Role of NaBH4 stabilizer in the oxazaborolidine-catalyzed asymmetric reduction of ketones with BH3-THF

When stabilized BH3_THF (BTHF) was added to a mixture of ketone and tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo [1,2-c] [1,3,2]oxazaborole (MeCBS-ozaxaborolidine, MeCBS) catalyst 1, low enantioselectivities resulted, Several relative rate experiments showed that a borohydride species in BTHF catalyzed the nonselective borane reduction of ketones, effectively competing with enantioselective MeCBS reduction of ketones, lowering the overall selectivity of the reaction. Improved enantioselectivities in the reaction are obtained by reversing the mode of addition (ketone to BTHF and catalyst), lowering the concentration of NaBH4 stabilizer in the BTHF solution (87-95% ee) and increasing the concentration or addition rate of BTHF. Decreased reaction temperature and increased catalyst loading only slightly improved the selectivity of the reaction. Upon reaction parameter optimization, simultaneous addition of substrate and BTHF to MeCBS catalyst stabilizer resulted in the highest overall enantioselectivities (96% ee) and diminished the effect of the borohydride. Alternatively, the addition of Lewis acids such as BF3_THF to the reaction mixture effectively destroyed the NaBH4 stabilizer in BTHF solutions, restoring the enantioselectivity to acceptable levels.