Titanium Tetrachloride and Chiral Aliphatic Alcohol as a New Lewis Acid Assisted Chiral Brønsted Acid for the Enantioselective Protonation of Silyl Enol Ether

Abstract

A complex of TiCl₄ and a chiral alcohol serves as highly reactive Lewis acid assisted chiral Brønsted acid (chiral LBA) for the enantioselective protonation of silyl enol ethers. Interestingly, the enantioselectivity depends on the preparation conditions of chiral LBA.

protonations - asymmetric synthesis - alcohols - titanium

References and Notes

1a Ishihara K. Kaneeda M. Yamamoto H. J. Am. Chem. Soc.  1994,  116:  11179 

1b Ishihara K. Nakamura S. Kaneeda M. Yamamoto H. J. Am. Chem. Soc.  1996,  118:  12874 

1c Ishihara K. Ishida Y. Nakamura S. Yamamoto H. Synlett  1997,  758 

1d Ishihara K. Nakamura S. Yamamoto H. Croat. Chem. Acta  1998,  69:  513 

1e Nakamura S. Kaneeda M. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  8120 

1f Ishibashi H. Ishihara K. Yamamoto H. Chem. Rec.  2002,  2:  177 

1g Ishihara K. Nakashima D. Hiraiwa Y. Yamamoto H. J. Am. Chem. Soc.  2003,  125:  24 

2a Ishihara K. Nakamura S. Yamamoto H. J. Am. Chem. Soc.  1999,  121:  4906 

2b Nakamura S. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  8131 

2c Ishihara K. Ishibashi H. Yamamoto H. J. Am. Chem. Soc.  2001,  123:  1505 

2d Ishihara K. Ishibashi H. Yamamoto H. J. Am. Chem. Soc.  2002,  124:  3647 

2e Kumazawa K. Ishibashi H. Ishihara K. Yamamoto H. Org. Lett.  2004,  6:  2551 

2f Ishibashi H. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2004,  126:  11122 

2g Uyanik M. Ishibashi H. Ishihara K. Yamamoto H. Org. Lett.  2005,  7:  1601 

3

When the preparation temperature was higher than -20 °C, a small amount of 2-chloro-2-phenylethanol was observed.

4

The concentration of the reaction also affects the enantioselectivity [40% ee (R) in Scheme [2] , 34% ee (R) in Scheme [3] (preparation conditions: -78 °C, 1 h)].

5

General Procedure for Enantioselective Protonation of Silyl Enol Ether Derived from 2-Phenylcyclohexanone.
To a solution of 1 (16 mL, 0.11 mmol) in CH₂Cl₂ (1 mL) was added a 1.0 M solution of TiCl₄ in CH₂Cl₂ (110 mL, 0.11 mmol) dropwise at 0 °C under nitrogen. After being stirred for 30 min at 0 °C, the solution was cooled to -78 °C and a solution of freshly prepared silyl enol ether (24.6 mg, 0.1 mmol) in CH₂Cl₂ (0.5 mL) was added dropwise along the wall of the flask over a 5 min period. After the solution was stirred for 1 h at -78 °C, the reaction was quenched with sat. aq NaHCO₃, extracted with Et₂O twice, dried over anhyd MgSO₄, filtered and concentrated. Purification of the crude product by column chromatography on silica gel (eluent: hexane-Et₂O) provided 2-phenylcyclohexanone in quantitative yield. The ee values were determined by analytical HPLC (OD-H, hexane-i-PrOH, 99.5:0.5).

6

The reaction gave a 65% ee (R) product when 1·TiCl₄ was prepared at 0 °C for 15 min.

7 Lee C.-S. Kuo C.-N. Shao M.-Y. Gau H.-M. Inorg. Chem. Acta  1999,  285:  254 

8 Nakamura E. Kuwajima I. Chem. Lett.  1983,  59 

9 Nakamura E. Shimada J. Horiguchi Y. Kuwajima I. Tetrahedron Lett.  1983,  24:  3341