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SUPPLEMENTARY INFORMATION

Highly enantioselective Cu-catalysed asymmetric 1,4-addition of diphenylzinc to cyclohexenone

Diego Peña, Fernando López, Syuzanna R. Harutyunyan, Adriaan J. Minnaard,* and Ben L. Feringa*

Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,

Nijenborgh 4, 9747 AG Groningen, The Netherlands.

Fax: (+31) 50-3634296; Tel: (+31) 50-3634278; E-mail: b.l.feringa@chem.rug.nl

General Procedures.

All reactions were performed in a dry argon atmosphere using standard Schlenk techniques. Solvents were reagent grade, dried and distilled before use following standard procedures. Conversions and enantiomeric excesses were determined by capillary GC analysis with a Chiraldex A-TA column. Phosphoramidites 1,1 2,2 33 and 44 were prepared according to published procedures. 2-Cyclohexenone 5, ZnPh2 and Cu(OTf)2 were purchased from Aldrich and used without further purification. ZnCl2 was purchased from Merck, dried under vacuum at 90 oC over 3h and used without further purification. 3-Phenyl cyclohexanone 6 was identical in all respects to an independently prepared sample. The absolute configuration of product 6 was determined by comparing the sign of the optical rotation with literature values.5

General Procedure for the Asymmetric Conjugate Addition.

In a Schlenk tube equipped with septum and stirring bar, ZnPh2 (0.38 mmol) was dissolved in toluene (1 mL). To the resulting solution, a mixture of cyclohexenone 5 (0.25 mmol), Cu(OTf)2 (2.5 (mol) and ligand 1-4 (5 (mol) in toluene (1.5 mL) was added at –60 oC. After two vacuum-argon cycles, the reaction mixture was stirred under argon at –60 oC during 16 hours. Subsequently, NH4Cl (1M, 1 mL) was added to the reaction mixture. The organic phase was filtered over a short silica column and subjected to conversion and ee determination (capillary GC).

In situ preparation of ZnPh2 from PhLi.

In a Schlenk tube equipped with septum and stirring bar, ZnCl2 (0.38 mmol) was stirred at 90 oC under vacuum during three hours, followed by the addition of Et2O (1 mL) under argon at room temperature. To the resulting solution, PhLi (0.76 mmol, 1.8 M in Et2O) was added at 0 oC. The reaction mixture was stirred under argon at 0 oC during 15 minutes. In experiments with salt-free ZnPh2, LiCl was removed by filtration under argon. Volatiles were removed under vacuum, toluene (1.5 mL) was added under argon and the resulting suspension was used without further purification in the corresponding conjugate addition to cyclohexenone 5 (0.25 mmol).

In situ preparation of ZnPh2 from PhMgBr.

In a Schlenk tube equipped with septum and stirring bar, ZnCl2 (0.38 mmol) was stirred at 90 oC under vacuum during three hours, followed by the addtion of Et2O (1 mL) under argon at room temperature. To the resulting solution, PhMgBr (0.76 mmol, 3 M in Et2O) was added at 0 oC. The reaction mixture was stirred under argon at room temperature during 2 hours. In experiments with salt-free ZnPh2, dry dioxane (1 mL) was added in order to precipitate magnesium salts. After filtering out salts under argon, volatiles were removed under vacuum. Toluene (1.5 mL) was added under argon and the resulting suspension was used without further purification in the corresponding conjugate addition to cyclohexenone 5 (0.25 mmol).

In situ preparation of ZnPh2 from Ph3B.

In a Schlenk tube equipped with septum and stirring bar, a mixture of Ph3B (0.6 mmol) and ZnEt2 (3.6 mmol, 1M in hexane) was stirred at room temperature under vacuum during one hour. Toluene (1 mL) was added and the resulting mixture stirred under vacuum at 80 oC. Toluene (3 mL) was added under argon and the resulting suspension was used without further purification in the corresponding conjugate addition to cyclohexenone 5 (0.5 mmol).

In situ preparation of ZnPh2 from PhB(OH)2.

In a Schlenk tube equipped with septum and stirring bar, PhB(OH)2 (1.25 mmol) was dissolved in toluene (0.5 mL). To the resulting mixture, ZnEt2 (2.5 mmol, 1 M in hexane) was added dropwise at 0 oC. After stirring under argon at 70 oC during 16 hours, volatiles were removed under vacuum. Toluene (3 mL) was added under argon and the resulting suspension was used without further purification in the corresponding conjugate addition to cyclohexenone 5 (0.5 mmol).

Procedure for the Asymmetric Conjugate Addition of PhMgBr:

In a Schlenk tube equipped with septum and stirring bar, CuBr SMe2 (30.0 μmol, 6.16 mg) and ligand 6[1] (36 μmol, 21.0) were dissolved in tBuOMe (2.0 mL) and stirred under argon at room temperature for 20 min. Cyclohexenone (0.20 mmol) was then added and after stirring for 5 min at that temperature the mixture was cooled to – 75 oC. PhMgBr (3.0 M solution in Et2O, 0.22 mmol) was added dropwise during 5 min and the resulting mixture was further stirred at that temperature for 2h. MeOH (0.5 mL) was added and the mixture was allowed to reach rt. Then, aqueous NH4Cl solution (1M, 2 mL) was added to the mixture. The organic phase was separated, filtered over a short silica column, subjected to conversion and ee determination (capillary GC) and concentrated. When the reaction is carried out in Et2O 5 mol% of CuBr SMe2 and 6 mol% of ligand 7 were used.

References.

1) L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries, R. Naasz, B. L. Feringa, Tetrahedron, 2000, 56, 2865.

2) D. Peña, A. J. Minnaard, J. G. de Vries and B. L. Feringa, J. Am. Chem. Soc., 2002, 124, 14552.

3) H. Bernsmann, A. J. Minnaard, B. L. Feringa, to be submitted.

4) R. Hulst, N. K. de Vries and B. L. Feringa, Tetrahedron: Asymmetry, 1994, 5, 699.

5) J.-G. Boiteau, A. J. Minnaard, B. L. Feringa, J. Org. Chem., 2003, 68, 9481.

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