2,6-Lutidine → Benzyl (2S)-3-cyclobutyl-2-hydroxypropanoate

HRID 2301169Notes

Reaction equation

HRID 2301169 reaction equation
[OH:1][C@@H:2]([CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CC1C=CC=C(C)N=1.[Si:41]([O:48][CH2:49][C@@H:50]1[C@@H:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:53][NH:52][CH2:51]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:1][C@@H:2]([CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].[Si:41]([O:48][CH2:49][C@@H:50]1[C@@H:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:53][N:52]([C@H:2]([CH2:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:51]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]

Participants

8

Reactant 5

HCID 79372,6-LutidineHCID 67749Trifluoromethanesulfonic anhydrideHCID 81531DiisopropylethylamineHCID 21341073(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidineHCID 53678805Benzyl (2S)-3-cyclobutyl-2-hydroxypropanoate

Product 2

HCID 53678805Benzyl (2S)-3-cyclobutyl-2-hydroxypropanoateHCID 1317226812-(R)-(3-(R)-(t-Butyldimethylsilyloxymethyl)-4-(S)-phenyl-pyrrolidin1-yl)-3-(cyclobutyl)propionic acid, benzyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 1.84 g (7.8 mmol) of 2-(S)-hydroxy-3-(cyclobutyl)propionic acid, benzyl ester (Hydroxy Ester 2) in 30 mL of CH2Cl2 at −5° C. was treated with 1.40 mL (8.4 mmol) of trifluoromethanesulfonic anhydride maintaining the internal temperature at less than 0° C. The resulting mixture was stirred cold for 2 min, then treated with 1.10 mL (9.6 mmol) of 2,6-lutidene, maintaining the internal temperature at less than 0° C. The resulting mixture was stirred cold for 30 min, then treated with a solution of 2.65 g (9.5 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (Pyrroldine 1) in 10 mL of CH2Cl2 and 3.00 mL (31.2 mmol) of DIEA. The resulting mixture was warmed to rt and stirred for 20 h. The reaction was quenched with 50 mL of sat'd NaHCO3 and the quenched mixture was extracted with 200 mL of ether. The ether extract was dried over MgSO4 and concentrated. Flash chromtography on 150 g of silica gel using 20:1 v/v hexanes/ether as the eluant afforded 3.23 g (81 % based on Hydroxy Ester 2) of the title compound: 1H NMR (300 MHz) δ −0.25 (s, 3H), −0.21 (s, 3H), 0.84 (s, 9H), 1.57-2.07 (8H), 2.29-2.39 (2H), 2.66-2.77 (m, 2H), 2.93 (q, J=7.8, 1H), 3.06 (t, J=8.4, 1H), 3.19 (t, J=8.4, 1H), 3.26 (dd, J=2.1, 6.3, 1H), 3.45-3.60 (m, 2H), 5.15 (s, 2H), 7.17-7.38 (10H).

Workup

  1. temperaturemaintaining the internal temperature at less than 0° C
  2. stirringThe resulting mixture was stirred cold for 30 min
  3. stirringstirred for 20 h
  4. customThe reaction was quenched with 50 mL of sat'd NaHCO3
  5. extractionthe quenched mixture was extracted with 200 mL of ether
  6. extractionThe ether extract
  7. dry with materialwas dried over MgSO4
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-802b92433aba4b93b0d1407b83b467a8
Source dataset
uspto-grants-2002_12
Patent number
US06498161B1

Reaction notes

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