2,6-Lutidine → 2-(R)-(3-(R)-(t-Butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 330 mg (1.3 mmol) of benzyl (S)-hexahydromandelate (from EXAMPLE 1, Step F) in 6.5 mL of CH2Cl2 at −78° C. was treated with 0.26 mL (1.5 mmol) of trifluoromethanesulfonic anhydride. The resulting mixture was stirred cold for 5 min and then treated with 0.30 mL (2.6 mmol) of 2,6-lutidine maintaining the internal temperature below −70° C. The resulting mixture was stirred cold for 15 min and then was treated with 0.46 mL (2.6 mmol) of DIEA. The resulting mixture was stirred cold for 15 min and then was treated with a solution of 300 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) in 1.0 mL CH2Cl2. The reaction was warmed to 0° C. and stirred for 5 h. The reaction was partitioned between 50 mL of ether and 25 ml of H2O and the layers were separated. The aqueous layer was extracted with 25 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography using 9:1 v/v hexanes/EtOAc as the eluant afforded 221 mg (31%) of the title compound: RF: 0.72 (4:1 v/v hexanes/EtOAc); 1H NMR (500 MHz) δ 0.002 (s, 3H), 0.005 (s, 3H), 0.87 (s, 9H), 0.98-1.80 (9H), 2.01-2.07 (m, 2H), 2.33-2.37 (m, 1H), 2.70-2.74 (m, 2H), 2.90 (q, J=8.0, 1H), 3.12 (t, J=8.0, 1H), 3.20-3.24 (m, 2H), 3.49 (dd, J=7.5, 8.5, 1H), 3.58 (dd, J=5.0, 10.0), 5.18 (s, 2H), 7.18-7.41 (10H).

Provenance & Evidence