Lipase-Catalyzed Desymmetrization of Quaternary Carbon-Containing 1,3-Propanediols: A New Entry to the Asymmetric Synthesis of α-Substituted Serine Analogues

Ping Tian; Ming-Hua Xu; Zhi-Qian Wang; Zu-Yi Li; Guo-Qiang Lin

doi:10.1055/s-2006-939713

LETTER

Lipase-Catalyzed Desymmetrization of Quaternary Carbon-Containing 1,3-Propanediols: A New Entry to the Asymmetric Synthesis of α-Substituted Serine Analogues

Ping Tian^a, Ming-Hua Xu^b, Zhi-Qian Wang^a, Zu-Yi Li^a, Guo-Qiang Lin*^a
^a Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. of China
Fax: +86(21)64166263; e-Mail: lingq@mail.sioc.ac.cn;
^b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China

Abstract

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Abstract

A new approach to the asymmetric synthesis of α-substituted serine analogues was developed. The method utilizes a lipase-catalyzed esterification desymmetrization protocol. In the presence of PPL, a series of benzyl-substituted quaternary 2-nitropropane-1,3-diols were successfully desymmetrized by selective acetylation in very good yields and enantioselectivities (up to 95% ee).

Key words

α-substituted serine - lipase-catalyzed - desymmetrization - 2-nitropropane-1,3-diols

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References

References and Notes

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7 For a review, see: Rosini G. In Comprehensive Organic Synthesis Trost BM. Pergamon; New York: 1992. Vol. 2: p.321

8

Compound 2a: mp 60-61 °C; [α]_D ²⁰ +12.8 (c 1.5, CHCl₃); ee 92%. FT-IR (film): 3475, 2943, 1749, 1548, 1235, 1048, 703, 602 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.30 (m, 5 H), 4.56 (AB, 2 H, J = 12.0 Hz), 4.00 (AB, 2 H, J = 8.5 Hz), 3.24 (s, 2 H), 2.10 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 132.7, 129.9, 128.8, 127.9, 92.5, 62.5, 61.1, 37.5, 20.6; LRMS (EI, 70 eV): m/z (%) = 146 (27), 129 (37), 128 (21), 117 (47), 115 (21), 91 (65), 43 (100); Anal. Calcd for C₁₂H₁₅NO₅: C, 56.91; H, 5.97; N, 5.53. Found: C, 56.96; H, 5.81; N, 5.65.

9

We attempted to use 2-NHBoc- and 2-NHAc-substituted 1,3-diols as substrates instead of 2-nitropropane-1,3-diol, however, esterification in the presence of PPL gave very poor yields.

