Tetrahydrofuran → (4s)-6-[(s)-(4-Tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropyl-3,4-dihydro-spiro[chromen-2,1'-cyclobutan]-4-ol

Participants

Reaction Steps

Under argon, 2.1 mg (0.014 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 3 ml of abs. tetrahydrofuran, 102 μl (0.575 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 70 mg (0.144 mmol) of 6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A), dissolved in 3.25 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 18 h. 2 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 26 mg (37% of theory, 86% ee) of Example 34 and 29 mg (42% of theory, 89% ee) of Example 35. Subsequent chromatographic separation of 15 mg of Example 34 on a chiral phase [column: Chiralpak AD-H, 250×20 mm; mobile phase: isopropanol/isohexane 5:95; flow rate: 15 ml/min; 24° C.; detection: 260 nm] gives 10.6 mg of Example 34 having an ee of >99%.

Provenance & Evidence