Asymmetric synthesis of chiral Roche ester and its derivatives via Rh-catalyzed enantioselective hydrogenation with chiral phosphine-phosphoramidite ligands

Methyl 3-hydroxy-2-methylpropionate, known as the Roche ester, was prepared with high enantioselectivity (up to 96.7% ee) via the Rh-catalyzed asymmetric hydrogenation of methyl 2-hydroxymethylacrylate with a chiral 1,2,3,4-tetrahydro-1-naphthylamine-derived phosphine-phosphoramidite ligand (THNAPhos 5a) even at a low catalyst loading (0.1 mol %). An investigation on the substrate scope revealed that the ester group present in the substrate has a significant effect on the enantioselectivity, and the substrate with the bulkier ester group tended to give lower enantioselectivity.

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(R)-3-Hydroxy-2-methylpropionic acid methyl esterC5H10O3Ee = 96.7%[α]D20=-22.8 (c 0.85, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-3-Hydroxy-2-methylpropionic acid ethyl esterC6H12O3Ee = 95.7%[α]D20=-22.2 (c 1.0, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-3-Hydroxy-2-methylpropionic acid i-propyl esterC7H14O3Ee = 90.5%[α]D20=-16.0 (c 1.2, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-3-Hydroxy-2-methylpropionic acid n-butyl esterC8H16O3Ee = 95.3%[α]D20=-14.8 (c 0.9, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-3-Hydroxy-2-methylpropionic acid t-butyl esterC8H16O3Ee = 79.1%[α]D20=-11.6 (c 1.15, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-3-Hydroxy-2-methylpropionic acid benzyl esterC11H14O3Ee = 90.1%[α]D20=-24.2 (c 0.85, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)