Efficient Synthesis of a Key Intermediate of Neurokinin Receptor Antagonists Using a Bifunctional Asymmetric Catalyst

Abstract

We report herein an efficient synthetic method for the preparation of 2-[(2R)-arylmorpholin-2-yl]ethanol, a key inter­mediate of neurokinin receptor antagonists. Catalytic asymmetric cyanosilylation of ketone 3 using titanium complex 4 was employed to introduce the required stereochemistry.

Key words

asymmetric - catalysis - ketones - ligands - titanium

References

• 1 Regoli D. Boudon A. Fauchere J.-L. Pharmacol. Rev.  1994,  46:  551 ; and references cited therein
• 2 Nishi T, Fukazawa T, Kurata H, Ishibashi K, Nakajima K, Yamaguchi T, and Itoh K. inventors; Sankyo Co. Ltd, Japan,  EP-776893-A1. 
• 3 Nishi T. Ishibashi K. Nakajima K. Iio Y. Fukazawa T. Tetrahedron: Asymmetry  1998,  9:  3251 
• 4 A synthetic method using iodoetherification and optical resolution was already reported: Takemoto T. Yukiko lio Y. Nishi T. Tetrahedron Lett.  2000,  41:  1785 
• 5 Hamashima Y. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2000,  122:  7412 
• 6 Clay RJ. Collom TA. Karrick GL. Wemple J. Synthesis  1993,  290 
• 9 Hamashima Y. Kanai M. Shibasaki M. Tetrahedron Lett.  2001,  42:  691 
• 10 Masumoto S. Yabu K. Kanai M. Shibasaki M. Tetrahedron Lett.  2002,  43:  2919 
• 11 Yabu K. Masumoto S. Yamasaki S. Hamashima Y. Kanai M. Du W. Curran DP. Shibasaki M. J. Am. Chem. Soc.  2001,  123:  9908 

7

A representative procedure: To a suspension of the chiral ligand (0.0565 mmol) in toluene (1 mL) was added Ti(i-Pr)₄ (16 mL, 0.054 mmol) at ambient temperature, and the whole mixture was stirred at 75 °C for 1 h. After the yellow solution was cooled to room temperature, toluene was evaporated under reduced pressure. The resulting pale yellow residue was further dried in vacuo for 1 h. The residue was dissolved in THF (0.9 mL), then (CH₃)₃SiCN (14 mL, 0.108 mmol) was added using an ice bath, and the whole was stirred at room temperature for 30 min. To this catalyst solution, ketone 3 (180 mg, 0.54 mmol) in THF (0.9 mL) was added, followed by the addition of (CH₃)₃SiCN (144 mL, 1.08 mmol) at 30 °C. The reaction was monitored by TLC, and after the reaction period described in Table [2] , pyridine (0.1 mL) and H₂O (1 mL) were added. Usual workup gave the crude cyanohydrintrimethylsilylether 9. ¹H NMR (CDCl₃, δ in ppm): 0.02 (6 H, s), 0.16 (9 H, s), 0.84 (9 H, s), 2.08-2.15 (1 H, m), 2.20-2.28 (1 H, m), 3.60-3.66 (1 H, m), 3.73-3.79 (1 H, m), 7.35 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 7.46 (1 H, d,
J = 8.5 Hz), 7.60 (1 H, d, J = 2.0 Hz).

8

¹H NMR (400 MHz, CDCl₃) δ: 0.04 (3 H, s), 0.01 (3 H, s), 0.87 (9 H, s), 1.44 (2 H, br. s), 1.88 (1 H, ddd, J = 14.6 Hz, 3.7 Hz, 3.7Hz), 2.16 (1 H, ddd, J = 14.6 Hz, 10.2 Hz, 4.6 Hz), 2.86 (1 H, d, J = 13.1 Hz), 2.91 (1 H, d, J = 13.1 Hz), 3.53 (1 H, ddd, J = 10.3 Hz, 10.2 Hz, 3.7 Hz), 3.73 (1 H, ddd, J = 10.3 Hz, 4.6 Hz, 3.7 Hz), 4.91 (1 H, br. s), 7.22 (1 H, dd, J = 8.6 Hz, 2.2 Hz), 7.42 (1 H, d, J = 8.6 Hz), 7.56 (1 H, d, J = 2.2 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 5.82, 5.77, 17.94, 25.70, 39.61, 53.27, 60.40, 77.21, 125.21, 128.28, 130.10, 130.59, 132.44, 145.46. IR (liquid film) cm ¹: 3454, 2954, 2930, 1092, 837. HRMS: 364.1275 (calcd for C₁₆H₂₈NO₂Cl₂Si 364.1266).

12

A representative procedure: To a suspension of the chiral ligand (0.030 mmol) in THF (0.3 mL), Gd(i-PrO)₃ (0.2 M solution in THF, 75 mL, 0.015 mmol) was added at 0 °C, and the mixture was stirred at 45 °C for 30 min. The solvent was evaporated at ambient temperature, the resulting white powder was dissolved in EtCN (0.1 mL), and (CH₃)₃SiCN (60 mL, 1.5 equiv) was added at -40 °C. After stirring for 15 min, the reaction was started by adding a solution of ketone 3 (0.30 mmol) in EtCN (0.1 mL).