Creation of Quaternary Stereogenic Centers via Copper-Catalyzed Asymmetric Conjugate Addition of Alkenyl Alanes to α,β-Unsaturated Cyclic Ketones

Abstract

SimplePhos ligands proved to be very powerful ligands in the generation of quaternary stereogenic centers by Michael addition of alkenyl-aluminum reagents to cyclic enones. Using commercially available and easily accessible alkenylbromides as alane precursors the present procedure offers a facile access to β-alkenyl-substituted cyclohexanones with high enantioselectivities up to 96%.

Key words

aluminum - alkenes - copper - Michael addition - asymmetric catalysis

References and Notes

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15

General Procedure for the Cu-Catalyzed ACA Employing Alkenylalanes Exemplified for Product 5 To a solution of 2-propenylbromide (480 µL, 653 mg, 5.4 mmol, 1.0 equiv) in MTBE (6.0 mL) was added under inert atmosphere a fresh solution of t-BuLi (6.75 mL, 10.8 mmol, 1.6 M in pentane, 2.0 equiv) at -78 ˚C. The reaction was stirred for 30 min at this temperature. Then a fresh solution of Me₂AlCl (6.0 mL, 5.4 mmol, 0.9 M in heptane, 1.0 equiv) was added, and the reaction mixture was stirred for another 2 h maintaining the temperature at -78 ˚C. Now the cooling bath was removed, and the reaction vessel was immediately submerged in a water bath. The alane was stirred over night at r.t., and 1 h before use of the solution for catalysis stirring was stopped to ensure precipitation of the salts. Then, 10.5 mL corresponding to 2.0 equiv of the supernatant solution of alane was taken out with a syringe and slowly added to the metal complex. In a separate flask, CuTc (28.5 mg, 0.15 mmol, 10 mol%), ligand L11 (93.5 mg, 0.17 mmol, 11 mol%), and Et₂O (5.0 mL) were thoroughly stirred at r.t.
for 1 h. Then the flask was cooled to -30 ˚C, and the corresponding alane (10.5 mL, 3.0 mmol, 2.0 equiv) was added. After 15 min of stirring 3-methyl-2-cyclohexenone 4 (170 µL, 165 mg, 1.50 mmol, 1 equiv) was added, and the reaction mixture was stirred for 18 h at this temperature. Then the reaction mixture was quenched at -30 ˚C with MeOH (1.0 mL) and let warm to r.t. An aqueous solution of HCl (10%, 15 mL) was added, followed by Et₂O (50 mL). Extraction of the aqueous phase with Et₂O (2 × 50 mL) and addition of NaOCl solution (10%, 4 mL) to the combined organic solvents afforded a pale yellow suspension which after extensive shaking turned into a blue suspension.^¹6 After removal of the aqueous phase the organic phase was dried over Na₂SO₄, and the solvent was removed in vacuo. The remaining crude oil was purified by flash chromatography (SiO₂; pentane-Et₂O = 7:1), and the pure compound 5 was afforded as a colorless oil with a pleasant eucalyptus like fragrance (194 mg, 1.27 mmol, 85%, R _f  = 0.23 in pentane-Et₂O = 9:1). The analytical data were in accord with the ones reported in the literature.^¹7 Chiral separation: Chirasil
DEX-CB, 60-0-1-115-0-20-170, 50 cm/s, t _R1 = 44.80 min, t _R2 = 47.35 min.

16

NaOCl solution was added to oxidize remaining SimplePhos ligand L11 and thus facilitate the purification.