Enantioselective Addition of a Trifluoromethyl Anion to Aryl Ketones and Aldehydes

Abstract

The identification and development of a catalyst for the enantioselective nucleophilic addition of a trifluoromethyl anion to a ketone is described. An easily prepared cinchonine-derived catalyst was used in amounts as low as 4 mol% to afford enantiomeric excess as high as 92%.

Key words

alkaloids - ketones - aldehydes - asymmetric catalysis - fluorine - nucleophilic additions - substituent effects

References

• 1 McClinton MA. McClinton DA. Tetrahedron  1992,  48:  6555 
• 2 Langlois BR. Billard T. Synthesis  2003,  185 ; and references cited therein
• 3 Takeshi N. Ait-Mohand S. Médebielle M. Dolbier WR. Tetrahedron Lett.  2002,  43:  4317 
• 4 Prakash GKS. Krishnamurti R. Olah GA. J. Am. Chem. Soc.  1989,  111:  393 
• 5 Singh RP. Shreeve JM. Tetrahedron  2000,  56:  7613 
• 6 Prakash GKS. Mandal M. Olah GA. Org. Lett.  2001,  3:  2847 
• 7 Iseki K. Nagai T. Kobayashi Y. Tetrahedron Lett.  1994,  35:  3137 
• 8 Kuroki Y. Iseki K. Tetrahedron Lett.  1999,  40:  8231 
• 9 Sternberg ED. Vollhardt KPC. J. Org. Chem.  1984,  49:  1574 
• 13 Kacprzak K. Gawronski J. Synthesis  2001,  961 
• 14 Ando A. Miura T. Tatematsu T. Shiori T. Tetrahedron Lett.  1993,  34:  1507 
• 15 Lygo B. Wainwright PG. Tetrahedron  1999,  55:  6289 
• 17 Still WC. Kahn M. Mitra A. J. Org. Chem.  1978,  43:  2923 

10

The enantiomeric excess was determined by evaluation of the corresponding diol (obtained by treating the silyl ether with TBAF followed by NaOH) by HPLC (Chiracel OD, 4.6 × 250 mm; 40 °C; 1.5 mL/min; 230 nm; hexanes-i-PrOH-TFA, 90:10:0.1). The absolute configuration was determined single crystal X-ray analysis of 4-bromobenzoate(6d).

11

The starting material was obtained by esterificaton of alcohol 3 with 3,4-dimethoxybenzoyl chloride (CH₂Cl₂, Et₃N, DMAP, 100%) and Friedel-Crafts acylation (AcCl, TiCl₄, CH₂Cl₂, 89%).

12

The enantiomeric excess was determined by evaluation of the corresponding tertiary alcohol (obtained by treating the silyl ether with TBAF) by HPLC (Chiracel OD, 4.6 × 250 mm; 40 °C; 1.5 mL/min; 230 nm; hexanes-i-PrOH-TFA, 80:20:0.2).

16

The absolute stereochemistry was not determined.