Preparation of Distant Quaternary Carbon Stereocenters by Double Selective Ring‐Opening of 1,1‐Biscyclopropyl Methanol Derivatives

Abstract The diastereoselective double carbometalation reaction of cyclopropenes provides, in a single‐pot operation, two ω‐ene‐[1,1]‐bicyclopropyl ester derivatives. One regioisomer then undergoes a Pd‐catalyzed addition of aryl iodide to provide skipped dienes possessing several distant stereocenters including two congested quaternary carbon centers with excellent diastereoselectivity.


General procedure for the double carbometalation reaction leading to 10a1-5 and 10b1-5
To a suspension of CuI (2 mmol, 1 equiv.) in 16 mL of THF, MeLi (1.6 M in diethyl ether, 2 mmol, 1 equiv.) was added dropwise at -45 °C. The reaction mixture was allowed to stir for 30 min after which cyclopropene ester 6 (2 mmol dissolved in 2 mL of THF, 1 equiv.) was added dropwise over a period of 5 min. The reaction mixture was stirred at -45 °C until TLC shows complete consumption of the starting cyclopropene 6 (the reaction was usually completed in 45 min). Then, methylphenyl cyclopropene (2.4 mmol, 1.2 equiv.) dissolved in 2 mL of THF was added over 15 min. Allow the reaction to slowly warmup from -45 °C to -20 °C for 1.5 h (until consumption of the second cyclopropene monitored by TLC). After cooling the reaction temperature to -30 °C, allyl bromide (5 equiv.) was added, and the reaction mixture was slowly warm up to -20 °C for 1 h. The reaction was hydrolyzed with a 3:1 aqueous saturated solution of ammonium chloride and ammonium hydroxide 20 mL (10 mL per mmol). The aqueous layer was extracted twice with diethyl ether and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Products were isolated through column chromatography using 1% diethyl ether and petroleum ether as eluents to get the two products in 15-21% yield.

General procedure for the reduction of 10a1-5 and 10b1-5 into 4a1-5 and 4b1-5
To a well stirred solution of 10a,b (0.5mmol, 1 equiv.) in diethyl ether (5 mL) at -35 °C was added DIBAL-H (2 equiv., 1 M solution in hexane) under argon atmosphere. The reaction was generally completed in 60 min and then hydrolyzed with a solution of ammonium chloride (10 mL per mmol). The formation of a white precipitate was observed after 10 min, which becomes clearer after the addition of 1 N HCl and further stirring. The aqueous layer was extracted twice with diethyl ether and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was then purified by column chromatography using 10-40% diethyl ether and petroleum ether to provide 4a,b in 70-80% yields.

General procedure for the isomerization (compounds 11a-c)
The alkene zipper catalyst (CAS Number: 930601-66-4) (5 mol%, CAUTION: the catalyst is air sensitive and thus should be handled under an inert atmosphere) was added into a flame dried round bottom flask under Ar atmosphere. 2 mL of dichloroethane was then added followed by a solution of alcohol 10 (0.5 mmol) in 0.5 mL of dichloroethane. The reaction mixture was stirred for 10 minutes at room temperature until apparition of an homogeneous solution and the flask was then placed on a pre-heated oil bath at 50 °C for 20-24 h. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled down to room temperature, diluted with Et2O (15 mL) and filtered over a small bed of silica. The combined diethyl ether fractions were concentrated, and subjected to a column chromatography to provide the products 11a-c.
General procedure for the remote Heck arylation of w-ene biscyclopropyl carbinol 4a1-5 A magnetic stirring bar was placed into a vial of 10 mL capacity that was charged with the alcohol (0.12 mmol), aryl iodide (1.5 equiv.), Pd(OAc)2 (15 mol%), (p-CF3C6H4)3P (15 mol%), NaHCO3 (2.5 equiv.), pre-activated molecular sieves (4Å size, powdered, 30 mg/mmol) and tetrabutylammonium chloride (TBACl) (2 equiv.) followed by addition of EtOAc (1 mL). The reaction mixture was then purged with argon and sealed with a Teflon cap. The reaction mixture was stirred for 10 min at room temperature to obtain a homogeneous solution and was then placed on a pre-heated oil bath at 85-90 °C for 20-24 h. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled down to room temperature, diluted with Et2O (15 mL) and filtered over a small bed of silica. The combined diethyl ether fractions were concentrated, and the crude reaction mixture was purified by column chromatography to provide the expected products.
General procedure for the remote Heck arylation of (E)-propenyl biscyclopropyl carbinol 11a-c A magnetic stirring bar was placed into a vial of 10 mL capacity that was charged with the alcohol (0.15 mmol), aryl iodide (1.5 equiv.), Pd(OAc)2 (15 mol%), (p-CF3C6H4)3P (15 mol%), NaHCO3 (2.5 equiv.), pre-activated molecular sieves (4Å size, powdered, 30 mg/mmol) and tetrabutylammonium chloride (TBACl) (2 equiv.) followed by addition of toluene (1 mL). The reaction mixture was then purged with argon and sealed with a Teflon cap. The reaction mixture was stirred for 10 min at room temperature to obtain a homogeneous solution and was then placed on a pre-heated oil bath at 95-100 °C for 20-24 h. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled down to room temperature, diluted with Et2O (15 mL) and filtered over a small bed of silica. The combined diethyl ether fractions were concentrated, and the crude reaction mixture was purified bycolumn chromatography to provide the expected products.