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A Pressure-Dependent Asymmetric Catalytic Hydrogenation of an Unsaturated Acid

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19 February 2007

A full paper has appeared which describes in detail the mechanism of enantioselective catalytic hydrogenation of a complex unsaturated carboxylic acid, the last step in the synthesis of a prostaglandin D2 receptor antagonist. (D M Tellers et al, J Am Chem Soc., 2006, 128, 17063-17073). From a scale up point of view, the first problem to solve was the low solubility of the unsaturated acid in most solvents. Normally this has been solved by
using the triethylamine salt, but in this case the solubility was still low. The chemists, from Merck Process R&D Dept at Rahway, USA, screened a wide range of salts and found that the tetramethylguanidine salt had one of the best solubilities (collidine, potassium and cesium salts were also useful). The TMG salt had the advantage that, even if an enantiomeric excess of only 80% was produced in the hydrogenation, it could be increased to 99% by a single crystallization.

A key discovery, important in the optimization and scale-up of the asymmetric hydrogenation, was the sensitivity of the ee to pressure and temperature and that there was an interaction effect between the two parameters. At 1500psi, the ee would drop to 20% whereas at low pressure (25psi) an ee of 92% at 40 degrees could be obtained, though this was slightly lower (90%) at 20 or 60 degrees. At 65psi the ee was better at 60 degrees but dropped to 80% at room temperature.

A detailed mechanistic study determined that the initial unsaturated acid is in rutheniumcatalysed equilibrium with an endocyclic isomer, which is hydrogenated in high ee without ressure dependence, whereas the original E-unsaturated acid is also hydrogenated in high ee, but the ee is pressure dependent. Deuterium studies were used to elucidate the mechanism. The Z isomer, which might have been expected to be formed in any
isomerisation, is not formed. It was separately synthesized and shown to give high ee product but the reaction was also pressure sensitive.