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

HRID 1386668Notes

Reaction equation

HRID 1386668 reaction equation
[C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.CCN(C(C)C)C(C)C.[Si:51]([O:58][CH2:59][C@@H:60]1[C@@H:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:63][NH:62][CH2:61]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>C(Cl)Cl>[Si:51]([O:58][CH2:59][C@@H:60]1[C@@H:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:63][N:62]([C@H:2]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:61]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]

Participants

7

Reactant 5

HCID 79372,6-LutidineHCID 67749Trifluoromethanesulfonic anhydrideHCID 81531DiisopropylethylamineHCID 21341073(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidineHCID 54322505Benzyl (s)-hexahydromandelate

Product 1

HCID 1317227902-(R)-(3-(R)-(t-Butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl esterYield 42.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

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).

Workup

  1. stirringThe resulting mixture was stirred cold for 15 min
  2. stirringThe resulting mixture was stirred cold for 15 min
  3. stirringstirred for 5 h
  4. customThe reaction was partitioned between 50 mL of ether and 25 ml of H2O
  5. customthe layers were separated
  6. extractionThe aqueous layer was extracted with 25 mL of ether
  7. dry with materialThe combined organic phases were dried over MgSO4
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-22eabf5288344c53a24345d72f924811
Source dataset
uspto-grants-2001_07
Patent number
US06265434B1

Reaction notes

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