Concise Synthesis of Chiral N-Benzyl-α,α-Diarylprolinols through Shi Asymmetric Epoxidation

Abstract

A concise and practical synthesis of chiral N-benzyl-α,α-diaryl-2-prolinols was developed through Shi asymmetric epoxidation, followed by double nucleophilic substitution of bromo-containing olefins. A series of enantioenriched N-benzyl-α,α-diaryl-2-prolinols were obtained with excellent enantioselectivities (96% ee) in moderate to good yields (40–76% yield). For the first time, enantiopure N-benzyl-α,α-diphenyl-2-prolinol was obtained from bromo-containing olefin using this methodology.

Key words

synthesis - chiral N-benzyl-α,α-diaryl-2-prolinols - asymmetric epoxidation

• References and Notes

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• 11 General Experimental Procedure for the Synthesis of 4a–g A mixture solution of 5,5-diphenyl-4-pentenyl bromide (2a, 1 g, 3.3 mmol) in MeCN–DMM (1:2, v/v, 24 mL), and Na₂B₄O₇·10H₂O (0.62 g, 1.6 mmol), tetrabutylammonium hydrogen sulfate (45 mg, 0.13 mmol), and Shi catalyst (0.42 g, 1.65 mmol) in a buffer solution [4·10^–4 M aq Na₂(EDTA), 16 mL] was cooled to 0 °C in an ice bath. A solution of Oxone (5.06 g, 8.25 mmol) in 4·10^–4 M aq Na₂(EDTA) solution (20 mL) and a solution of K₂CO₃ (5 g, 36 mmol) in deionized water were, respectively, added dropwise through two separate addition funnels over a period of 3 h at 0 °C. After addition, the reaction was stirred for another 3 h at this temperature and then diluted with H₂O (150 mL). The resulting solution was extracted with PE (2 × 150 mL), dried over Na₂SO₄, and concentrated to afford the crude 3a (1.56 g, >95% purity), which was applied to next step without purification. The mixture solution of the above obtained crude 3a (1.56 g, ca. 3.3 mmol), benzyl amine (0.706 g, 6.6 mmol), K₂CO₃ (0.91 g, 6.6 mmol), and freshly activated 4 Å MS (1.56 g) in MeCN (10 mL) was refluxed for 12 h. The resulting solution was filtered and evaporated to give the crude product which was purified over silica gel chroma-tography (EtOAc–PE = 1:20 to 1:10) to afford 0.86 g of 4a as a white solid. Compound 4a: yield 76%; 96% ee. [α]_D ²² +91.5 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8 Hz, 2 H), 7.61 (d, J = 8 Hz, 2 H), 7.35–7.06 (m, 11 H), 4.03–3.99 (m, 1 H), 3.26 (d, J = 16 Hz, 1 H), 3.06 (d, J = 16 Hz, 1 H), 2.98–2.93 (m, 1 H), 2.43–2.35 (m, 1 H), 2.03–1.93 (m, 1 H), 1.84–1.63 (m, 3 H). Compound 4b: yield 70%; 96% ee. [α]_D ²² +98.4 (c 1.0, CHCl₃). IR (KBr): ν = 3400, 2975, 2887, 2808, 1649, 1600, 1502, 1223, 1037, 836 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.65 (m, 2 H), 7.56–7.51 (m, 2 H), 7.28 (m, 3 H), 7.08 (m, 6H), 3.96–3.92 (m, 1 H), 3.29 (d, J = 16 Hz, 1 H), 3.10 (d, J = 16 Hz, 1 H), 2.98–2.95 (m, 1 H), 1.99–1.90 (m, 1 H), 1.75 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 128.2, 128.0, 127.0, 126.9, 126.9, 126.8, 126.8, 115.0, 114.8, 114.8, 114.6, 77.3, 70.6, 60.6, 55.5, 29.8, 24.1. HRMS: m/z calcd for C₂₄H₂₄F₂NO: 