Todd:Asymmetric Hydrogenation of PZQ Enamide

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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.

Results

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

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.

Conclusion

Acknowledgements

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

References

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