Asymmetric Hydrogenation of PZQ-enamide

Published by MatTodd on 11 August 2010 - 10:25am

A 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.


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

MatTodd's picture

Craig - yes indeed. The page of negative results is gradually being assembled here.

ndt228's picture

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.

MatTodd's picture

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.

MatTodd's picture

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).

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.

Or using formic acid as the reducing agent in your standard enamine reduction?


MatTodd's picture

Cool idea - make from PZQ?

kilomentor's picture


In trying to get my head around this project, I note that the idea of obtaining a chiral praziquantel was reported [20% ee; the report says 20% optical purity whatever that is] in the original patent US4001411 (CA1036606; working with the Canadian equivalent patent is easier for me here). Is that correct? I quote the relevant part and the example below: (column 11 - MHT)
“The reduction of compounds - 4 can also be controlled so that solely one antipode of compounds - 1 is produced, or is obtained to a predominant extent. This can be done, for example, by asymmetrical hydrogenation. A suitable catalyst for this reaction is Raney nickel, for example, which had previously been treated with asymmetrically modifying reagents,  e.g., with aqueous solutions of optically active hydroxy or amino acids, e.g., tartaric acid, citric acid, alanine, isoleucine,  lysine, phenylalanine, valine, or leucine.  
Furthermore, heavy metal c a t a l y s t s applied to natural or synthetic polymers can be utilized for an asymmetrical hydrogenation, for example palladium or platinum on silk or on specifically prepared silic gel or polyamino acid supports as described in the literature. In the homogeneous phase, an asymmetrical hydrogenation is accomplished, for example, on optically active soluble rhodium complexes. The asymmetrical hydrogenation is effected under the above-indicated conditions, preferably at 1-3 atmospheres and temperatures of between 20 and 50ºC.
The s t a r t i n g compounds - 4 can be prepared, for example,  by dehydrogenating a corresponding compound of Formula - 1,  saturated i n the 11b-(1)-position , with sulfur, selenium,  chloranil , or another dehydrogenating agent known from the literature. Such a reaction is of interest, in particular if the compound saturated if the 11b(1)-position is present as an optically active antipode and is less effective than the other possible antipode . In this case, the less effective antipode can be converted, by dehydrogenation, into compound-4, and the latter can be converted by subsequent hydrogenation, into the more effective saturated racemate of formula 1 or, by asymmetrical hydrogenation, primarily into the more effective antipode of Formula 1.”

Column 32 (MHT):

15 g. of a nickel-aluminum alloy (1 : 1) is introduced in incremental portions and under agitation into 200 ml. of 20% sodium hydroxide solution within 5 minutes; the mixture is maintained at 80' for 45 minutes, then allowed to settle, decanted off, washed with water, and 1,000 ml. of 1% (-)-tartaric acid solution is added thereto, adjusted to pH 5 with 1N sodium hydroxide solution. The mixture is heated under agitation for 90 minutes to 80°, decanted, and washed with water and methanol.  The thus-obtained (-)-tartaric acid - Raney nickel catalyst is added to a solution of 322 mg. of 2-(4-fluorobenzoy1)-4-0x0- 2,3,6,7-tetrahydro-4~-pyrazino[2,l-a]isoquinoline (obtainable by dehydrogenation of (2) - or of (+) -2- (4-f luorobenzoyl) -HPI with sulfur) in 40 ml. of methanol. The reaction mixture is hydrogenated under normal pressure and at room temperature.  After the catalyst has been filtered off and the solvent evaporated,  (-)-2-(4-fluorobenzoy1)-HPI is obtained in 23% optical purity; m.p. 190-193°; [a] = - 7.5O
Analogously, (-)-2-cyclohexylcarbonyl-HPI is obtained in 20% optical purity; m.p. 122-127ºC; [α] = - 29.3O; from 2-cyclohexylcarbony1-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]- isoquinoline (m.p. 140-141°) .”
Does example 11 when applied to (-)-2-cyclohexylcarbonyl-HPI not work?
MatTodd's picture

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.

Can you make and/or hydrogenate the enamide of PZQ amine?

Michael Wolfle's picture

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.