Enantioselective fluorination of α-branched aldehydes and subsequent conversion to α-hydroxyacetals via stereospecific C–F bond cleavage

The highly enantioselective fluorination of α-branched aldehydes was achieved using newly developed chiral primary amine catalyst.

The solution was refluxed for 15 h under argon atmosphere. The resulting mixture was poured into saturated aq.NH 4 Cl, and the whole mixture was filtered to remove the catalyst, then extracted with ethyl acetate. The organic extracts were dried over Na 2 SO 4 and concentrated. The crude mixture was purified by silica gel column chromatography (hexane : CH 2 Cl 2 = 5:1) to give 75% yield of (R)-15 (white solid). 1  To a solution of (R)-15 (1.46 mmol) and NiCl 2 (PPh 3 ) 2 (95.5 mg, 0.146 mmol, 10 mol%) in TBME (14.6 mL) was added 3M ethereal solution of MeMgI (2.92 mL, 8.76 mmol, 6 equiv) at 0 ºC. The solution was refluxed for 16 h under argon atmosphere. This mixture was poured into ice-cooled 1M HCl, and the whole mixture was filtered to remove the catalyst. The filtrate was poured into saturated aq.NaHCO 3 , and extracted with dichloromethane. The organic extracts were dried over Na 2 SO 4 and concentrated. The crude mixture was purified by silica gel column chromatography (hexane : CH 2 Cl 2 = 10:1) to give 91% yield of (R)-16 (white solid To a suspension of (R)-2a 3 or (R)-2b (5.25 mmol), tetrabutylammonium hydrogen sulfate (356.5 mg, 1.05 mmol, 20 mol%) and K 2 CO 3 (7.26 g, 52.5 mmol, 10 equiv) in CH 3 CN (105 mL) was added ethyl isocyanoacetate (688 μL, 6.30 mmol, 1.2 equiv) at 0 ºC. The solution was refluxed for 16 h under argon atmosphere. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to afford (R)-17.
The solution was stirred at room temperature for 1 h under argon atmosphere. The resulting mixture was poured into ice-cooled saturated aq.NaHCO 3 and extracted with CH 2 Cl 2 . The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel to afford (R)-1.

CO 2 Et
Br F S17
General procedure: Enantioselective fluorination of 3 was carried out according to the procedure described in page S6. After completion of the reaction, MeOH (2.64 mL)/NaOMe (1.32 mmol, 5 equiv.) or ethylene glycol (2.64 mL)/NaH (1.32 mmol, 5 equiv) were added at 0 °C. The mixture was stirred at room temperature, then diluted by adding sat.NaHCO 3 aq., and extracted with Et 2 O. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give -hydroxylacetals 10-12.
MeI (0.408 mmol, 2 equiv.) was added to the mixture, and stirred for 60 min at 0 °C. The reaction was quenched by adding sat. NH 4 Cl aq. and extracted with Et 2 O. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford 19.
The crude mixture was purified by silica gel column chromatography (hexane : ethyl acetate = 4 : 1) to give 55% yield of 10k (pale yellow oil

H NMR measurement of hemiacetal derived from 4.
After fluorination of 3a, NaHCO 3 aq. was added to the mixture, and extracted with Et 2 O. The organic layer was dried over Na 2 CO 3 and concentrated to give the crude mixture of 4a. 1 H NMR measurement of 4a in CD 3 OD clearly showed the generation of hemiacetal as a diastereomeric mixture (dr = 6 : 4).