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.
(additional authors - add alphabetically. Please consider adding yourself and helping to write this paper, particularly if you have already helped out over at the relevant The Synaptic Leap site)
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.
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.
