Chemoenzymatic synthesis of the enantiomerically pure 1,2,3,4-tetrahydroquinoline moiety of the antithrombotic (21R)- and (21S)-argatroban

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 3-methyltetrahydroquinoline sulfonyl group; the drug is usually prepared and administered as a mixture of C-21-diastereoisomers. By means of a biocatalytic transformation enantiomerically pure (R)- and (S)-synthons, suitable for the synthesis of separate (21R)- and (21S)- argatroban, were obtained.

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(R)-3-(1′-Hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinolineC15H21NO3>98% ee (by HPLC)[α]D20=+11.8 (c 1 CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (R)

(R)-3-(1′-Hydroxy-methyl)-1-tertbutyloxycarbonyl-1,2,3,4-tetrahydroquinoline, 1′-acetateC17H23NO4>98% ee (by HPLC)[α]D20=-28.7 (c1 CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (R)

(R)-3-Methyl-1,2,3,4-tetrahydroquinolineC10H13N>98% ee (by HPLC)[α]D20=-73.4 (c 3 MeOH)Source of chirality: Enzymatic resolutionAbsolute configuration: (R)