Aza-Henry Route to PZQ

Aza-Henry route to PZQ

We have designed a new synthesis of PZQ based on a catalytic, asymmetric aza-Henry reaction (Scheme 1). The key step is the generation of the new stereogenic centre in 4. From here, the reduction to 5 should be facile with e.g. samarium iodide.1 From 5, the two steps to PZQ are known from the original report.2

Aza-Henry Route to Praziquantel
Aza-Henry route to PZQ
The catalytic, asymmetric Henry reaction has recently been the focus of some interest in the literature (Figure 1). Some of the most promising methods are organocatalytic.3 The reaction in our case needs to be performed on the sometimes problematic substrate 3. We will be attempting this reaction with a couple of known catalysts, followed by some simple variants, and will report the results when we have them. If any groups who have published on this subject would be willing to donate small quantities of existing catalysts to this effort, this would be enormously appreciated.
Aza-Henry Catalysts
Aza-Henry Catalysts

A final issue is that the dihydroisoquinoline 3 is not commercially available. There are many simple routes to this compound, such as a potassium permanganate-mediated oxidation from tetrahydroisoquinoline. However, the synthesis of 3 also needs to be efficient and inexpensive if the whole route is not to be compromised.
Recrystallisation of PZQ may be achieved with diethyl ether in hexane.8

What the Community can do

With regards our first proposed route:
a) Advice from groups experience in this chemistry would be very useful.
b) Donations of catalysts for screening of the aza-Henry reaction would also be very useful.
c) Students in such groups can attempt one or more of the reactions in our proposed route and try to maximize the route's efficiency. This applies to all steps, but is particularly relevant for the asymmetric step.
With regards scale-up, advice from process/industrial chemists on any given step with regards to scale-up issues would be very valuable. This applies to both synthesis and purification.
Technical Issues:
For discussions of routes, a regular blog-style of discussion is probably fine. For posting chemical structures, I would recommend using e.g. Chemdraw and posting gifs. To do this you 'creat content' and submit gifs to the image gallery. There is an option when doing this of attaching Chemdraw .cdx files, which may be useful for us. When inserting images please use thumbnails - image sizes can be a little erratic.
For reporting of experimental data, it would be most useful if quality scientific conventions were maintained, and that if a result is claimed, it is properly reported. The open source community relies on honesty and repeatability rather than peer-review. Certainly the route we arrive it will need to work well in the real world!
1. K. Yamada, S. J. Harwood, H. Gröger and M. Shibasaki, Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
2. J. Seubert, R. Pohlke and F. Loebich, Experientia 1977, 33, 1036-1037.
3. J. Seayad and B. List, Org. Biomol. Chem. 2005, 3, 719-724.
4. A. P. Venkov and S. M. Statkova-Abeghe, Tetrahedron 1996, 52, 1451-1460.
5. J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron 1998, 54, 7395-7400.



Reduction of Aliphatic Nitro Groups


Request for Help

We have been working for a little while on the aza-Henry route to PZQ. We're going to submit a paper to an open access journal on some of this work, but I thought we should post on something we're looking at now, since we've come up against an unexpectedly difficult step and need some help.
We've been trying to reduce an aliphatic nitro group (picture is below). The compound is a model case for PZQ that we've been looking at. This reduction looks to be a very simple reaction, and we did not expect problems.
Aliphatic nitro reductionAliphatic nitro reduction
Shibasaki has reported on the reduction of aza-Henry beta-nitroamines like this.1 The literature contains few reliable procedures for aliphatic nitro reduction2 – aromatic nitro groups are no problem. We've tried regular hydrogenation, Raney Nickel, SmI2 and LiAlH4. Jim Anderson at Nottingham recently published a very nice paper resurrecting Al-Hg amalgam as a reagent for this transformation, and we are having luck with it.3 This post is a very overdue appeal to the community at large:
a) Does anyone know of any other good reaction conditions for this reaction?
b) Does anyone have any advice on good ways to isolate the resulting diamines?
1. K. Yamada, S. J. Harwood, H. Groger and M. Shibasaki, Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
2. S. L. Ioffe, V. A. Tartakovskii and S. S. Novikov, Russ. Chem. Rev. 1966, 35, 19-32.
3. J. C. Anderson and H. A. Chapman, Synthesis 2006, 3309-3315.

Suggested conditions

Dear Matt,
This may come too late, but you could look into using conditions published by AGMBarrett for aliphatic nitro group reductions, by transfer hydrogenation.  Its in Tet Lett but there's an open-access link here:

Updates to Aza-Henry Catalysts

Just a quick update compiled by one of my students, Wing Yan, on some aza-Henry catalysts not included in the first post.

Aza Henry Catalyst Update 1