Tricarbonyl Chromium complex route to Praziquantel

Published by kilomentor on 18 October 2010 - 5:01pm


In my blog on Synaptic Leap, Kilomentor, I suggested that the problem in synthesizing the active enantiomer (eutomer) of praziquantel is that the system contains so many sp2 atoms that it is rather flat so selecting with high selectivity one side of the system to delivery a hydrogen atom is challenging. One means to overcome the problem is to introduce another functionality to introduce large scale asymmetry then introduce the hydrogen and then remove the stereotopical directing group. Aside from imagining in our particular case what that group could be, there is also the cost of the directing group and the efficiency of the introducing and removing steps.
First and quickly, let us contemplate what that stereotopical directing group could be. Cobalt tricarbonyl complexes of tetrahydroisoquinolines are known. Because the pi bound cobalt tricarbonyl can be above or below the aryl ring, enantiomers of the structure exist. Not only will the organometallic complex make the two faces very different for delivering a hydrogen atom to create a saturated carbon at where it is needed but the arganometallic complex will make with hydrogen acidic in case equilibration is required. Forming such a complex and decomposing such a complex can be part of plethora of slightly differing schemes to reach the eutomer of praziquantel.
The difficulty is that the ingredients for making such a complex are very expensive relative to our price target.
If we were to examine such type route we would need a highly efficient way to use the organometallic complex catalytically or to recycle it efficiently.
I have no idea how a catalytic use could be effected but recycling might be possible. It might be that conditions could be discovered where the chromium tricarbonyl complex of some resolved praziquantel intermediate could transfer the tricarbonyl chromium function to some racemic starting material which does not have its tetrahedral stereochemical centre set yet.
I have tried to show this in a figure that I will try to attach.    



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MatTodd's picture

Interesting idea. The problem, as you correctly identify, is cost. PZQ is needed enantiopure on a ton scale, which is the kicker.