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Asymmetric Hydrogenation of PZQ-enamide
Communityschisto research community
A possible solution to the large-scale preparation of enantiopure PZQ is the approach shown below, originally suggested by Craig Williams.
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.
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):
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.