Synlett 2003(10): 1539-1541
DOI: 10.1055/s-2003-40847
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Oliver Meyer, Jean-Michel Becht, Günter Helmchen*
Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49(6221)544205; e-Mail: g.helmchen@urz.uni-heidelberg.de;
Further Information

Publication History

Received 6 June 2003
Publication Date:
24 July 2003 (online)

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.

    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.