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.

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

References

1a Mann A. Boulanger T. Brandau B. Durant F. Evrard G. Heaulme M. Desaulles E. Wermuth C.-G. J. Med. Chem.  1991,  34:  1307 

1b Karla R. Ebert B. Thorkildsen C. Herdeis C. Johansen TN. Nielsen B. Krogsgaard-Larsen P. J. Med. Chem.  1999,  42:  2053 

2 Olpe HR. Demiéville H. Baltzer V. Bencze WL. Eur. J. Pharmacol.  1978,  52:  133 

3a Herdeis C. Hubmann HP. Tetrahedron: Asymmetry  1992,  3:  1213 

3b Langlois N. Dahuron N. Wang H.-S. Tetrahedron  1996,  52:  15117 

3c Licandro E. Maiorana S. Baldoli C. Capella L. Perdicchia D. Tetrahedron: Asymmetry  2000,  11:  975 

3d Schoenfelder A. Mann A. Le Coz S. Synlett  1993,  63 

4a Thakur VV. Nikalje MD. Sudalai A. Tetrahedron: Asymmetry  2003,  14:  581 

4b Corey EJ. Zhang F.-Y. Org. Lett.  2000,  2:  4257 

4c Anada M. Hashimoto S.-I. Tetrahedron Lett.  1998,  39:  79 

4d Resende P. Almeida WP. Coelho F. Tetrahedron: Asymmetry  1999,  10:  2113 

5a Wang M.-X. Zhao S.-M. Tetrahedron Lett.  2002,  43:  6617 

5b Brenna E. Caraccia N. Fuganti C. Fuganti D. Grasseli P. Tetrahedron: Asymmetry  1997,  8:  3801 

See also:

6a Sonesson C. Larhed M. Nyqvist C. Hallberg A. J. Org. Chem.  1996,  14:  4756 

6b Carpes MJS. Correia CRD. Tetrahedron Lett.  2002,  43:  741 

7 Sakai M. Hayashi H. Miyaura N. Organometallics  1997,  16:  4229 

8a Takaya Y. Ogasawara M. Hayashi T. Sakai M. Miyaura N. J. Am. Chem. Soc.  1998,  120:  5579 

8b Takaya Y. Senda T. Kurushima H. Ogasawara M. Hayashi T. Tetrahedron: Asymmetry  1999,  10:  4047 

8c Fagnou K. Lautens M. Chem. Rev.  2003,  103:  169 

9 De Vita RJ. Frontier AJ. Schoen WR. Wyvratt MJ. Fisher MH. Cheng K. Chan WW.-S. Butler BS. Smith RG. Helv. Chim. Acta  1997,  80:  1244 

10a Frigerio M. Santagostino M. Sputore S. J. Org. Chem.  1999,  64:  4537 

10b More JD. Finney NS. Org. Lett.  2002,  4:  3001 

11 Ando K. Oishi T. Hirama M. Ohno H. Ibuka T. J. Org. Chem.  2000,  65:  4745 

12 Sakuma S. Sakai M. Itooka R. Miyaura N. J. Org. Chem.  2000,  65:  5951 

13a As a rule, the rate of the 1,4-addition is increased by water, see: Hayashi T. Takahashi M. Takaya Y. Ogasawara M. J. Am. Chem. Soc.  2002,  124:  5052 

13b However, with dioxane/H₂O 5:1 as solvent reduced yields of <10% were obtained (entry 7). Following a recent report of Genêt et al., we also probed ethylene glycol as solvent (entry 8), but no reaction occurred, see: Amengual R. Michelet V. Genêt J.-P. Synlett  2002,  1791 

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.

16 Hayashi T. Synlett  2001,  879 

17 Senda T. Ogasawara M. Hayashi T. J. Org. Chem.  2001,  66:  6852