Enantioselective Synthesis of (-)-(R)-Baclofen and Analogues via Rhodium-Catalysed Conjugate Addition of Boronic Acids

Abstract

Highly enantioselective syntheses of the antispastic drug (-)-(R)-Baclofen and analogues have been achieved by using rhodium-catalysed asymmetric 1,4-additions of arylboronic acids to 4-amino-but-2,3-enoic acid derivatives.

Key words

asymmetric synthesis - catalysis - addition reaction, rhodium - arylboronic acid

References

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14

The reaction did not proceed with 1 mol% of catalyst. With (S)-Tol-BINAP as chiral ligand the yield of the 1,4-addition product was <10%.

15

Typical Procedure (Preparation of 8a): A solution of [Rh(acac)(C₂H₄)₂] (1.00 mg, 3.87 µmol, 0.03 equiv) and (S)-BINAP (3.62 mg, 5.81 µmol, 0.045 equiv) in anhyd dioxane (2 mL) was stirred for 90 min at r.t. under an atmosphere of argon. To this solution Cs₂CO₃ (84.10 mg, 258 µmol, 2 equiv), 4-chloro-phenylboronic acid (100.75 mg, 645 µmol, 5 equiv), 4a (34.0 mg, 129 µmol, 1 equiv) and H₂O (0.2 mL) were successively added at r.t. and the mixture was heated at 100 °C for 48 h. Then EtOAc was added and the mixture was extracted with H₂O. The organic layer was dried and concentrated in vacuo. Flash-chromatography on silica gel (EtOAc/petroleum ether 15:85) furnished 42.3 mg (96%) of (R)-8a as a yellowish oil with 87% ee. Ester 8g was prepared in same way, except that only 1 mL of dioxane and 0.1 mL of H₂O were used.