The Synaptic Leap

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.
 

To host the raw data from the Pictet-Spengler approach to the enantioselective synthesis of PZQ Michael has started an Electronic Lab Notebook. We're using the open source Southampton Lab Blog interface for this, since we're collaborating with them on a couple of things related to this site.
 
Given that it's open source, the lab blog system can be changed and enhanced by anyone. This is a great chance to make the lab blog perfect for experimental organic chemistry, e.g:
 
1. How do we best report TLC data - at the moment we're taking photos, but this is cumbersome.

 Novel method to cure malaria
 
 
http://www.hsph.harvard.edu/news/press-releases/2010-releases/kinase-tra...

It's been a great week for the PZQ project, since we've had an injection of real help from the people we most need - process chemists. Much of this has arisen from a discussion I started on LinkedIn, which then became emails, but all participants have either actively participated on this site, or granted permission for the posting of information here. Nick Tyrell from Almac Sciences has already provided a huge amount of great advice for several aspects of the synthesis, mostly for the resolution of PZQamine.

 

 
The Pictet-Spengler cyclisation of the acetal 4 to the tetrahydroisoquinoline substructure 5 was conducted in concentrated sulfuric acid. The reaction showed a complete conversion to the tricycle in a very good yield and with high purity. The product was isolated by extraction from the basic aqueous solution, no further purification was needed. No side products were observed in the 1H NMR spectrum.

 

 
The next step in the PZQ synthesis via the Pictet-Spengler route is an aminoalkylation of the chloroacetamide 2 with aminoacetaldehyde dimethyl acetal 3. The aminoacetal also acted as a base to trap the HCl which was generated during the reaction and therefore 2.1 equivalents were used. The aminoacetal could be easily recovered by basic liberation of its HCl-salt which precipitated from the cold toluene solution. The crude product was obtained as a brown oil and was isolated by forming the HCl-salt 4 in an overall yield of 79%. (lit.[1] 67%)
 

 

 
Here we started another synthetic approach to PZQ. The Pictet-Spengler route, used for the industrial synthesis of (rac)-PZQ, offers a straightforward way to this anthelmetic drug in 5 steps.[1]
Starting from inexpensive 2-phenylethylamine and chloroacetyl chloride the amide 2 can be obtained in a short reaction time with high yield. 
 

 

 
This experiment was conducted in order to examine whether the cyclohexanoyl amid bond could be cleaved under mild acidic conditions by using a 50 vol% TFA solution in DCM. After 48 h under refluxing temperature 99% of the starting material could be recovered.
As a result, this procedure can be used for the scission of acid-labile protecting groups of prospective derivatives of PZQ without touching the cyclohexanoyl group.