Diisopropylamine → (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate

Temperature

-50 °C

To a solution of diisopropylamine (19.93 milliliters (mL), 142 millimoles (mmol)) in anhydrous THF (99 mL) at −50° C. (deficient dry ice/acetone bath) was added n-butyllithium (n-BuLi; 54.3 mL, 130 mmol, 2.5 M in hexanes). This solution was removed from the cold bath for 15 minutes (min), then re-cooled to −50° C. To the lithium diisopropylamide (LDA) was added a solution of (S)-methyl 3-hydroxybutanoate (6.64 ml, 59.3 mmol) in THF (20.0 mL) dropwise over 15 min using a cannula. This solution was allowed to warm to −30° C. over 30 min, stirred at −30° C. for 1 h, and recooled to −78° C. To the enolate was added a solution of 1-bromo-3-methylbut-2-ene (13.7 mL, 119 mmol) in anhydrous 1,2-dimethoxyethane (20.0 mL, 193 mmol) dropwise over 15 min. The cold bath was at −60° C. after 1 h at which time the reaction flask was removed from the bath and stirred without cooling for 1.5 h. The reaction was quenched by the addition of sat. aq. ammonium chloride (NH4Cl; 50 mL), diluted with EtOAc (50 mL), and the phases were separated. The aqueous phase was further extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with sat. aq. sodium chloride (NaCl, brine; 50 mL), dried over sodium sulfate Na2SO4, filtered, and concentrated to dryness. The crude residue was purified by flash column chromatography (120 grams (g) silica gel (SiO2), 0→40% EtOAc/hexanes) to afford the title compound (9.5 g, 51.0 mmol, 86%) as a slightly yellow oil: IR (thin film) 3452, 2971, 2929, 1730, 1437, 1198, 1160 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.11-5.01 (m, 1H), 3.92 (p, J=6.3 Hz, 1H), 3.70 (s, 3H), 2.78 (s, 1H), 2.46-2.28 (m, 3H), 1.69 (d, J=1.4 Hz, 3H), 1.62 (s, 3H), 1.23 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.54, 134.14, 120.30, 67.78, 52.72, 51.52, 27.90, 25.73, 21.46, 17.64.

1. customThis solution was removed from the cold bath for 15 minutes (min)
2. temperatureto warm to −30° C. over 30 min
3. customrecooled to −78° C
4. waitThe cold bath was at −60° C. after 1 h at which time
5. customthe reaction flask was removed from the bath
6. stirringstirred
7. temperaturewithout cooling for 1.5 h
8. customThe reaction was quenched by the addition of sat. aq. ammonium chloride (NH4Cl; 50 mL)
9. additiondiluted with EtOAc (50 mL)
10. customthe phases were separated
11. extractionThe aqueous phase was further extracted with EtOAc (2×50 mL)
12. washthe combined organic extracts were washed with sat. aq. sodium chloride (NaCl, brine; 50 mL)
13. dry with materialdried over sodium sulfate Na2SO4
14. filtrationfiltered
15. concentrationconcentrated to dryness
16. customThe crude residue was purified by flash column chromatography (120 grams (g) silica gel (SiO2), 0→40% EtOAc/hexanes)

ORD record

ord-bccc43aa834d4f4da8cc544b07d30c93

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09247741B2