Copper-catalyzed asymmetric methylation of fluoroalkylated pyruvates with dimethylzinc

The catalytic asymmetric methylation of fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the presence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various α-fluoroalkylated tertiary alcohols with CF3, CF2H, CF2Br, and n-CnF2 n +1 (n = 2, 3, 8) groups in good-to-high yields and enantioselectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantioselectivity. Moreover, the methylation of simple perfluoroalkylated ketones is found to be facilitated by only chiral phosphines without copper.

Then, a solution of trifluoropyruvate hydrate in ethanol was stirred at 70 °C for 4 h, and evaporated.
The hemiacetal pyruvate was purified by distillation with P 2 O 5 to provide the corresponding trifluoropyruvate (1c,d) (reaction 2).

Typical procedure III: Cu-catalyzed asymmetric methylation of fluoroalkylated pyruvate
To a mixture of CuTC (1.0 mg, 0.005 mmol) and (R)-BTFM-Garphos (5.7 mg, 0.0048 mmol) was added CH 2 Cl 2 (1.0 mL) at room temperature under argon atmosphere, and the solution was stirred for 12 h. The solvent was removed under reduced pressure, and the prepared catalyst was dissolved in TBME (0.5 mL) under argon atmosphere. After the solution was cooled to −90 °C, Me 2 Zn (1.0 M in heptane, 0.4 mL, 0.4 mmol) followed by fluoroalkylated pyruvate 1 (0.2 mmol) in TBME (0.5 mL) were added in 30 min. The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated aq. NH 4 Cl. The organic layer was separated and the aqueous layer was extracted with Et 2 O twice. The combined organic layer was dried over anhydrous Na 2 SO 4 and evaporated under controlled pressure (350 mmHg). The concentrated solution was used without purification for the next protection reaction. The yield of alcohol product 2 was determined by 19 F NMR analysis using benzotrifluoride (BTF) as an internal standard.
To a solution of DMAP (2.4 mg, 0.02 mmol) and the crude alcohol in CH 2 Cl 2 (2.0 mL) was added NEt 3 (56 L, 0.4 mmol) at room temperature under argon atmosphere. After the reaction mixture was cooled to 0 °C, p-nitrobenzoyl chloride (56mg, 0.3 mmol) was added. Then the mixture was warmed to room temperature and stirred for 1 h. After 1 N HCl (5.0 mL) was added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with Et 2 O twice. The combined organic layer was washed with saturated aq. NaHCO 3 , water, and brine, and then dried over anhydrous MgSO 4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give p-nitrobenzoylated alcohol 2'. Enantiomeric excess was determined by chiral HPLC analysis.
The absolute configuration was not determined. 1