A Mixed-Ligand Approach Enables the Asymmetric Hydrogenation of an α-Isopropylcinnamic Acid en Route to the Renin Inhibitor Aliskiren

Jeroen A.F. Boogers, Ulfried Felfer, Martina Kotthaus, Laurent Lefort, Gerhard Steinbauer, André H.M. de Vries, Johannes G. de Vries

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Abstract

An asymmetric hydrogenation process for an α-isopropyl dihydrocinnamic acid derivative, an intermediate for the renin inhibitor aliskiren, has been developed using a rhodium catalyst ligated with a chiral monodentate phosphoramidite and a nonchiral phosphine. Whereas catalysts based on two equivalents of monodentate phosphoramidites gave promising results, the rate of hydrogenation and ee of the product could be improved spectacularly by the addition of monodentate nonchiral triarylphosphines to these catalysts. This remarkable mixed-ligand catalyst has been identified using high-throughput experimentation. With the best catalysts turnover numbers >5000 mol mol-1, turnover frequencies >1000 mol mol-1 h-1, and ee’s up to 95% have been achieved.
Original languageEnglish
Number of pages7
JournalOrganic Process Research & Development
Volume11
Issue number3
DOIs
Publication statusPublished - 2007

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