Chelation-controlled diastereoselective reduction of alpha-fluoroketones.

The effect of Ti-based Lewis acids on the reduction of alpha-fluoropropiophenone was examined to determine whether chelation control could be used to direct the diastereoselectivity of conversion to an alpha-fluoro alcohol. Pretreatment of alpha-fluoropropiophenone with TiCl4 followed by reduction with LiBH4 in diethyl ether or methylene chloride provided the syn diastereomer predominantly, while use of Ti(OiPr)4 under identical conditions provided the anti diastereomer as the major product. The products are consistent with a chelation-controlled mechanistic pathway in the former reduction and a nonchelation pathway in the latter case. Detailed 1H, 13C, and 19F NMR studies were consistent with chelation between TiCl4 and alpha-fluoropropiophenone under the reaction conditions utilized in this study. Reduction of other alpha-fluoroketones in the presence of TiCl4 also provided a high degree of diastereoselectivity in the conversion to alpha-fluoro alcohols, showing the generality of this approach.