Diastereoselective synthesis of an argatroban intermediate, ethyl (2R,4R)-4-methylpipecolate, by means of a Mandyphos/rhodium complex-catalyzed hydrogenation

The synthetic antithrombotic argatroban is a dipeptide between the nonproteogenic (2R,4R)-4-methyl-2-piperidine carboxylic acid and l-arginine, in turn bonded to a methyltetrahydroquinoline sulfonyl group. An extensive screening of transition metal-based complexes with different ligands was performed in order to identify the best catalyst for the diastereoselective hydrogenation of a suitable 4,5-dehydropiperidine precursor aimed toward a synthesis of the (2R,4R)-4-methyl piperidine moiety.

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Ethyl (2R,4R)-4-methyl-2-piperidine carboxylateC9H17NO298:2 dr (by GC)[α]D20=-22 (c 5, CH3CH2OH)Source of chirality: chiral auxiliary and asymmetric hydrogenationAbsolute configuration: (2R,4R)

Ethyl [(S)-1-phenylethyl]imino ethanoateC12H15NO2[α]D20=-46.0 (c 1, CHCl3)Source of chirality: (S)-1-phenyl ethylamineAbsolute configuration: (1S)

(2R)-1-[(1′S)-1′-Phenylethyl]-2-ethoxycarbonyl-4-methyl-4,5-dehydro piperidineC17H23NO2[α]D20=-6.9 (c 1, CHCl3)Source of chirality: chiral auxiliaryAbsolute configuration: (1′S,2R)