Methyl Acrylate → methyl 4-(tert-butoxycarbonyl((S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)amino)-3-hydroxy-2-methylenebutanoate

HRID 627140

Reaction equation

HRID 627140 reaction equation
[Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][CH:22]=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].N12CCC(CC1)CC2>O.CO.C(OCC)(=O)C>[C:16]([O:15][C:14]([N:13]([C@@H:10]([CH:11]=[CH2:12])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:21][CH:22]([OH:23])[C:25](=[CH2:26])[C:24]([O:28][CH3:29])=[O:27])=[O:20])([CH3:19])([CH3:18])[CH3:17]

Participants

7

Reactant 3

HCID 7294Methyl Acrylate2×HCID 7527Quinuclidine2×HCID 89863148(S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-oxoethyl)carbamate2×

Product 1

HCID 89851332methyl 4-(tert-butoxycarbonyl((S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)amino)-3-hydroxy-2-methylenebutanoateYield 80%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-oxoethyl)carbamate (Intermediate 99, 16.1 g, 46.8 mmol), methyl acrylate (6.3 mL, 70 mmol), and methanol (about 2 mL), under nitrogen at ambient temperature, was added Quinuclidine (2.1 g, 19 mmol) as a solid. The mixture was then stirred for 1 day; analysis by TLC (15% ethyl acetate in hexanes) indicated incomplete conversion of starting material. Another 0.8 eq of quinuclidine was added every 24 hours; another 0.75 eq methyl acrylate and 1 mL methanol were added every two days. After 6 days total, the reaction was diluted with water and extracted with ethyl acetate. TLC indicated that only one extraction with about 250 mL ethyl acetate was needed to bring all the crude product into the organic layer, which was then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Normal-phase chromatography (5-30% ethyl acetate in hexanes, 220-g column, 35 minutes) afforded the desired compound (16 g, 80%, pale oil) as a mixture of diastereomers, with about 10 mol % of starting aldehyde present according to proton NMR analysis. The material was taken forward in this state.

Workup

  1. waitAfter 6 days total
  2. extractionextracted with ethyl acetate
  3. extractionTLC indicated that only one extraction with about 250 mL ethyl acetate
  4. washwas then washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-5d033dc43e3845008ed1fd1e3711fb17
Source dataset
uspto-grants-2016_04
Patent number
US09309245B2

Linked notes

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