Role of NaBH₄Stabilizer in the Oxazaborolidine-Catalyzed Asymmetric Reduction of Ketones with BH_3-THF

Abstract

When stabilized BH(3-)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 NaBH(4) 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 BF(3-)THF to the reaction mixture effectively destroyed the NaBH(4) stabilizer in BTHF solutions, restoring the enantioselectivity to acceptable levels.

Effect of BF3 on the enantioselective reduction of trifluoromethyl ketones using a chiral lactam alcohol with borane

“…Nettles et al reported that the NaBH 4 species in BH 3 ÁTHF participated in a non-selective uncatalyzed reduction that reduced the overall enantioselectivity (65% ee) of the CBS reduction of acetophenone compared to the high enantioselectivity of 95% ee when the non-stabilized BH 3 ÁTHF was used. 13 Therefore, in order to examine the role of NaBH 4 in the CBS reduction of trifluoromethyl ketone, we used the borane generated in situ from tetra-nbutylammonium borohydride (TBAB) and methyl iodide (MeI) 14 instead of the commercial nonstabilized borane. 15 Unfortunately, only a slight increase in selectivity was observed (entry 6).…”

“…These results imply that properly degraded BH 3 ÁTHF is superior to the NaBH 4 stabilized and non-stabilized BH 3 ÁTHF probably due to the by-produced butoxyborane species caused by the reduction of THF with BH 3 ÁTHF during storage, although this species had no effect on the enantioselectivity for the reduction of acetophenone. 13 Nettles et al also described that the addition of a Lewis acid removed or deactivated the borohydride (NaBH 4 ) in BH 3 ÁTHF and that the BF 3 ÁTHF complex (3-8 mol %) proved to be the best with a high enantioselectivity for the reduction of acetophenone among the examined Lewis acids (ZrCl 4 , AlCl 3 , FeCl 3 , and TiCl 4 ). 13 Fu et al simultaneously reported that the chemo-and enantioselectivities were dramatically enhanced by using an acid (BF 3 ÁOEt 2 and p-toluenesulfonic acid, 5 mol %) as a scavenger 16 for the NaBH 4 stabilizer in BH 3 ÁTHF for the reduction of a ketone with a chiral 4-phenyl-2-oxazolidinone auxiliary.…”

“…13 Nettles et al also described that the addition of a Lewis acid removed or deactivated the borohydride (NaBH 4 ) in BH 3 ÁTHF and that the BF 3 ÁTHF complex (3-8 mol %) proved to be the best with a high enantioselectivity for the reduction of acetophenone among the examined Lewis acids (ZrCl 4 , AlCl 3 , FeCl 3 , and TiCl 4 ). 13 Fu et al simultaneously reported that the chemo-and enantioselectivities were dramatically enhanced by using an acid (BF 3 ÁOEt 2 and p-toluenesulfonic acid, 5 mol %) as a scavenger 16 for the NaBH 4 stabilizer in BH 3 ÁTHF for the reduction of a ketone with a chiral 4-phenyl-2-oxazolidinone auxiliary. 17 Therefore, we expected that addition of BF 3 ÁTHF could enhance the enantioselectivity for the reduction of 2,2,2-trifluoroacetophenone with oxazaborolidine 1a.…”

Effect of borane source on the enantioselectivity in the enantiopure oxazaborolidine‐catalyzed asymmetric borane reduction of ketones

“…Investigations into the mechanism of the catalytic asymmetric reduction were also conducted [2,3]. Some researchers have paid much attention to the factors that affect the enantioselectivity in the asymmetric reduction, such as the structure [1,2,4], the stability [2a,5] and the loading amount [2a,5a,6] of catalysts, the type [7] and amount [2a,6c] of borane sources, the order and rate of the addition of a ketone or a borane complex into a reductive system [1d,6c], the reduction temperature [5d,6c,8], the solvent [5a,6c,7a,d], the additive [8g, 9,10], the secondary reduction [9a,11], the stabilizer in borane [12], the electronic effects of both ketones [4a,5a,10,13,14] and catalysts [4a,10,14], the kinetics of the asymmetric reduction [15], etc. Although some investigators have referred that different enantioselectivities could be observed with different borane sources [7], all of them evaluated the effect at about room temperature.…”

Effect of the Secondary Reduction on the Enantioselectivity and Function of Additives in the Chiral Oxazaborolidine‐Catalyzed Asymmetric Borane Reduction of Ketones

“…Numerous new efficient oxazaborolidine catalysts have been reported, and a lot of applications have appeared until now [1]. In comparison with the numerous attempts to search for new catalysts to improve the enantioselectivity and to carry out the mechanistic investigation of the catalytic asymmetric reduction [2] [3], some investigators have studied the factors which affect the enantioselectivity in the asymmetric reduction, such as the structure [1] [2] [4], the stability [2a] [5] (including dimerization), and the loading amount [2a] [5a] [6] of the catalyst, the borane source [7] and amount [2a] [6c], the order and rate of the addition of a ketone or borane into a reductive system [1d] [10], the secondary reduction [9a] [11], the stabilizer in borane [12], the electronic effects of both ketones [4a] [5a] [10] [13] and catalysts [10] [14], etc. Although a few studies have dealt with the effects of the secondary reduction [9a] [11] and the additives [8g] [9] [10] on the enantioselectivity of the asymmetric reduction, these effects are still unclear.…”