Highly Stereoselective Syntheses of Proline-Derived Vicinal Amino Alcohols through Grignard Addition onto N-Tosylprolinal

Abstract

A highly diastereoselective Grignard addition to N-tosyl-l-prolinal has been developed to deliver a variety of proline-derived vicinal amino alcohols in good to excellent yields with high diastereoselectivities. A similar selectivity was also obtained by using N-tosyl-d-prolinal. The methodology has been applied to the synthesis of medicinally important 3-hydroxy-2-phenylpiperidines.

Key words

prolinol - Grignard addition - diastereoselectivity - aziridinium ion - natural products

• References and Notes

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• 28 Addition of Grignard Reagents to the Aldehyde; General Procedure: To a stirred solution of crude 10 (253 mg, 1.0 mmol, 1.0 equiv) in anhydrous THF at –78 °C was added RMgBr (1.3 mmol, 1.3 equiv) slowly over a period of 5 min, and stirring was continued for 4 h. The reaction was quenched with sat. aq NH₄Cl (2 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by column chromatography to afford the desired product 15.( R )-Phenyl [(S)-1-Tosylpyrrolidin-2-yl] methanol [(–)-15a)]: White crystalline solid; R_f 0.51 (EtOAc–hexane, 20%). ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 8.25 Hz, 2 H), 7.38 (m, 2 H), 7.29–7.32 (m, 4 H), 7.20–7.24 (m, 1 H), 5.22 (m, 1 H), 3.76–3.80 (m, 1 H), 3.29–3.35 (m, 2 H), 3.21–3.27 (m, 1 H), 2.39 (s, 3 H), 1.77–1.86 (m, 1 H), 1.51–1.60 (m, 1 H), 1.14–1.32 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 140.6, 134.0, 129.9, 128.2, 127.7, 127.4, 126.2, 75.0, 66.1, 50.6, 25.7, 24.4, 21.6. IR (film): 3499, 3120, 2980, 1795, 1654, 1560, 1510, 1499, 1475, 1460, 930, 750 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for [C₁₈H₂₂NO₃S]⁺: 332.1315; found: 332.1333. [α]_D ^20.7 –156.4 (c = 0.042, MeOH).(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]ethanol [(–)-15b)]: Colorless oil; R_f 0.40 (EtOAc–hexane, 20%). ¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.12 Hz, 2 H), 7.29 (d, J = 8.01 Hz, 2 H), 4.15 (m, 1 H), 3.44–3.48 (m, 1 H), 3.27–3.37 (m, 2 H), 2.67 (br, 1 H), 2.39 (s, 3 H), 1.67–1.87 (m, 2 H), 1.50–1.62 (m, 1 H), 1.22–1.31 (m, 1 H), 1.12 (d, J = 6.45 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.8, 134.1, 129.8, 127.6, 69.0, 65.8, 50.5, 26.1, 24.5, 21.5, 18.4. IR (film): 3503, 1654, 1561, 1402, 1331, 1159, 1059, 983, 662 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for [C₁₃H₂₀NO₃S]⁺: 270.1158; found: 270.1181. [α]_D ^22.2 –64.6 (c = 0.47, CH₂Cl₂).(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]but-3-en-1-ol [(–)-15c)]: Colorless oil; R_f 0.43 (EtOAc–hexane, 20%). ¹H NMR (400 MHz, CDCl₃): δ = 7.67 (d, J = 8.23 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 5.80–5.90 (m, 1 H), 5.07–5.13 (m, 2 H), 4.05–4.09 (m, 1 H), 3.49–3.53 (m, 1 H), 3.26–3.38 (m, 2 H), 2.39 (s, 3 H), 2.14–2.26 (m, 2 H), 1.83–1.92 (m, 1 H), 1.70–1.77 (m, 1 H), 1.50–1.58 (m, 1 H), 1.22–1.31 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.7, 134.8, 134.1, 129.8, 127.7, 127.6, 117.4, 72.2, 64.4, 50.3, 37.8, 25.8, 24.6, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for [C₁₅H₂₂ NO₃S]⁺: 296.1315; found: 296.1336. [α]_D ^22.8 –90.3 (c = 0.43, CH₂Cl₂).(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]prop-2-en-1-ol [(–)-15d)]: Colorless gel; R_f 0.49 (EtOAc–hexane, 20%). ¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.71 (m, 2 H), 7.30 (d, J = 7.95 Hz, 2 H), 5.79–5.86 (m, 1 H), 5.30–5.36 (dt, J = 17.27, 1.58 Hz, 1 H), 5.17–5.21 (dt, J = 10.56, 1.55 Hz, 1 H), 4.46 (br, 1 H), 3.59–3.63 (m, 1 H), 3.26–3.39 (m, 2 H), 2.96 (d, J = 4.61 Hz, 1 H), 2.4 (s, 3 H), 1.70–1.83 (m, 2 H), 1.53–1.62 (m, 1 H), 1.22–1.30 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 136.4, 134.0, 129.8, 127.6, 116.8, 74.5, 64.6, 50.6, 26.7, 24.5, 21.5; IR (film): 3584, 3099, 2981, 2059, 1870, 1655, 1544, 1474, 1154, 933 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for [C₁₄H₁₉NO₃S]⁺: 282.1158; found: 282.1178. [α]_D ^27.0 –102.24 (c = 0.0352, MeOH).(R)-1-[(S)-1-Tosylpyrrolidin-2-yl]prop-2-yn-1-ol [(–)-15e)]: White crystalline solid; R_f 0.47 (EtOAc–hexane, 20%). ¹H NMR (500 MHz, CDCl₃): δ = 7.71 (d, J = 8.07 Hz, 2 H), 7.31 (d, J = 7.97 Hz, 2 H), 4.67 (br, 1 H), 3.67–3.70 (m, 1 H), 3.45–3.50 (m, 1 H), 3.42 (br s, 1 H), 3.29–3.34 (m, 1 H), 2.43 (d, J = 1.96 Hz, 1 H), 2.42 (s, 3 H), 1.96–2.0 (m, 1 H), 1.85–1.93 (m, 1 H), 1.73–1.80 (m, 1 H), 1.70 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 133.9, 129.9, 127.6, 81.8, 74.4, 65.3, 64.3, 50.9, 27.9, 24.5, 21.6; IR (film): 3500, 3110, 2270, 1460, 1420, 1339, 1158, 1094 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for [C₁₄H₁₇NO₃S + Na]⁺: 302.0821; found: 302.0845. [α]_D ^20.7 –105 (c = 0.042, MeOH).
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