[(1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]methanol

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: ((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol (5, 7.89 g, 0.040 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (23.68 mL), under nitrogen. Lipase acrylic resin (Candida Antarctica Lipase B, Sigma-Aldrich, Saint Louis, Mo.) (417.5 mg, 5.0 wt %) was added. Vinyl acetate (5.56 mL, 0.060 mol, 1.5 equiv.) was added, and the reaction mixture was stirred at 20-25° C. while monitoring the ratio of mono-acetate and diacetate (8-9 h) by HPLC and TLC (EtOAc/Heptane=1/1). Upon reaction completion, the lipase was removed by filtration and rinsed with 2-methyl-THF (71.04 mL). The filtrate and the rinse were combined and washed with 15% NaCl aq. solution (27.63 mL) followed by sat. aqueous NaCl solution (23.68 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl acetate, 6 (9.59 g). Upon reaction completion the lipase was removed by filtration rinsed with 2-methyl-THF (71.04 mL) washed with 15% NaCl aq. solution (27.63 mL) The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF

Conditions: temp:-7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (4, 10.08 g, 0.052 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (75.60 mL) under nitrogen. The solution was cooled to −5 to −10° C., and 2.0 M Lithium tetrahydroborate in THF (39.34 mL, 0.079 mol, 1.5 equiv.) was added to the reaction mixture while maintaining the internal temperature below 0° C. The reaction was stirred at 20-25° C. for 14-16 hours and monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once the reaction was completed, the reaction mixture was cooled to 0-5° C. and reverse quenched into a pre-cooled (0-5° C.) 20% aqueous citric acid solution (50.40 mL, 1.67 equiv.) at such a rate as to maintain the internal temperature below 5° C. Once the quench was complete, the reaction mixture was warmed to 20-25° C. and stirred for at least 20 min. The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol; 5 (10.29 g). while maintaining the internal temperature below 0° C the reaction mixture was cooled to 0-5° C. reverse quenched into to maintain the internal temperature below 5° C the reaction mixture was warmed to 20-25° C. stirred for at least 20 min The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL) washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL) The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF