Catalyst screening for the Brønsted-catalysed Pictet-Spengler reaction to PZQ

Published by Michael Wolfle on 4 August 2010 - 3:23am

We started catalyst screenings for the asymmetric Pictet-Spengler reaction. So far, we have tested several achiral Brønsted-acidic catalysts to determine acid strength which is required to cyclize the open-chain praziquantel intermediate 1 to the tetrahydroisoquinoline heterocycle 2.
 
Scheme1
 
Catalysts:
 
(+/-)-BINOL-N-triflyl phosphoramide     NN-bis[3,5-bis(trifluoromethyl)phenyl]thiourea
 (+/-)-BINOL-N-triflyl phosphoramide 3  and N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea 4
 
As previous experiments showed only strong Brønstedt-acids (e.g. conc. sulphuric acid, methane sulfonic acid) are able to convert the inactivated arene compound 1 to the Pictet-Spengler product 2. Therefore we are looking for strong chiral proton donors to catalyse this specific reaction.
 
We are using the racamate/achiral equivalents 3 and 4 of chiral catalysts in order to prove the activity of these Brønsted-acids for the acid-catalysed PS reaction. However, the conversion of the dimethoxyacetal 1 hasn't been successful yet as a result of the too low acidity of the catalysts.
 
To increase the acidity of the catalyst we have started the synthesis of 1,1-Binaphthyl-2,2-disulfonate 5 and 1,1-Binaphthyl-2,2-disulfonimide 6.
 
BINOL-sulfonate

The recent results and the raw data of these experiments can be viewed at our Electronic Lab Notebook here.