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An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716
journal contribution
posted on 2016-01-07, 00:00 authored by Staffan Karlsson, Henrik Sörensen, Sören M. Andersen, Angele Cruz, Per RybergA classical
resolution of a racemic carboxylic acid through salt
formation and an asymmetric hydrogenation of an α,β-unsaturated
carboxylic acid were investigated in parallel to prepare an enantiomerically
pure alkanoic acid used as a key intermediate in the synthesis of
an antiplaque candidate drug. After an extensive screening of rhodium-
and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation
that gave the alkanoic acid with 90% ee, and after a subsequent crystallization
with (R)-1-phenylethanamine, the ee was enriched
to 97%. The chiral acid was then used in sequential Negishi and Suzuki
couplings followed by basic hydrolysis of a nitrile to an amide to
give the active pharmaceutical ingredient in 22% overall yield.