Synlett 2007(13): 2057-2060  
DOI: 10.1055/s-2007-984889
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Magali Vuagnoux-d’Augustin, Stefan Kehrli, Alexandre Alexakis*
Département de Chimie Organique, Université de Genève, 30, Quai Ernest Ansermet, 1211 Genève 4, Switzerland
Fax: +41(22)3793215; e-Mail: Alexandre.Alexakis@chiorg.unige.ch;
Further Information

Publication History

Received 11 May 2007
Publication Date:
12 July 2007 (online)

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.

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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.

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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.