Asymmetric Hydrogenation of PZQ-enamide
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schisto research communityA possible solution to the large-scale preparation of enantiopure PZQ is the approach shown below, originally suggested by Craig Williams.
First step:
We have a decent approach to this involving heating in a sulfur melt. This needs improvement, but we can generate gram quantities of the intermediate PZQ-enamide easily.
Second step:
This is the key. A number of different catalysts for this reaction have been tried [data coming soon, sorry] but no conversion has been observed. Reduction with rhodium on carbon quantitatively generates rac PZQ, so the enamide is reactive. The geometry of the enamide here is awkward in that the exocyclic carbonyl is not able to direct a metal-based asymmetric catalyst to the double bond, as in the classical model. It's a challenging reduction.
This second part of the synthetic route needs people who have expertise in screening hydrogenation catalysts, or people who have in their posession unusual catalysts for asymmetric hydrogenation that might be appropriate for this kind of reaction. The Todd group can mail people samples of the PZQ-enamide for this screening (plus samples of PZQ for the assay). Most any column will separate PZQ enantiomers. If you are interested in helping with this part of the project, please reply below.
Relevant groups/papers to consider (please fee free to suggest others here by editing the page):
Bernhard Breit
August 2010: We received our first offer of help with the asymmetric hydrogenation. Laurent Lefort from DSM in the Netherlands, has offered to include our substrate in future catalyst screening that they are undertaking. This is a great offer. Laurent has a great deal of relevant experience in this area. Aug 31st: The Todd lab has mailed a sample of the enamide plus a reference sample of PZQ to DSM. October 20: Second set of DSM results posted here. January 25 2011: Third, larger screen from DSM posted in the same place as the others.
Comments
Reply to failed asymmetric hydrogenation
I was encouraged by the fact that rhodium on carbon produced racemic material. What other catalysts produce racemic material? Also please provide a list of asymmetric catalysts that failed. Craig Williams
Failed hydrog page
Craig - yes indeed. The page of negative results is gradually being assembled here.
Failed Hydrog of PZQ Enamide - another explanation ?
I believe that you are making the substrate by an oxidation with sulphur ? It could be that despite whatever clean-up is employed, sufficient "S" in some form makes it through to the hydrogentaion & poisons your catalyst. You could test for this fairly simply by repeating the literature reaction you used to test your set-up with the addition of (say) an equimolar amount of your PZQ enamide. If the test reaction still goes to same extent/outcome you know there's probably nothing wrong with your substrate. If the test reaction fails in the presence of the substrate, then it could need more purification. You could try washing with an oxidant for example.
Cheers
Nick
Contamination with S?
Nick - that's a neat suggestion. We'll investigate, both by doing the control you suggest, as well as by making the enamide in a different way. Any experiments along these lines will be posted on TSL with a link below.
Contamination with S does not seem to be a problem
The first results from catalyst screening from DSM are given here and they seem to suggest that if there is any S present in the enamide that the S does not interefere with asymmetric hydrogenation (in this case with MonoPhos).
Reduction
Any thoughts as to the viability of attempting a reduction of the corresponding PZQ-amidoxime - should introduce a chelation capable group to activate the hydrogenation catalyst (depending on the geometry of the amide). Obviously reduction of the amidoxime might compete, but might be sufficiently slow to allow for selectivity.
O=C2CN(C=C1c3ccccc3CCN12)C(=N\O)/C4CCCCC4
Or using formic acid as the reducing agent in your standard enamine reduction?
Alastair
Amidoxime
Cool idea - make from PZQ?
Enantioselective hydrogenation
Column 32 (MHT):
Modification of RaNi
Thanks for this - well spotted. (I inserted a link to the original patent in your post below and two additional notes to where to find the sections you cite.)
Yes, we saw this a while back and to be honest dismissed it (offline) as predating the revolution in homogeneous asymmetric catalysis. As a method it's probably quite inexpensive. Do we know anyone who still uses this kind of modification of a heterogeneous catalyst on a preparative scale to generate products with high e.e.s?
There are lots of compounds described in this patent, with a lot of optical activity data given. "Optical purity" I take to mean an approximation of e.e. given a linear extrapolation of e.e. with optical rotation, i.e. no Horeau effect nonlinearltiy, which probably holds with this compound. It's what you quote when you don't have HPLC to hand. Unless I missed it, the optical rotation data in the patent is given without concentrations - the solvent is assumed to be chloroform based on the disclaimer in column 21.
PZQ amine
Can you make and/or hydrogenate the enamide of PZQ amine?
Hydrogenation of PZQamine enamide
Thanks John - yes, this could work. We haven't considered it yet because the oxidation of PZQamine (i.e. with sulfur) requires an additional step with work-up and purification. But it may be easier to hydrogenate the enamide with Pd/C, Rh/C or Raney Ni. We will give it a go.