在药物合成中，醇是一种重要中间体。由于手性的药物越来越多，手性醇的合成近年 来越来越受到重视。常用的方法有：不对称酮还原为手性的仲醇、Sharpless 不对称双 羟化、Sharpless 不对称羟胺化、通过不对称环氧化引入手性和从手性-氨基酸合成手性-羟基酸等。
不对称酮还原为手性的仲醇的方法常用的有：CBS 还原法、不对称氢化和 YEAST 还原法等。
1、CBS 还原法
(R)-2,3-Dihydro-1H-inden-1-ol. A 250-mL, three-necked, round-bottomed flaskis equipped with a Teflon-coated thermocouple probe, a 125-mL pressure-equalizing addition funnel, nitrogen inlet, and Teflon-coated magnetic stirring bar. The flask is charged with the (S)-oxazaborolidine-borane complex (2.91 g, 10.0 mmol), purged with nitrogen, and charged with dry dichloromethane (10 mL). To the stirred solution is added borane-methyl sulfide (10 M, 20 mL, 200 mmol). The solution is cooled to −20°C and the addition funnel charged with a solution of 1-indanone (26.4 g, 200 mmol) in dry dichloromethane (75 mL). The 1-indanone solution is then added dropwise over a 4–6 hr period while maintaining the internal temperature of the reaction mixture at −20±5°C. After the addition is complete, the reaction mixture is stirred for 2 hr at −20°C. After the reaction is complete, the mixture is cautiously poured into a 1-L flask containing magnetically-stirred, pre-cooled (−20°C) methanol (300 mL). The cooling bath is removed, and the stirred mixture allowed to warm to room temperature (20–25°C). After evolution of hydrogen ceases, the mixture is concentrated by distillation (1 atm) to a volume of ca. 50 mL. Methanol (200 mL) is added, and the distillation repeated . The residue containing the product and diphenylprolinol is diluted with methanol (100 mL) and then loaded onto a 2.5 × 30-cm column packed with Amberlyst 15 (NH+4) at ca. 2.5 mL/min, collecting 40-mL fractions. The column is rinsed with methanol until the product is eluted. The column is then rinsed with 1 M methanolic ammonia until the diphenylprolinol is eluted. The fractions containing the product (2–15) are combined, and then concentrated under reduced pressure (40°C, 100 mm) to give 26.2 g of crude product as a white crystalline solid. The crude product is dissolved in hexane (260 mL) at 50–60°C in a 500-mL, round-bottomed flask fitted with a mechanical stirrer. The product is allowed to crystallize as the stirred mixture is slowly cooled to 20–25°C. The mixture is stirred for 4 hr at 20–22°C, filtered, and the cake washed with hexane (2 × 25 mL). The product is dried in a vacuum oven (30°C, 10 mm) to constant weight to yield 24.1–25.2 g (90–94%) of the title compound as a white crystalline solid.
2、不对称氢化
A. Preparation of catalyst solution. A 250-mL, round-bottomed flask fitted with a septum and magnetic stirring bar is charged with 486.9–488.2 mg (0.985–0.990 × 10−3 mol) of chloro(1,5-cyclooctadiene)rhodium(I) dimer and, under argon, with 1.20 g (2.15 × 10−3 ml) of (2S, 4S) -N-tert-butyloxycarbonyl-4-diphenylphosphino-2- diphenyl phosphino methyl pyrrolidine, (S, S)-BPPM. The sealed flask is charged by cannula, under argon, with 150 mL of degassed benzene and stirred under argon for 15 min at room temperature. The catalyst is transferred by cannula, under argon, into the autoclave (see below).
B. Asymmetric hydrogenation. A stainless steel stirred autoclave with a total volume of 500 mL is charged with 25.6 g (0.2 mol) of ketopantoyl lactone. The autoclave is flushed with argon and the catalyst solution (see above) is added by cannula, under argon. The autoclave is sealed and hydrogenation is carried out at 40°C, 750-psig hydrogen and 950–1050 rpm for 48 hr. Care should be taken to flush all the lines before connecting to the autoclave. After the autoclave is cooled to room temperature, it is vented and opened. The reaction mixture is then transferred to a 500-mL, round-bottomed flask and most of the solvent is removed by rotary evaporator. Distillation of this reddish solid affords 24–25.6 g (92–98%) of D-(−)-pantoyl lactone: bp 90–110°C (4 cm); [α]D25 −39.3℃ to −42.4℃ ( c 2, H2O) (78 to 84% e.e.) and.The pantoyl lactone thus obtained (25.41 g), [α]D25 −40.8° (80.5% e.e.) is refluxed with 75 mL benzene and 290 mL of UV-grade hexanes. The cloudy solution is stirred briskly overnight as solids form. Filtration of the solids and drying for 3 hr at 0.25 mm, 30°C in a vacuum oven affords 21.51 g of product; [α]D25 −47.7° (94.27% e.e.). This material is again refluxed and crystallized from 30 mL of benzene and 116 mL of UV-grade hexanes to afford 19.97 g (77%) of product; [α]D25 −49.87° (98.5% e.e.). Anal. calcd. for C6H10O3: C, 55.37; H, 7.75. Found: C, 55.34; H, 7.57.
3、Yeast Reduction of Ethyl Acetoacetate3: (S)-( + )-Ethyl 3-Hydroxybutanoate
A 4-L, three-necked, round-bottomed flask equipped with mechanical stirrer, bubble counter, and a stopper is charged with 1.6 L of tap water, 300 g of sucrose, and 200 g of baker's yeast, which are added with stirring in this order. The mixture is stirred for 1 hr at about 30°C, 20.0 g (0.154 mol) of ethyl acetoacetate is added, and the fermenting suspension is stirred for another 24 hr at room temperature. A warm (ca. 40°C) solution of 200 g of sucrose in 1 L of tap water is then added, followed 1 hr later by an additional 20.0 g (0.154 mol) of ethyl acetoacetate. Stirring is continued for 50–60 hr at room temperature. When the reaction is complete by gas chromatographic analysis, the mixture is worked up by first adding 80 g of Celite and filtering through a sintered-glass funnel (porosity 4, 17-cm diam). After the filtrate is washed with 200 mL of water, it is saturated with sodium chloride and extracted with five 500-mL portions of ethyl ether. The combined ether extracts are dried over magnesium sulfate, filtered, and concentrated with a rotary evaporator at 35°C bath temperature to a volume of 50–80 mL. This residue is fractionally distilled at a pressure of 12 mm through a 10-cm Vigreux column, and the fraction boiling at 71–73°C (12 mm) is collected to give 24–31 g (59–76%) of (S)-( + )-ethyl 3-hydroxybutanoate; the specific rotation [α]25D + 37.2° (chloroform, c 1.3) corresponds to an enantiomeric excess of 85% .
The enantiomeric excess may be enhanced by several crystallizations of the 3,5-dinitrobenzoate derivative or else by using "starved" yeast.
