Asymmetric synthesis of γ-branched amines via rhodium-catalyzed reductive amination

Amines bearing γ-stereocenters are highly important structural motifs in many biologically active compounds. However, reported enantioselective syntheses of these molecules are indirect and often require multiple steps. Herein, we report a general asymmetric route for the one-pot synthesis of chiral γ-branched amines through the highly enantioselective isomerization of allylamines, followed by enamine exchange and subsequent chemoselective reduction. This protocol is suitable for establishing various tertiary stereocenters, including those containing dialkyl, diaryl, cyclic, trifluoromethyl, difluoromethyl, and silyl substituents, which allows for a rapid and modular synthesis of many chiral γ-branched amines. To demonstrate the synthetic utility, Terikalant and Tolterodine are synthesized using this method with high levels of enantioselectivity.

Reduction: To a dry 20 mL round-bottom flask was charged with a stir bar, purged with N2 three times, followed by the addition of unsaturated amide (4.0 mmol), dry THF (3 mL) and dry toluene (6 mL, V(tol)/V(THF)=2). The flask was then cooled in ice bath, and added RedAl solution (2.0 equiv, 3.5 M) dropwised. The reaction was allowed to stir at 0 °C for 2 hours then warmed up to rt for another 4 hours. The reaction crude was cooled in ice bath and quenched by the addition of 10 mL 5 M NaOH solution and 20 mL toluene. After stirring for 30 minutes, the crude was transferred to a separatory funnel. Organic layer was separated, washed by 5 M NaOH solution twice, dried over MgSO4, concentrated in vacuo and further purified by Al2O3 column chromatography.
Reduction, Chlorination, and SN2 were carried out under same conditions as described above.  β-Silyl substituted allylic diethylamine substrate 4q was synthesized by following method, modified from literature. 6 Hydroalumination: 6 To a dry 100 mL schlenk flask was charged with a stir bar, purged with N2 three times, followed by the addition of dry THF (30 mL) and 2.8 mL RedAl solution (8.5 mmol, 1.7 equiv). The flask was then cooled in ice bath, then added 5 mL THF solution of 3-phenyl-2-propyn-1-ol (5.0 mmol, 1.0 equiv) dropwise. The reaction was allowed to warm up to rt and stir for 4 hours. Then, the reaction flask was then cooled to -10 °C followed by the slow addition of 2.0 mL EtOAc to quench excess Red-Al then stirred at -10 °C for another 15 min. The resulting mixture was then cooled to -78 °C, followed by the addition of I2 (10 mmol, 2.0 equiv) in one portion under nitrogen flow. The reaction crude was then allowed to stir at -78 °C for another hour before being quenched by 15 mL sat. Rochelle salt solution and 25 mL sat.
Na2S2O3 solution at 0 °C. The biphasic mixture was then stirred vigorously at rt overnight, and extracted by Et2O three times. The combined organic layer was then dried over MgSO4, concentrated in vacuo and used for next step without further purification.
Chlorination and SN2 were carried out under same conditions as described above.
Vinyl silane synthesis: To a dry 200 mL schlenk flask was charged with a stir bar, purged with N2 three times, followed by the addition of dry THF (25 mL) and starting vinyl iodine (5.0 mmol, 1.0 equiv). The flask was then cooled to -78 °C, followed by the slow addition of nBuLi (12 mmol, 2.4 equiv) over 10 min. The resulting crude was allowed to stir at -78 °C for another 30 min, before the addition of chloro(dimethyl)phenylsilane (15 mmol, 3.0 equiv). The resulting mixture was allowed to stir at -78 °C for another 2 hours followed by being quenched with sat. NaHCO3 solution, extracted by Et2O three times. The combined organic layer was then dried over MgSO4, concentrated in vacuo and further purified by Al2O3 column chromatography.  After 22 h, the reaction vial was cooled to 0 °C followed by the addition of NaBH4 (0.18 mmol, 1.5 equiv) and 1.0 ml MeOH. The resulting mixture was allowed to stir at 0 °C for 1 h then warmed up to rt for another 1 h. The crude reaction was quenched by the addition of DCM, concentrated in vacuo and then re-dissolved in DCM, washed with sat. NaHCO3 solution. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography to afford the desired product 3.
General procedure for Rh-catalyzed reductive amination of allylic diethylamine with primary alkyl amine nucleophiles (General procedure C) General procedure C: [Rh(COD)Cl]2 (2.0 mg, 0.0036 mmol, 1.5 mol %), (R)-BINAP (4.5 mg, 0.0072 mmol, 3.0 mol %), NaBAr4 F (6.4 mg, 0.0072 mmol, 3.0 mol %), THF (0.2 mL), and allylic diethylamine (1, 0.24 mmol, 1.0 equiv) were added to a 4 mL vial equipped with a stir bar in the glove box under nitrogen atmosphere. The resulting solution was allowed to stir for 6 h at 40 °C (unless otherwise noted), followed by the addition of primary alkyl amine (2, 0.29 mmol, 1.2 equiv) then continued stirring at 60 °C for another 12 h. After 12 h, the reaction vial was cooled to 0 °C followed by the addition of NaBH4 (0.18 mmol, 1.5 equiv) and 1.0 ml MeOH. The resulting mixture was allowed to stir at 0 °C for 1 h then warmed up to rt for another 1 h. The reaction crude was then quenched by the addition of DCM, concentrated in vacuo and then redissolved in DCM, washed with sat. NaHCO3 solution. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by basic alumina chromatography to afford the desired product 3.