Dynamic kinetic resolution of α-chloro β-keto esters and phosphonates: hemisynthesis of Taxotere® through Ru-DIFLUORPHOS asymmetric hydrogenation

The dynamic kinetic resolution (DKR) of racemic α-chloro β-ketoesters and α-chloro β-ketophosphonates through ruthenium-mediated asymmetric hydrogenation is reported. The corresponding α-chloro β-hydroxyesters and α-chloro β-hydroxyphosphonates were obtained in good to high enantio- and diastereomeric excesses using, in particular, the atropisomeric ligand DIFLUORPHOS. This methodology allowed an efficient preparation of the anti phenylisoserine side chain of Taxotere® which has been used for the hemisynthesis of the cancer therapeutic agent itself. In addition, 13C NMR in chiral oriented solvents was used to investigate the DKR effect.

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Methyl (2R,3R)-2-chloro-3-hydroxy-3-phenyl-propanoateC10H11ClO3Ee 92%De 96%[α]D = −43 (c 1.1, CHCl3)Absolute configuration: (2R,3R)Source of chirality: catalytic asymmetric hydrogenation

trans-Methyl (2S,3R)-3-phenyl-glycidateC10H10O3Ee 93%De 98%[α]D = +162 (c 1.5, CHCl3)Absolute configuration: (2S,3R)Source of chirality: catalytic asymmetric hydrogenation

Methyl (2S,3S)-3-azido-2-hydroxy-3-phenyl-propanoateC10H11N3O3Ee 93%De 96%[α]D = +42 (c 0.3, CHCl3)Absolute configuration: (2S,3S)Source of chirality: catalytic asymmetric hydrogenation

Methyl (2S,3S)-2-hydroxy-3-(N-tert-butoxycarbonylamino)-3-phenyl-propanoateC15H21NO5Ee 93%De 96%[α]D = +33 (c 0.5, CHCl3)Absolute configuration: (2S,3S)Source of chirality: catalytic asymmetric hydrogenation