model! There’s a nice review (Chem. Rev.) by Cha from the mid 90′s that talks about these types of systems.
Great blog by the way…
Will