10

General Procedure. 1,3-Diols 1h-r (0.5 mmol) and PPL (160 mg) were added to vinyl acetate (5 mL). The reaction mixture was stirred for a few hours as indicated in Table [2] at 30 °C. After filtration over Celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (PE-EtOAc) to afford mono-acetate 2.
Compound 2j: [α]_D ²⁰ +11.01 (c 4.90, CHCl₃); ee 95%; HPLC (Chiralpak AD; hexane-i-PrOH, 80:20): t _R 11.5 min (major), t _R 15.1 min (minor); FT-IR (film): 3485, 2945, 1749, 1548, 1233, 1017, 850, 425 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.32-7.27 (m, 2 H), 7.12-7.09 (m, 2 H), 4.57-4.42 (m, 2 H), 3.91-3.87 (m, 2 H), 3.25 (s, 2 H), 2.14-2.13 (m, 1 H), 2.06 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 171.0, 134.1, 131.4, 131.4, 131.4, 131.3, 129.1, 92.4, 62.5, 60.9, 36.8, 20.8; LRMS (EI): m/z (%) = 163 (34), 151 (50), 150 (31), 145 (98), 127 (35), 125 (84), 115 (67), 43 (100); Anal. Calcd for C₁₂H₁₄ClNO₅: C, 50.10; H, 4.90; N, 4.87. Found: C, 50.38; H, 4.97; N, 4.68.
Compound 2k: [α]_D ²⁰ -11.72 (c 1.74, CHCl₃); ee 88%; HPLC (Chiralpak AD; hexane-i-PrOH, 80:20): t _R 8.2 min (major), t _R 10.9 min (minor); FT-IR (film): 3481, 2944, 1749, 1547, 1227, 1046, 848, 524 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.13 (dt, 2 H, J = 6.6, 2.4 Hz), 7.01 (dt, 2 H, J = 6.6, 2.4 Hz), 4.53, 4.45 (AB, 2 H, J = 12.0 Hz), 3.90 (s, 2 H), 3.24 (s, 2 H), 2.14 (s, 3 H); LRMS (EI, 70 eV): m/z (%) = 165 (38), 164 (61), 147 (71), 146 (26), 135 (84), 134 (37), 109 (89), 43 (100); Anal. Calcd for C₁₂H₁₄FNO₅: C, 53.14; H, 5.20; N, 5.16. Found: C, 53.08; H, 4.97; N, 4.98.
Compound 2l: [α]_D ²⁰ +10.14 (c 3.87, CHCl₃); ee 91%; HPLC (Chiralpak AD; hexane-i-PrOH, 70:30): t _R 13.2 min (major), t _R 20.7 min (minor); FT-IR (film): 3503, 2948, 1750, 1607, 1350, 1048, 858, 518 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 8.19 (d, 2 H, J = 7.8 Hz), 7.32 (d, 2 H, J = 7.8 Hz), 4.54, 4.50 (AB, 2 H, J = 12.3 Hz), 3.90 (d, 2 H, J = 6.0 Hz), 2.78 (t, 1 H, J = 6.0 Hz), 2.15 (s, 3 H); LRMS (EI, 70 eV): m/z (%) = 192 (17), 191 (27), 174 (26), 161 (22), 146 (26), 116 (25), 115 (29), 43 (100); Anal. Calcd for C₁₂H₁₄N₂O₇: C, 48.32; H, 4.73; N, 9.39. Found: C, 48.58; H, 4.73; N, 8.89.
Compound 2m: [α]_D ²⁰ +14.11 (c 3.60, CHCl₃); ee 90%; HPLC (Chiralpak AD-H; hexane-i-PrOH, 80:20): t _R 8.4 min (major), t _R 9.7 min (minor); FT-IR (film): 3484, 2940, 1751, 1548, 1368, 1235, 1046, 848 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.12 (d, 2 H, J = 7.8 Hz), 7.04 (d, 2 H, J = 7.8 Hz), 4.55, 4.43 (AB, 2 H, J = 12.3 Hz), 3.95-3.83 (m, 2 H), 3.23 (s, 2 H), 2.59 (t, 1 H, J = 6.9 Hz), 2.32 (s, 3 H), 2.05 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 137.7, 129.7, 129.5, 92.6, 62.6, 61.1, 37.2, 21.0, 20.6; LRMS (EI): m/z (%) = 161 (20), 160 (33), 145 (61), 143 (52), 131 (69), 105 (100), 91 (22), 43 (58); Anal. Calcd for C₁₃H₁₇NO₅: C, 58.42; H, 6.41; N, 5.24. Found: C, 58.53; H, 6.68; N, 5.06.
Compound 2n: [α]_D ²⁰ +8.01 (c 1.60, CHCl₃); ee 91%; HPLC (Chiralpak AD-H; hexane-i-PrOH, 80:20): t _R 11.2 min (major), t _R 13.7 min (minor); FT-IR (film): 3489, 2960, 1749, 1614, 1515, 1251, 849, 532 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.67 (dd, 2 H, J = 8.4, 2.1 Hz), 6.84 (dd, 2 H, J = 8.4, 2.1 Hz), 5.27-5.24 (br, 1 H), 4.55, 4.43 (AB, 1 H, J = 12.3 Hz), 4.05-3.88 (m, 3 H), 3.79 (s, 3 H), 3.20 (s, 2 H), 2.12 (s, 3 H); LRMS (EI): m/z (%) = 283 (M⁺, 21), 176 (23), 159 (23), 147 (28), 121 (100), 85 (15), 83 (23), 43 (39); HRMS (EI): m/z calcd for C₁₃H₁₇NO₆: 283.1056; found: 283.1050; Anal. Calcd for C₁₃H₁₇NO₆: C, 55.12; H, 6.05; N, 4.94. Found: C, 55.11; H, 5.85; N, 4.61.
Compound 2r: [α]_D ²⁰ +7.79 (c 1.36, CHCl₃); ee 89%; HPLC (Chiralpak AD; hexane-i-PrOH, 70:30): t _R 9.9 min (major), t _R 11.7 min (minor); FT-IR (film): 3475, 2946, 1751, 1548, 1234, 1048, 742, 600 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.37 (d, 1 H, J = 1.8 Hz), 6.34 (dd, 1 H, J = 3.0, 1.8 Hz), 6.21 (d, 1 H, J = 3.0 Hz), 4.51 (s, 2 H), 4.05-3.89 (m, 2 H), 3.43, 3.38 (AB, 2 H, J = 15.3 Hz), 2.61-2.46 (m, 1 H), 2.11 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 170.5, 147.4, 142.8, 110.7, 109.8, 91.7, 63.0, 62.1, 30.1, 20.6; LRMS (EI, 70 eV): m/z (%) = 243 (M⁺, 1), 137 (40), 136 (56), 108 (27), 107 (41), 81 (100), 79 (37), 53 (26), 43 (98); Anal. Calcd for C₁₀H₁₃NO₆: C, 49.38; H, 5.39; N, 5.76. Found: C, 49.16; H, 5.57; N, 5.61.

