Todd:Asymmetric Hydrogenation of PZQ Enamide

=Asymmetric Hydrogenation of PZQ Enamide=

Muneer Ahamed, School of Chemistry, The University of Sydney, NSW 2006, Australia Bun Chan, School of Chemistry, The University of Sydney, NSW 2006, Australia Laurent Lafort, DSM Chemicals, The Netherlands Piero Olliaro, Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia Nick Tyrell, Almac Sciences, Authors from Development Chemicals/Creative Chemistry, subject to confirmation.

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Abstract
Results towards the enantioselective synthesis of the important drug praziquantel are described that employ the racemate as the starting material. The stereocentre is destroyed by an oxidation reaction and attempts are described towards the selective reconstruction of the stereocentre through catalytic asymmetric hydrogenation. The unusual geometry of the enamide substrate prevents effective interaction with the catalysts employed, but alteration of the substrate structure provided a lead result which has been rationalised by molecular modeling.

Introduction
Important aim is the inexpensive generation of (R)-praziquantel. One possible method is to start from the racemate and employ stereoablation, since asymmetric hydrogenation is the most efficient catalytic, asymmetric process with wide employment in process scale synthesis. No literature precedence for the successful catalytic asymmetric hydrogenation of enamides with this geometry. Project was initiated and run using a mixture of open source and contract research.

Oxidation of Praziquantel to the PZQ Enamide
Known reaction. Gives a reasonable yield, and has been partly optimised. Other oxidants. Question of whether we see rotamers, comparison with PZQ, and whether this matters.

Attempts at PZQ Enamide Hydrogenation
http://www.thesynapticleap.org/node/326 First round of attempts Sulfur poisoning Second round of attempts

Attempts at Benzoyl Enamide Hydrogenation
Discovery of first lead using alternative substrate. Synthesis of this substrate.

Discussion
The outcome of the attempted asymmetric hydrogenation of the PZQ enamide was very different to the benzoyl derivative. In the former, there was no conversion. From the mechanism typically invoked for such processes, this would seem to imply the rhodium centre is unable to coordinate the double bond for delivery of the hydrogen.

Three model enamide structures were evaluated in complexation with a model of a chiral rhodium complex. Enamide 1 was used to approximate a typical structure known to be reduced well be a number of the catalysts assayed. Enamide 2 was used to approximate the PZQ enamide and enamide 3 as a model of the benzoyl enamide.



When these enamides were allowed to interact with a the model rhodium system (after the rate-determining hydrogen insertion step, but the precursor to hydrogen transfer to the double bond), the PZQ enamide case behaved very differently from the other two model systems. Clear evidence of Rh-C bonding was observed in the latter, but poor olefin-Rh interaction was observed for the PZQ enamide, as can be seen from the large Rh-C distances and lack of any apparent lengthening of the bond between the two carbons of the double bond.

The amide in the enamide prefers to be planar to maximise orbital interaction between the lone pair in what was the non-bonding p-orbital on the nitrogen sp2 centre and the carbonyl pi* orbital. Geometrically this prevents interaction between the double bond and the rhodium centre. For there to be such an interaction, the substituents on the amide nitrogen must move towards the rhodium centre, converting the nitrogen atom into a more pyrmaidalized centre rather than a planar one. This reduces the effectiveness of the amide orbital interactions. Such movement would normally be considerably unfavourable, and explain the lack of interaction in the case of the PZQ-enamide. The benzoyl enamide, however, appears to be able to undergo such a distortion, and compensate for it through a new interaction on the other side of the amide. The aromatic ring has changed its alignment to allow a greater degree of overlap between the aromatic pi system and the carbonyl pi* orbital (dihedral angles in red). Presumably it is this compensation that allows the molecule, as a whole, to interact with the rhodium to give a productive hydrogenation reaction.



Acknowledgements
We thank Sigma Aldrich for a donation of several catalyst ligands at the outset of this project.

Synthesis of PZQ Enamide
http://www.thesynapticleap.org/node/291 http://www.thesynapticleap.org/node/325

Conditions Employed for Hydrogenations
http://www.thesynapticleap.org/node/326