380.1820 [M + H]⁺; found: 380.1797. Compound 4c: yield 40%; 96% ee. [α]_D ²² +101.1 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 8 Hz, 2 H), 7.45 (d, J = 8 Hz, 2 H), 7.24–7.21 (m, 3 H), 7.06 (d, J = 8 Hz, 2 H), 6.83–6.78 (m, 4 H), 4.85 (br, 1 H), 3.89–3.86 (m, 1 H), 3.75 (s, 1 H), 3.69 (s, 3 H), 3.30 (d, J = 12 Hz, 1 H), 3.02 (d, J = 12 Hz, 1 H), 2.37–2.30 (m, 1 H), 1.97–1.87 (m, 1 H), 1.78–1.71 (m, 1 H), 1.65–1.57 (m, 2 H). Compound 4d: yield 75%; 96% ee. [α]_D ²² +94.5 (c 1.0, CHCl₃). IR (KBr): ν = 3290, 3027, 2965, 2919, 2806, 1507, 1454, 1381, 1099, 1038, 803, 699 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8 Hz, 2 H), 7.47 (d, J = 12 Hz, 2 H), 7.28–7.21 (m, 3 H), 7.13–7.08 (m, 6 H), 3.98–3.93 (m, 1 H), 3.33 (d, J = 16 Hz, 1 H), 3.04 (d, J = 16 Hz, 1 H), 2.96–2.90 (m, 1 H), 2.41–2.32 (m, 1 H), 2.30 (s, 3 H), 2.24 (s, 3 H), 2.04–1.94 (m, 1 H), 1.91–1.73 (m, 1 H), 1.69–1.59 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 143.9, 139.6, 135.5, 135.3, 128.7, 128.7, 128.5, 127.9, 126.6, 125.2, 77.6, 70.6, 60.6, 55.5, 29.8, 24.1, 20.9. HRMS: m/z calcd for C₂₆H₃₀NO: 372.2322 [M + H]⁺; found: 372.2292. Compound 4e: yield 76%; 96% ee. [α]_D ²² +90.8 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.55 (s, 1 H), 7.47 (d, J = 8 Hz, 1 H), 7.41 (s, 1 H), 7.36 (d, J = 8 Hz, 1 H), 7.30–7.13 (m, 5 H), 7.04 (d, J = 6 Hz, 1 H), 6.98 (d, J = 8 Hz, 1 H), 6.90 (d, J = 8 Hz, 1 H), 3.94–3.90 (m, 1 H), 3.18 (d, J = 12 Hz, 1 H), 3.02 (d, J = 12 Hz, 1 H), 2.93–2.91 (m, 1 H), 2.38–2.35 (m, 7 H), 2.03–1.94 (m, 1 H), 1.81–1.56 (m, 3 H). Compound 4f: yield 77%. 96% ee. [α]_D ²² +88.8 (c 1.0, CHCl₃). IR (KBr): ν = 3426, 2964, 2930, 1652, 1607, 1452, 1414, 1261, 1099, 1030, 818, 699 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.61 (d, J = 12 Hz, 2 H), 7.47 (d, J = 8 Hz, 4 H), 7.17–7.03 (m, 9 H), 4.85 (br s, 1 H), 3.96–3.91 (m, 1 H), 3.27 (d, J = 16 Hz, 1 H), 3.02 (d, J = 16 Hz, 1 H), 2.92–2.89 (m, 1 H), 2.62–2.51 (m, 4 H), 1.94–1.93 (m, 1 H), 1.76–1.74 (m, 1 H), 1.61–1.54 (m, 2 H), 1.21–1.10 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.3, 144.1, 141.8, 141.6, 139.7, 128.5, 127.9, 127.4, 127.3, 126.6, 125.4, 125.2, 77.7, 70.8, 60.6, 55.6, 29.9, 28.4, 28.3, 24.2, 14.4, 15.4. HRMS: m/z calcd for C₂₆H₃₀NO: 400.2635 [M + H]⁺; found: 400.2611. Compound 4g: yield 68%. 96% ee. [α]_D ²² +94.8 (c 1.0, CHCl₃). IR (KBr): ν = 3333, 3061, 3028, 2963, 2871, 2804, 1488, 1403, 1092, 1012, 809, 699 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (d, J = 12 Hz, 2 H), 7.51 (d, J = 12 Hz, 2 H), 7.30–7.22 (m, 7 H), 7.06 (d, J = 8 Hz, 2 H), 5.07 (br s, 1 H), 3.95–3.91 (m, 1 H), 3.33 (d, J = 20 Hz, 1 H), 3.10 (d, J = 16 Hz, 1 H), 2.98–2.94 (m, 1 H), 2.43–2.37 (m, 1 H), 1.98–1.92 (m, 1 H), 1.74–1.62 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 146.6, 145.2, 139.4, 132.7, 132.5, 128.7, 128.7, 128.6, 128.5, 127.3, 127.3, 127.2, 77.4, 70.6, 60.8, 55.7, 30.0, 24.2. HRMS: m/z calcd for C₂₄H₂₄Cl₂NO: 412.1229 [M + H]⁺; found: 412.1209.