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.
Enamides have attracted enormous interest in recent years as important building blocks for the synthesis of various important intermediates and also in the asymmetric synthesis of medicinally useful compounds. The asymmetric hydrogenation of enamides is one of the most heavily-used industrial asymmetric transformations; there are many examples of this reaction being used in the synthesis of important drug molecules and active pharmaceutical intermediates. This reaction therefore seemed to be an excellent choice for the inexpensive production of (R)-PZQ, were it possible to transform the racemic drug into the PZQ-enamide. Such a strategy would be formally a stereoablative strategy since the stereocentre is destroyed and recreated.
Here we 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.
Relevant recent review of asymm hydrog 10.1039/c2cs15312b.

Results

Oxidation of Praziquantel to the PZQ Enamide

Known reaction. Gives a reasonable yield, and has been partly optimised.
We began our attempt at the stereoablative synthesis of (R)-PZQ by converting racemic PZQ into enamide. The reaction involves oxidation at the benzylic stereocentre to generate an achiral product. Initial efforts to carry out this transformation using copper (I) chloride in dry DMF (120 oC, 16 h) did not give the desired product, and only returned the starting material. Similarly heating in DMF with sulfur (120 oC, 24 h) also gave no conversion. However when the reaction was carried out using a literature procedure with two equivalents of elemental sulfur, where the sulfur and rac-PZQ solids were simply melted under solvent free conditions for 15 minutes, a dark brown oil was obtained. The desired enamide could be obtained from this mixture by flash column chromatography in 63% yield. The product was recrystallised from diethyl ether to give the enamide as colourless needles.
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.

Scheme X. Structures Employed in the Modeling of Enamides

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.

Scheme X. Key Bond Angles and Distances in the Interaction Between Model Enamides and a Rhodium Complex. Values in parentheses are those after interaction with the complex

Conclusion

Acknowledgements

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

Experimental Protocols

Catalyst Screening

Spreadsheet of cumulative data can be found here - www.bit.ly/PZQHydrog. Please enter new data directly - email Murray or Mat for access rights.

Synthesis of PZQ Enamide

Synthesis of PZQ Enamide

Link to online lab book

Procedure:
A mixture of rac-PZQ (1.0 g, 3.2 mmol) and sulfur (0.210 g, 6.4 mmol) under Ar was heated at 190°C for 15 min with a heat gun. The resulting dark brown solid was dissolved in ethyl acetate, evaporated on silica gel and purified by column chromatography (20-40% EtOAc/Hex) to give the enmide as a pale yellow solid (0.455 g, 1.46 mmol, 46%)

1H NMR
13C NMR

Chiral HPLC Data:
Single peak, as expected, with a retention time of 15.77 minutes using a CHIRALCEL OD-H column, 40% IPA:Hexane with 0.1% TEA and a flow rate of 0.7 mL/min - HPLC trace

Synthesis of Benzoyl Enamide

Coming ASAP

Conditions Employed for Hydrogenations

These will vary, but are described here and the conditions are also listed in the Results Spreadsheet.

Computational Methods

Standard density functional theory calculations were carried out with the GAUSSIAN 09 program. Geometries were obtained at the B3-LYP level of theory with the 6-31G(d) basis set. The vibrational frequencies of stationary points were inspected to ensure that they corresponded to minima on the potential energy surface. Improved relative energies were obtained at the M06-2X level with the 6-311+G(3df,2p) basis set. Zero-point vibrational energies, thermal corrections to enthalpy and entropies were obtained using B3-LYP/6-31G(d) harmonic vibrational frequencies, scaled using appropriate literature scale factors. We account for the effect of solvation using the SMD continuum model with CH₂Cl₂ parameters. Energies in the text correspond to relative free energies at 298 K.

References

(May be found in the public Mendeley group here, but should also be listed below. Direct links or DOIs in addition to citation please)