Reaction #1340609

Reaction equation

(3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine

Dimethyl sulfoxide

oxalylchloride

citric acid

→

title compound

(3S)-1-Benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine

Solvents

dichloromethane

triethylamine

triethylamine

dichloromethane

dichloromethane

triethylamine

Conditions

Workup

1. 1
   workup.STIRRINGby stirring at the same temperature for 30 minutes
2. 2
   workup.WAITfurther at −43° C. for 1 hour
3. 3
   workup.STIRRINGby stirring for 45 minutes
4. 4
   workup.STIRRINGby stirring for 10 minutes
5. 5
   ExtractionThe obtained aqueous layer was extracted with dichloromethane (200 mL×2)
6. 6
   WashThe combined organic layer was washed by saturated brine (100 mL)
7. 7
   Dryingdried over anhydrous sodium sulfate
8. 8
   FiltrationAfter filtration
9. 9
   Concentrationthe filtrate was concentrated under reduced pressure
10. 10
    Otherto thereby yield a crude aldehyde as a pale yellow oilily substance
11. 11
    workup.STIRRINGby stirring for another 24 hours
12. 12
    workup.ADDITIONThereafter, silica gel (100 g) was added to the reaction mixture
13. 13
    workup.STIRRINGby stirring for 24 hours
14. 14
    ConcentrationThe reaction mixture was concentrated under reduced pressure
15. 15
    workup.WAITleft
16. 16
    workup.WAITto stand for 24 hours
17. 17
    OtherThe residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=7:3)

Procedure

Dimethyl sulfoxide (5.10 mL, 59.3 mmol) was added to a solution of oxalylchloride (5.00 mL, 57.3 mmol) in dichloromethane (100 mL), and the mixture was stirred at −78° C. for 20 minutes. Subsequently, a solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine (8.00 g, 22.8 mmol) in dichloromethane (85 mL) was added dropwise slowly thereto, followed by stirring at the same temperature for 30 minutes, and further at −43° C. for 1 hour. Subsequently, triethylamine (30 mL) was added thereto, and the temperature of the resultant mixture was elevated to an ice cooling temperature, followed by stirring for 45 minutes. Thereafter, a 10% aqueous citric acid solution (100 mL) was added to the resultant mixture, followed by stirring for 10 minutes. The obtained aqueous layer was extracted with dichloromethane (200 mL×2). The combined organic layer was washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield a crude aldehyde as a pale yellow oilily substance. Subsequently, triethylamine (0.50 mL, 3.59 mmol) was added to a solution of the crude aldehyde compound (2.5 g, 7.18 mmol) in dichloromethane (10 mL). The resultant mixture was stirred at room temperature for 24 hours, and triethylamine (0.50 mL, 3.59 mmol) was further added thereto, followed by stirring for another 24 hours. Thereafter, silica gel (100 g) was added to the reaction mixture, followed by stirring for 24 hours. The reaction mixture was concentrated under reduced pressure, and left to stand for 24 hours. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=7:3), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:3)) as a colorless oily substance (750 mg, 28%).

Source