Enantioselective Copper-Catalyzed Conjugate Addition to 2- or 3-Substituted Cyclopent-2-en-1-ones: Construction of Stereogenic Quaternary Carbon Centers

Abstract

Trimethyl- and triethylaluminum undergo enantioselective conjugate addition to 2- and 3-substituted cyclopent-2-en-1-ones in the presence of catalytic amount of a copper salt and a phosphoramidite or a diphosphite ligand. Thus, chiral quaternary centers can be built with up to 93% ee.

aluminum - copper - Michael addition - asymmetric ­catalysis - ligands

References and Notes

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13

General Procedure for the Cu-Catalyzed A.C.A. of R ₃ Al in the Presence of Phosphoramidite Ligand
A flame-dried Schlenk tube was charged with [CuOTf]₂·C₆H₆ (2.0 mol%) and L3 (8.0 mol%). Then Et₂O (2.5 mL) was added and the mixture was stirred at r.t. for 30 min. Afterwards, the substrate (1.0 equiv, 1.0 mmol) in Et₂O (0.5 mL) was added dropwise at r.t. and the reaction mixture was stirred for further 5 min before being cooled to -30 °C. Then, R₃Al was introduced dropwise over 2 min. Once the addition was complete the reaction mixture was left at
-30 °C overnight. The reaction was hydrolyzed by the addition of MeOH at -30 °C, followed by 2 N HCl (3 mL) at r.t. Subsequently, Et₂O (10 mL) was added and the aqueous layer was separated and extracted further with Et₂O (3 × 3 mL). The combined organic fractions were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The oily residue was purified by flash column chromatography (pentane-Et₂O) to yield the 1,4-adduct. Gas chromatography on a chiral stationary phase indicated the ee.

14

General Procedure for the Cu-Catalyzed A.C.A. of R ₃ Al in the Presence of Diphosphite Ligand
A flame-dried Schlenk tube was charged with Cu(OTf)₂ (4.0 mol%) and L6 (8.0 mol%). Then, Et₂O (8.0 mL) was added and the mixture was stirred at r.t. for 30 min. Afterwards, the substrate (1.0 equiv, 1.0 mmol) in Et₂O (0.5 mL) was added dropwise at r.t. and the reaction mixture was stirred for further 5 min before being cooled to -30 °C. Then, R₃Al was introduced dropwise over 2 min. Once the addition completed, the reaction mixture was left at -30 °C overnight. The reaction was hydrolyzed by the addition of MeOH at -30 °C, followed by aq sat. NH₄Cl solution (3 mL) at r.t. Subsequently, Et₂O (10 mL) was added and the aqueous layer was separated and extracted further with Et₂O (3 × 3 mL). The combined organic fractions were washed with brine (5 mL), dried over anhyd Na₂SO₄, filtered, and concentrated in vacuo. The oily residue was purified by flash column chromatography (pentane-Et₂O) to yield the 1,4-adduct. Gas chromatography on a chiral stationary phase indicated the ee.

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