Selective reductions. 53. Asymmetric reduction of α-fluoromethyl ketones with B-chlorodiisopinocampheylborane and B-isopinocampheyl-9-borabicyclo[3.3.1]nonane. Combined electronic and steric contributions to the enantiocontrol process

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A systematic study of the asymmetric reduction of aryl and alkyl α-fluoroalkyl ketones with (−)-diisopinocampheylchloroborane ((−)-DIP-Chloride, 1), and (−)- B-isopinocampheyl-9-borabicyclo[3.3.1]nonane ( R-Alpine-Borane, 2) has been made. In the case of reagent 1, the direction of asymmetric induction in the chiral reduction of aryl trifluoromethyl ketones differs from that of the corresponding mono- and difluoromethyl ketones. For example, while 2-fluoro, and 2,2-difluoroacetophenones are reduced with 1 to the R-alcohols in 95% and 85% ee, respectively, 2,2,2-trifluoroacetophenone is reduced, under neat conditions at room temperature, to the S-alcohol in 90% ee. Though DIP-Chloride reduces unhindered prochiral dialkyl ketones in poor ee, alkyl α-fluoroalkyl ketones are reduced in improved ee depending on the number of α-fluorine atoms present in the ketone. While monofluoromethyl ketones provide moderate ee in the R-isomer, the di- and trifluoromethyl ketones are reduced in moderate to excellent ee in the opposite isomer. For example, 1-fluoro-2-octanone is reduced in 40% ee ( R), whereas 1,1-difluoro- and 1,1,1-trifluoro-2-octanone are reduced in 32% ( S), and 91% ee ( S), respectively. In the case of the asymmetric reduction of the above series of ketones with 2, the results are different. There is no change in the direction of chiral induction in the reduction of α-fluoroacetophenones with 2. 2-Fluoroacetophenone and 2,2-difluoroacetophenone are reduced with 2 to the R-alcohol in 89% and 97% ee, respectively. The reaction of 2,2,2-trifluoroacetophenone is very slow, only 90% complete in 45 d, and provides the R-alcohol in 32% ee. In contrast, while 1-fluoro- and 1,1-difluoro-2-octanone are reduced by 2 in 65% ( R) and 50% ee ( R), respectively, 1,1,1-trifluoro-2-octanone is reduced in 60% ee ( S), raising the question of which factors other than the steric size of the trifluoromethyl group, control the enantioselectivity of these reductions. The effect of steric versus electronic influence in such chiral reductions is discussed.