Isobutyryl chloride → HCID 86718450, compound

Temperature

-78 °C

A 1 dram vial equipped with a stir bar is charged with 14.3 mg (0.030 mmol, 1 equiv.) of 51 and 150 μL of THF. The solution was cooled to −78° C. in a dry ice/acetone bath, and 300 μL of a solution of LiTMP (0.5M in THF, 0.150 mmol, 5 equiv.) was added dropwise. The yellow solution was stirred at −78° C. for 10 minutes followed by warming to 0° C. in a water/ice bath for 10 minutes and then recooling to −78° C. prior to addition of 15.7 μL (0.15 mmol, 5 equiv.) of isobutyryl chloride. The reaction was stirred 30 minutes prior to quenching by the addition of 500 μL of saturated aqueous ammonium chloride. The solution was transferred to a separatory funnel with 15 mL of hexane, and the organic layer was washed sequentially saturated aqueous 10% aqueous hydrochloric acid, water, and brine; dried with MgSO4; and concentrated in vacuo. The crude product was found to contain an inseparable mixture of product and 51. The mixture was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate) and carried forward as a mixture. A 1 dram vial equipped with a stir bar is charged with 9.0 mg (0.016 mmol, 1 equiv.) of the mixture followed by 100 μL of THF. The vial was cooled in a water/ice bath and 18 μL of TBAF (1.0 M in THF, 0.018, 1.1 equiv.) is added. The mixture is stirred for 15 min at which time it is transferred to a separatory funnel, and the organic layer is washed sequentially saturated aqueous sodium bicarbonate, water, and brine. The organic layer is then dried with MgSO4 and concentrated in vacuo to give a yellow oil. The crude product is purified by preparative TLC (Rf=0.25 in 3:1 hexane:ethyl acetate) to give 4.1 mg (53% yield) of 56 as a clear oil. 1H NMR (500 MHz, CDCl3) δ 5.85 (s, 1H), 5.07-4.96 (m, 2H), 4.61 (dd, J=6.8, 15.5 Hz, 2H), 3.82 (s, 3H), 3.58 (dd, J=5.2, 11.3 Hz, 1H), 3.32 (s, 3H), 2.48 (ddd, J=7.5, 14.5, 34.2 Hz, 2H), 2.18-2.04 (m, J=5.9, 13.2, 17.3 Hz, 4H), 1.96 (s, 1H), 1.77 (dd, J=11.4, 13.4 Hz, 1H), 1.67 (d, J=3.0 Hz, 6H), 1.64 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H), 1.30-1.21 (m, J=2.6, 2.6 Hz, 1H), 1.14 (s, 3H), 1.12 (d, J=6.5 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H). HRMS-ESI (m/z): [M+H]+ calculated for C28H42O6, 475.3054. found, 475.3045.

1. customA 1 dram vial equipped with a stir bar
2. temperatureby warming to 0° C. in a water/ice bath for 10 minutes
3. customrecooling to −78° C.
4. stirringThe reaction was stirred 30 minutes
5. customto quenching by the addition of 500 μL of saturated aqueous ammonium chloride
6. customThe solution was transferred to a separatory funnel with 15 mL of hexane
7. washthe organic layer was washed sequentially saturated aqueous 10% aqueous hydrochloric acid, water, and brine
8. dry with materialdried with MgSO4
9. concentrationand concentrated in vacuo
10. additionan inseparable mixture of product and 51
11. customThe mixture was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate)
12. customA 1 dram vial equipped with a stir bar
13. temperatureThe vial was cooled in a water/ice bath
14. stirringThe mixture is stirred for 15 min at which time it
15. customis transferred to a separatory funnel
16. washthe organic layer is washed sequentially saturated aqueous sodium bicarbonate, water, and brine
17. dry with materialThe organic layer is then dried with MgSO4
18. concentrationconcentrated in vacuo
19. customto give a yellow oil
20. customThe crude product is purified by preparative TLC (Rf=0.25 in 3:1 hexane:ethyl acetate)

ORD record

ord-450067a647e84fb380db409bc2d8e728

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09321713B2