The Synaptic Leap

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 page will contain all examples of failed reactions in the attempted asymmetric hydrogenation of the PZQ enamide.
 
We are very grateful to Sigma-Aldrich for an initial donation of the catalysts employed below. Please note that we do not hold a library of other hydrogenation catalysts. Any suggestions for alternative catalysts are welcome, but in the interests of speed, the best suggestions here are catalysts + who could run the reactions (other than the Todd group) and to whom we could send PZQ enamide. This will accelerate the research.
 

Methods for the purification of PZQ can be collated here.
 
Literature
1. This paper describes the purification of enantiopure PZQ using "chloroform/methanol 0–0.3% MeOH as a solvent system."
2. This paper uses 1:1 EtOAc/petroleum ether ramping to pure EtOAc.
3. This paper uses "thick layer preparative chromatography [prep TLC] benzene/ethyl acetate 1/1, silica gel."
 

PZQ can’t be resolved as-is (unless anyone has any bright ideas how to resolve amides). One of the most promising strategies to prepare enantiopure praziquantel (using a strategy that starts from the racemate) is a classical resolution of praziquanamine (1, "PZQamine"). This molecule can either be made from scratch (it’s an intermediate in the current PZQ synthesis) or can be obtained in high yield from PZQ itself.
 
 

The PZQ-enamide is shown below. This is an intermediate in the stereoablative route to enantiopure PZQ.

HPLC trace for PZQ-enamide (using ChiralcelOD-H, solvents: Hex:IPA:TEA 60:40:0.1, Flow Rate: 0.7 mL/min) gives retention time: 15.772 mins. Original HPLC trace attached below.
 
(Note comparison HPLC trace for PZQ itself is here.)
 

There is good news regarding the separation of the racemic praziquanamine with chiral HPLC.

• Syncom B.V., The Netherlands, a CRO specialized in all aspects of organic synthesis, with a 20-year track record in resolution of chiral compounds, screened five different chiral HPLC columns, varied the eluent and used UV detection (220 and 260 nm) and a PDR-Chiral Advanced Laser Polarimeter.

The Pictet-Spengler reaction is used in the current industrial synthesis of rac-PZQ, and these reactions have been looked at on the Synaptic Leap here.
 
The PS has been used in the synthesis of PZQ, and we used it as the final step in our solid phase synthesis of PZQ, but both these syntheses were racemic.
 
Catalytic, asymmetric
General aim is this:

I recently gave a talk on open science at Ignite Sydney. These talks are a real challenge in that you have 5 minutes to get across an idea, with the slides rotating every 15 seconds behind you. The event was in a cool club/gallery in the middle of Sydney, and is the first talk I've ever given where I was preceded by a beatbox act. Apparently I was the first scientist to go to Ignite Sydney.