Bronsted Acid catalysed PS reaction update

23 Jan
Published by m.robertson

January 2012, Here's a quick update on where we are regards the Bronsted Acid catalysed Pictet-Spengler reaction.
 
Initial experiments showed promising results using the BINAP-disulfonic acid 2 at a loading of 10 %.  Although the reaction had not gone to completion we were confident that we could see evidence of both product 3 and intermediate enediamide 4 by LCMS.  Also observed was the undesired hemiaminal 5.

Carrying on from this result, further attempts were carried out to push the reaction to completion.  Increasing the catalyst 2 loading to 20 % and the solvent to toluene resulted in complete consumption of starting material 6.  Also, as an additional bonus, no hemiaminal 9 was detected.  However, TLC suggests that the major peak obtained from the LCMS is that of the enediamide 8.  Does this mean that the catalyst is going off in the reaction or is it being poisoned?  Further studies are required into this but we are having issues making more catalyst.

Following a procedure previously carried out in the lab, I have not been able to replicate the success of the Newman-Kwart rearrangement to obtain S-thiocarbamate 13.  After several failed attempts, new optimised conditons have been found to give S-thiocarbamate 13 in 40 % while recovering 30 % starting material 12.  Any attempt to push this reaction further resulted in degradation of both product 13 and starting material 12.  We are currently in the process of bringing forward enough S-thiocarbamate 13 so the BINAP-disulfonic acid 2 can be generated following the previously demonstrated procedure.
 

As a backup to this and to study an alternative catalyst, we are in the process of making JINGLEs catalyst 15.  JINGLEs 15 can be made in one step from diol 2

Once conditions are optimissed, we then plan on making the relevant enantiopure versions of the catalysts in an attempt to show some enantioselectivity.