Allyl bromide → (S)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate

Temperature

-78 °C

Step B (4): (S)-Methyl 2-(3-butyl-2-oxopyrrolidin-1-yl)acetate (0.5 g, 2.35 mmol) from step B (3) was dissolved in dry THF (30 mL) and cooled to −78° C. Lithium bis(trimethylsilylamide (1.0M in THF, 2.70 mL, 2.70 mmol, Aldrich) was added while the temperature was maintained below −60° C. The mixture was cooled to −78° C. and stirred for 15 min. A solution of allyl bromide (0.24 mL, 2.72 mmol, Aldrich) in 10 mL of THF was added dropwise and the resulting mixture was stirred for 48 h. The reaction was quenched with acetic acid (0.5 mL) and poured into 75 mL of 0.5 M H2SO4. The aqueous layer was extracted with EtOAc and the organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography (5-35% EtOAc/hexanes linear gradient) to give 170 mg (29% yield) of (s)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (diastereomer A, first to elute) as a colorless oil and 130 mg of (R)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (diastereomer B, second to elute) as a colorless oil. Data for diastereomer A: LC-MS (M+H)+=254.3; 1H NMR (500 MHz, CDCl3) δ 5.47-5.95 (m, 1H), 4.98-5.20 (m, 2H), 4.87 (dd, J=10.99, 4.88 Hz, 1H), 3.69 (s, 3H), 3.32-3.51 (m, 1H), 3.15-3.34 (m, 1H), 2.60-2.80 (m, 1H), 2.41-2.53 (m, 1H), 2.26-2.40 (m, 1H), 2.05-2.23 (m, 1H), 1.76-1.94 (m, 1H), 1.61-1.77 (m, 1H), 1.18-1.47 (m, 5H), 0.78-0.97 (m, 3H). Data for diastereomer B: LC-MS (M+H)+=254.36; 1H NMR (500 MHz, CDCl3) δ 5.57-5.78 (m, 1H), 4.99-5.18 (m, 2H), 4.88 (dd, J=10.99, 4.88 Hz, 1H), 3.69 (s, 3H), 3.32-3.48 (m, 1H), 3.21-3.32 (m, 1H), 2.64-2.79 (m, 1H), 2.34-2.53 (m, 2H), 2.10-2.30 (m, 1H), 1.74-1.91 (m, 1H), 1.46-1.74 (m, 1H), 1.20-1.40 (m, 5H), 0.78-1.00 (m, 3H).

1. temperaturewas maintained below −60° C
2. temperatureThe mixture was cooled to −78° C.
3. stirringthe resulting mixture was stirred for 48 h
4. customThe reaction was quenched with acetic acid (0.5 mL)
5. additionpoured into 75 mL of 0.5 M H2SO4
6. extractionThe aqueous layer was extracted with EtOAc
7. concentrationthe organic layers were concentrated in vacuo
8. customThe residue was purified by silica gel chromatography (5-35% EtOAc/hexanes linear gradient)

ORD record

ord-26bbe05fcd2a45dda9b88e7145dd7f8f

Source dataset

uspto-grants-2008_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07338974B2