An Efficient Synthesis of Enantiopure (2R,3R)-β-Methoxytyrosine

Abstract

Enantiopure (2R,3R)-β-methoxytyrosine was stereoselectively synthesized from ethyl 3-(4-hydroxyphenyl)-3-oxopropanoate protected by 2-methoxyethoxymethyl (MEM) (ee >98%). l-Aminoacylase-catalyzed resolution of the corresponding erythro-N-acetyl derivatives afforded (2S,3S)-(4-MEM)-β-methoxytyrosine (ee >99%). The conversion increased to 98% by optimizing the synthesis to yield enantiopure N-acetyl-(2R,3R)-(4-MEM)-methoxytyrosine. N-Acyl cleavage was accomplished under mild conditions.

Key words

amino acids - biosynthesis - asymmetric synthesis - enantio­selectivity - enzymes - natural products

• References and Notes

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• 18 Aminoacylase Resolution: A solution of 4 (3.7 g, 10 mmol) in a mixture of EtOH (36 mL) and 1 N NaOH (10.0 mL) was stirred for 1.5 h at 0 °C. This was then concentrated under reduced pressure to 3 mL. Deionized H₂O (84 mL) and 0.05 M CoCl₂ (1.7 mL) were then added to the residue, and the pH of the solution was adjusted to 7.5 with 1 N HCl. The mixture was stirred at 40 °C. The l-aminoacylase (40 mg) was added three times at 12 h intervals to this magnetically stirred solution. The pH was maintained at 7.5 with 0.1 N NaOH, and the mixture was concentrated under reduced pressure to 10 mL. The residue was cooled to 0 °C and acidified with cold concentrated HCl to pH 1. It was then extracted with EtOAc (3 × 50 mL), and these extracts were washed with 2% HCl (2 × 30 mL), dried over anhyd Na₂SO₄, and concentrated to yield N-acetyl enantiomer 7 (1.5 g, 88%). The aqueous layer was adjusted to pH 6.5 with 4.0 N NaOH and concentrated until the volume reached 5 mL. The precipitated crystals were collected on a filter, washed with a small amount of H₂O, and dried to give a tan solid 6 (1.06 g, 71%).