11

Compound 3: [α]_D ²⁰ +8.86 (c 1.00, CHCl₃); ee 91%; HPLC (Chiralpak AD; hexane-i-PrOH, 90:10): t _R 8.3 min (major), t _R 10.2 min (minor)]; FT-IR (film): 1734, 1591, 1545, 1462, 1278, 1120, 1013, 755 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.84 (d, 2 H, J = 8.4 Hz), 7.61 (d, 2 H, J = 8.4 Hz), 7.32-7.30 (m, 3 H), 7.10-7.07 (m, 2 H), 4.69 (s, 2 H), 4.57, 4.49 (AB, 2 H, J = 12.0 Hz), 3.39 (s, 2 H), 2.10 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃): δ = 169.6, 164.5, 132.0, 131.9, 131.1, 129.7, 129.0, 128.3, 127.6, 90.2, 62.6, 62.0, 38.1, 21.0; LRMS (EI, 70 eV): m/z (%) = 185 (48), 183 (49), 155 (15), 129 (100), 128 (35), 115 (23), 91 (31), 43 (71); Anal. Calcd for C₁₉H₁₈BrNO₆: C, 52.31; H, 4.16; N, 3.21. Found: C, 52.51; H, 4.13; N, 3.32. The crystallographic data for 3 have been deposited at CCDC under the registry number 287872. They can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; e-mail: deposit@ccdc.cam.ac.uk]. Empirical formula: C₁₉H₁₈BrNO₆; formula weight: 436.25; temperature: 293 (2) K; wavelength: 0.71073 Å; crystal system: monoclinic, space group: P2₁; unit cell dimensions: a = 11.786 (4) Å, α = 90°; b = 5.772 (17) Å, β = 110.218 (5)°; c = 15.276 (5) Å, γ = 90°; volume = 975.1 (5) Å^-3; Z = 2; ρ_calcd = 1.486 Mg/m³; F(000) = 444; final R indices [I>2σ(I)]: R ₁ = 0.020, ω_R2 = 0.1648; R indices (all data), R ₁ = 0.1880, wR ₂ = 0.2517.

12

Compound 4: FT-IR (film): 3358, 2978, 1746, 1717, 1498, 1245, 1168, 1047, 705, 603 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.31-7.17 (m, 5 H), 4.68-4.63 (br, 1 H), 4.62 (s, 2 H), 4.31, 4.24 (AB, 2 H, J = 11.1 Hz), 3.66, 3.54 (AB, 2 H, J = 9.6 Hz), 3.36 (s, 3 H), 3.24, 3.11 (AB, 2 H, J = 13.5 Hz), 2.08 (s, 3 H), 1.47 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃): δ = 170.5, 154.6, 136.0, 130.5, 128.1, 126.6, 96.8, 89.1, 68.1, 64.4, 57.5, 55.4, 28.3, 20.9. HRMS (ESI): m/z calcd for C₁₉H₂₉NO₆Na: 390.1887; found: 390.1892.

13

Compound 5: FT-IR (film): 3429, 2979, 1743, 1714, 1498, 1166, 1042, 703 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.30-7.14 (m, 5 H), 5.43 (br, 1 H), 4.64 (s, 2 H), 4.19, 3.92 (2 H, AB, J = 9.6 Hz), 3.50, 3.17 (2 H, AB, J = 13.2 Hz), 3.35 (s, 3 H), 1.45 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃): δ = 176.0, 154.5, 135.2, 130.0, 128.2, 127.0, 95.6, 79.7, 69.0, 64.7, 55.3, 37.1, 28.3; HRMS (ESI): m/z calcd for C₁₇H₂₅NO₆H: 338.1604; found: 338.1602.

14

Compound 6: mp 103-105 °C; [α]_D ²⁰ +97.6 (c 0.51, CH₃OH); ee 87%; (Chirobiofic V; MeOH-AcOH-Et₃N 100:0.1:0.1): t _R 4.5 min (major), t _R 5.4 min (minor); FT-IR (KBr): 3414, 2980, 1712, 1693, 1498, 1368, 1166, 702 cm^-1; ¹H NMR (300 MHz, CD₃OD): δ = 7.21 (s, 5 H), 4.14, 3.92 (AB, 2 H, J = 9.9 Hz), 3.34, 3.12 (AB, 2 H, J = 12.9 Hz), 1.48 (s, 9 H); ¹³C NMR (75 MHz, CD₃OD): δ = 168.6, 156.3, 138.2, 131.2, 129.0, 127.5, 80.0, 67.2, 65.5, 37.7, 28.9; LRMS (EI): m/z (%) = 150 (32), 104 (79), 91 (100), 57 (86), 56 (33), 44 (42), 41 (70), 39 (36); HRMS (ESI):
m/z calcd for C₁₅H₂₀NO₅H: 294.1347; found: 294.1351.