Formic Acid → (4R)-4-[(1S)-1-hydroxyethyl]-1-[(1R)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one

In a vial under N2, [Rh(C5Me5)Cl2]2 (62 mg, 0.10 mmol) and (1R,2R)-(−)-N-p-Tosyl-1,2-diphenylethylenediamine (87 mg, 0.24 mmol) were taken up in MeCN (1 mL). Triethylamine (0.1 mL, 0.7 mmol) was added and the resulting mixture was stirred 40 min prior to use. Meanwhile, a solution of (R)-4-acetyl-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.03 (1.06 g, 4.06 mmol) and triethylamine (3 mL, 21.3 mmol) in MeCN (20 mL) was cooled to an internal temperature of −10° C. under Ar in a jacketed 3-neck flask equipped with a thermocouple. Formic acid (0.525 mL, 13.9 mmol) was added during the cooling ramp once the internal temperature reached 0° C. Once the internal temperature reached −10° C., the aforementioned catalyst mixture was added in one portion, washing with additional MeCN (3×1 mL). The resulting orange solution was stirred for 48 h at −10° C. and was then warmed to r.t. Hydrochloric acid (3 M, 7.5 mL, 22.5 mmol) was added followed by dilution with EtOAc (50 mL) and brine (30 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto 10 g silica gel. The product was purified by silica gel chromatography (35% to 50% acetone in hexanes) to afford (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.05.

1. customequipped with a thermocouple
2. customreached 0° C
3. customreached −10° C.
4. additionthe aforementioned catalyst mixture was added in one portion
5. washwashing with additional MeCN (3×1 mL)
6. stirringThe resulting orange solution was stirred for 48 h at −10° C.
7. customThe phases were separated
8. extractionthe aqueous phase was extracted with EtOAc (50 mL)
9. dry with materialThe combined organic phase was dried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated onto 10 g silica gel
12. customThe product was purified by silica gel chromatography (35% to 50% acetone in hexanes)

ORD record

ord-adb6cc44731445dc89cbc225277b1f5b

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376441B2