Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst†

The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective SN2′-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper–DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.


Determination of ee
Sodium perborate (0.9 mmol) was added to 2 (0.3 mmol) in THF (2 mL) and water (2 mL). The reaction mixture was vigorously stirred for 4 h at room temperature. The reaction was quenched with water and then, extracted with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The product was purified by silica gel chromatography.

Detection of the Chiral Olefin Intermediate (Scheme 2)
A mixture of CuCl (5 mol %, 0.025 mmol), (R)-DTBM-Segphos (5.5 mol %, 0.0275 mmol) and KOtBu (1 mmol) in anhydrous toluene (2 mL) were stirred for 5 min in a Schlenk tube under an atmosphere of nitrogen. Pinacolborane (0.5 mmol) was added to the reaction mixture and stirred for another 15 min at room temperature. Substrate 1q dissolved in toluene (1 mL) was added. The reaction mixture was sealed, stirred at 60 °C and monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with diethyl ether (10 mL). After the aqueous layer was extracted with diethyl ether, the combined organic layers were dried over Na2SO4, and concentrated in vacuo. The product was purified by silica gel chromatography using hexanes/ethyl acetate as the eluent. The characterization data for 1q' was concordant with that previously reported in the literature. 4 133.8, 132.5, 128.0, 127.8, 127.7, 126.5, 126.0, 125.4, 113.5, 43.4, 20.8.

Suzuki-Miyaura Cross-Coupling Reaction of 2a (Scheme 3)
To a Schlenck tube, Pd2(dba)3 (2 mol%, 0.006 mmol), Ruphos (4 mol%, 0.012 mmol), 2a (0.25 mmol), bromobenzene (0.3 mmol) and NaOtBu (3 equiv, 0.9 mmol) were added. The mixture was dilu`ted with THF (0.5 mL) and H2O (0.05 mL) under an atmosphere of nitrogen. The mixture was stirred for 24 h at 80 °C, and monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with diethyl ether (10 mL). After the aqueous layer was extracted with diethyl ether and the combined organic layers were dried over Na2SO4, and concentrated in vacuo. The product 4 was purified by silica gel chromatography (hexanes) in 82% yield. The characterization data for 4 was concordant with that previously reported in the literature. 6

Hydrolysis of Allylic Acetate
The reaction of 1m-OAc under the standard reaction conditions afforded the corresponding allylic alcohol product by hydrolysis. Proposed mechanism of hydrolysis of 1m-OAc to generate an allylic alcohol is shown in Scheme S1-b. Moreover, no hydrolysis occurred absence of KOtBu base (Scheme S1-c). This result indicates that KOtBu base leads to hydrolysis of the starting allyic acetate.

Computational Details
To gain an insight into the origin of high enantioselectivity, we performed DFT calculations at the M06-2X/6-13G* level using a suite of Gaussian 09 programs. 7 Images of the 3D structures were rendered using CYLView. 8 Figure S1. Computed energy profiles of hydrocupration of 1m-OBz. S20 Figure S2. Transition state structures of the hydrocupration step.