A Summary of What is Needed Right Now

Published by MatTodd on 5 January 2010 - 8:42am

Subject 

Request for Help

Project A: Development of a low-cost enantioselective synthesis of PZQ. It's an open project, like everything on TSL.
Meaning?: contributors can change anything they wish on these pages.
If you wish to contribute: please don't leave comments here. Instead, edit the pages below directly or leave comments.
Other ways to interact: The Friendfeed page and the Lab Book Blog (for the Pictet-Spengler approach)
How about email? No. Please avoid emails if at all possible, since they're closed, and people can't be part of the process.
What's needed? Right now we need your help with these things:
 
1) CATALYSTS: A key reaction in the Pictet-Spengler approach to PZQ will be the reaction creating the stereogenic center. If you lab is involved in this area of research, and you have catalysts you are willing to share, please let us know (on this website). We would like to screen catalysts for this reaction. We can send starting material, or you can send us samples of catalysts. Primary data for this part of the project are now posted here.
 
2) CLASSICAL RESOLUTION: The specific problem we need help with is here. In a nutshell: we've had spectacular success with the cleavage of the amide in PZQ to give an intermediate called praziquanamine. Praziquanamine can also be synthesised from scratch. Syncom have discovered how to resolve this molecule. We now need to optimise this process, and could use more help from process chemists. If you work in this field, or know people who do, please pass on the link. Development Chemicals have discovered another resolution, using a different intermediate in PZQ synthesis. While this intermediate is not commercially-available (in small quantities), there is work needed here too - to replicate the resolution, increase its efficiency and to demonstrate that the inactive enantiomer of the intermediate can be recycled.
 
3) HYDROGENATION CATALYSTS/CATALYST SCREENING: A powerful approach would be the asymmetric hydrogenation of an oxidised form of PZQ, described here. The asymmetric reduction in question is a challenge. We need people with experience in this area to screen catalysts. We can mail out starting material. DSM have already started to help us with this - the more, the faster here.
 
4) LITERATURE: To help with aim 1 above, we need a good catalyst for the catalytic, asymmetric Pictet-Spengler reaction. Could someone help us assemble a comprehensive list here? This is a way you can really help us if you don't have access to a lab. Another thing we need help with is finding out the synthetic route employed by the main suppliers of PZQ. There's a lack of clarity there - more on this soon.
 
 
Solved problems:
1) HPLC advice: We previously required advice on enantioselective HPLC: The promising intermediate in the resolution work mentioned above is PZQamine. To assay its e.e. by HPLC we need to be able to separate the enantiomers on a column. Chiralcel-OD was not working for us but the appropriate conditions were rapidly found by Syncom here].
Demoted problems:
1) PRICES: We needed help obtaining prices for bulk starting materials for racemic PZQ syntheses. This required input from industrial chemists who know of suppliers of these materials for low prices. This problem is now less important since we are focussing on the use of an enantioselective Pictet-Spengler reaction, which employs the existing large-scale synthetic route precursor, making discussions of starting material costs redundant.

Comments

looks like an asymmetric hydrogenation of 1-carboxy-3,4-dihydroisoquinoline. those dehydro-alpha-aminoacids are great cases for asymmetric hydrogenation. Subsequent refunctionalization should be straightforward

MatTodd's picture

Instead of using that starting material, use an enamide derived from PZQ. This is described here. Any suggestions for catalysts?