(R)-4-Cyclohexyl-2,3-butadien-1-ol

(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).

19. A second full-scale run provided 9.82 g (65%) for the two steps.

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.