Diglyme → (2S,4S)-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester

Temperature

0 °C

To an oven-dried 100-mL 2-necked round-bottomed flask was added a solution of 1-(tert-butyloxycarbonyl)-4-C-methylene-L-proline tert-butyl ester (519 mg, 1.83 mmol) in 2-methoxyethyl ether (diglyme) (5 mL) followed at 0° C. by a solution of disiamylborane (12.8 ML of a 0.5M solution in tetrahydrofuran, 6.41 mmol) in diglyme (15 mL). After stirring for 15 minutes at 0° C., the cooling bath was removed, and the mixture was allowed to warm up for 15 minutes. The reaction was then quenched by the careful addition of water (25 mL). The reaction mixture was again cooled to 0° C., and the pH was adjusted to 8 with 3N sodium hydroxide. 30% Hydrogen peroxide (4 mL) was added dropwise slowly with the temperature maintained at 0° C. for 10 minutes. The cooling bath was removed for 10 minutes, and an additional 1.3 mL of 30% hydrogen peroxide was added, while maintaining the pH at 8 by addition of 3N sodium hydroxide. The pH was then adjusted to ~6 by the addition of glacial acetic acid. The mixture was partitioned between diethyl ether (100 mL) and water (50 mL), and the aqueous layer extracted with ether. The combined ethereal layers were washed with water, dried (MgSO4), and evaporated. Flash silica gel chromatography eluting with 20% acetone/hexane afforded the title compound as a colorless oil; yield 376 mg (68%).

1. customthe cooling bath was removed
2. temperatureto warm up for 15 minutes
3. customThe reaction was then quenched by the careful addition of water (25 mL)
4. temperatureThe reaction mixture was again cooled to 0° C.
5. addition30% Hydrogen peroxide (4 mL) was added dropwise slowly with the temperature
6. temperaturemaintained at 0° C. for 10 minutes
7. customThe cooling bath was removed for 10 minutes
8. additionan additional 1.3 mL of 30% hydrogen peroxide was added
9. temperaturewhile maintaining the pH at 8
10. additionby addition of 3N sodium hydroxide
11. additionThe pH was then adjusted to ~6 by the addition of glacial acetic acid
12. customThe mixture was partitioned between diethyl ether (100 mL) and water (50 mL)
13. extractionthe aqueous layer extracted with ether
14. washThe combined ethereal layers were washed with water
15. dry with materialdried (MgSO4)
16. customevaporated
17. washFlash silica gel chromatography eluting with 20% acetone/hexane

ORD record

ord-fdd056c540aa4ccd990d982667411533

Source dataset

uspto-grants-1998_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05821261