(R)-4-Cyclohexyl-2,3-butadien-1-ol
B. (R)-4-Cyclohexyl-2,3-butadien-1-ol ((R)-3). The crude product (R)-2 prepared above (20.80 g) is dissolved in 200 mL of THF in a 500-mL round-bottomed flask that contains a magnetic stir bar and is equipped with a solid addition funnel. The flask is placed in an ice-water bath and stirred while open to the atmosphere. To this solution is added TBAF·3H2O (32.0 g, 101 mmol) (Note 7) in one portion via a solid addition funnel. After the addition is complete, the ice-water bath is removed and the resulting mixture is allowed to stir at room temperature. After 2 h, the reaction is complete as monitored by TLC . The reaction mixture is poured into ice water (150 mL) in a 1-L beaker followed by addition of diethyl ether (300 mL). The mixture is transferred to a separatory funnel, the organic layer is separated, and the aqueous layer is extracted with ethyl ether (3 x 50 mL). The combined organic layer is washed with brine (100 mL) and dried over anhydrous Na2SO4 (15 g). After evaporation (15 mmHg with a water bath of 30 °C), the residue is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1 → 15:1) (Note 16) to afford 9.42 g of (R)-3 (62% combined yield over steps A and B) (Notes 17 and 18) as a light yellow liquid with 99% ee
The enantiomeric excess was determined by chiral HPLC (conditions: Chiralcel AS-H column, eluent: hexane/i-PrOH = 98/2, flow rate: 0.7 mL/min). The peaks were visualized at 214 nm with retention times of 17.2 (major isomer) and 20.3 min (minor isomer). Enantioenriched (R)-4-cyclohexyl-2,3-butadien-1-ol ((R)-3) exhibits the following characteristics:
[a]D28 = - 97.1 (c = 1.01, CHCl3);
1H NMR pdf(500 MHz, CDCl3) δ: 1.00-1.32 (m, 5 H), 1.62-1.77 (m, 6 H), 1.98-2.05 (m, 1 H), 4.10 (s, 2 H), 5.27-5.38 (m, 2 H);
13C NMR pdf(125 MHz, CDCl3) δ: 25.8, 25.9, 32.8, 32.9, 36.9, 60.7, 92.4, 99.4, 202.0; MS (EI) m/z (%): 152 (M+, 0.70), 55 (100);
IR (neat): v = 3331, 2924, 2851, 1961, 1448, 1302, 1258, 1214, 1062, 1012 cm-1;
HRMS calcd for C 10H16O [M+]: 152.1201, found: 152.1198.
16. The column (diameter = 80 mm) was packed with 390 g of silica gel (10-40 mm): a mixture of 4.0 L of petroleum ether (60-90 °C) and 0.2 L of ethyl acetate was first used as the eluent (~400 mL for each fraction); then a mixture of 3.8 L of petroleum ether (60-90 °C) and 0.25 L of ethyl acetate was used (~100 mL for each fraction). After evaporation of the solvents, 9.42 g of the product (R)-3 was obtained as a light yellow liquid.
17. The purity of the product (R)-4-cyclohexyl-2,3-butadien-1-ol ((R)-3) is 99% as determined by GC; GC conditions: hp-5 (30 m x 0.32 mm x 0.25 mm); oven: 50 °C for 2 min, then 20 °C/min, 250 °C for 10 min; inject: 320 °C; FID: 320 °C; split: 80:1; N 2: 20 mL/min.
18. The yield was calculated based on (S)-α,α-diphenylprolinol since it is the limiting reagent (1 equiv).
20. Determination of the enantiomeric excess of the product (R)-4-cyclohexyl-2,3-butadien-1-ol ((R)-3) required the synthesis of the corresponding racemic 4-cyclohexyl-2,3-butadien-1-ol (±)-3 (Scheme 1)
To a flame-dried Schlenk tube that contained a stir bar were added CuBr (7.4 mg, 0.05 mmol) and activated 4 Å molecular sieves (301.7 mg). Toluene (2 mL), tert-butyldimethyl(2-propynyloxy)silane 1 (170.5 mg, 1.0 mmol),cyclohexanecarboxaldehyde (124.0 mg, 1.1 mmol) and pyrrolidine (78.3 mg, 1.1 mmol) were then added sequentially under an argon atmosphere. The solution was then stirred at 25 °C until completion of the reaction as monitored by TLC (12 h). The crude reaction mixture was filtrated through a short pad of silica gel eluted with ether (20 mL). After evaporation, the crude product was used in the next step without further treatment. To another Schlenk tube that contained a stir bar were added anhydrous ground ZnI2 (147.0 mg, 0.45 mmol) and NaI (75.2 mg, 0.5 mmol).
The Schlenk tube was heated with a heating gun under vacuum (1 mmHg) for about 1 min, and the flask was refilled with argon. The above crude product was then dissolved in toluene (5 mL) and transferred to the Schlenk tube via a syringe under argon atmosphere. The Schlenk tube was then equipped with a condenser and placed in a pre-heated oil bath at 110 °C with stirring. After 6 h, the reaction was judged as complete by TLC, after which the crude reaction mixture was filtrated through a short pad of silica gel (diameter: 30 mm, height: 20 mm) with ether (20 mL) as the eluent. After evaporation, the crude product was then dissolved in THF (3 mL) and treated at 0 °C with TBAF·3H2O (316 mg, 1.0 mmol). The resulting mixture was allowed to warm to room temperature naturally with stirring. After 2 h, the reaction was complete, as determined by TLC, and H2O (10 mL) and ether (10 mL) were then added. The organic layer was separated and the aqueous layer was extracted with ether (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to afford 4-cyclohexyl-2,3-butadien-1-ol (±)-3 (113.0 mg, 74%) as a liquid.
