Desymmetrization of σ-Symmetric Biphenyl-2,6-diyl Diacetate Derivatives by Lipase-Catalyzed Hydrolysis: Unexpected Effect of C(3′)-Substituent on the Enantiotopic Group Selectivity

Abstract

Highly enantioselective desymmetrization of σ-symmetric 3′-substituted 2′,6′-dimethoxybiphenyl-2,6-diyl diacetate derivatives to the corresponding monoacetates was effected by using Rhizopus oryzae lipase (ROL) and porcine pancreatic lipase (PPL), despite the remoteness of the C(3′) substituent from the acetate groups. ROL promoted hydrolysis of the pro-S acetates, irrespective of the type of C(3′) substituent, whereas PPL promoted hydrolysis of the pro-R acetates, and selectivity was only attainable when the C(3′) substituent was a polar group.

Key words

enantioselective reaction - desymmetrization - axial chirality - biphenyls - lipase

• References and Notes


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• 6 For the preparation, see the Supporting Information.
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• 8 The enzymes that we tested were as follows: ROL: Rhizopus oryzae lipase (Amano, Lipase F-AP15), PPL: porcine pancreatic lipase (Sigma, Type II), MJL: Mucor javanicus lipase (Lipase M Amano 10), CRL: Candida rugosa lipase (Lipase AYS Amono), PFL: Pseudomonas fluorescence lipase (Lipase AK Amano), CAL: Candida antarctica lipase, typeB (MIK Pharm Co.), ANL: Aspergillus niger lipase (Lipase AS Amono), PCL: Pseudomonas cepacia lipase (Lipase PS Amono), BCL: Burkholderia cepacia lipase (Lipase PS Amono SD), PCamL: Penicillium camemberti lipase (Lipase G Amono 50), PLE: pig liver esterase (Sigma, esterase from porcine liver lyophilized powder).
• 9 Methyl (R)-2′-(Acetyloxy)-6′-hydroxy-2,6-dimethoxybiphenyl-3-carboxylate [(R)-(+)-5a]; Typical ProcedureTo a solution of 4a (503 mg, 1.30 mmol) in i-Pr₂O (12.5 mL) were added 0.1 M pH 7 phosphate buffer (25 mL) and PPL (252 mg). The mixture was vigorously stirred at 35 °C for 2.5 h, then diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, hexane–acetone (7:3)] to give a colorless oil; yield: 447 mg (1.29 mmol, quant; >99% ee); [α]_D ²⁵ +40 (c 1.9, CHCl₃).IR (neat): 3420, 3010, 2945, 2840, 1765, 1720, 1705, 1588, 1458, 1432, 1405, 1368, 1308, 1278, 1222, 1200, 1152, 1100, 1080, 1050, 1025, 970 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.95 (s, 3 H), 3.54 (s, 3 H), 3.79 (s, 3 H), 3.90 (s, 3 H), 5.62 (s, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.82 (dd, J = 8.0, 0.8 Hz, 1 H), 6.93 (dd, J = 8.4, 0.8 Hz, 1 H), 7.31 (dd, J = 8.4, 8.0 Hz, 1 H), 7.96 (d, J = 8.8 Hz, 1 H).¹³C NMR (100 MHz, CDCl₃): δ = 20.7, 52.1, 56.1, 62.1, 106.6, 114.3, 114.4, 114.9, 115.9, 117.5, 129.4, 133.7, 149.4, 154.7, 159.5, 161.6, 166.0, 168.7. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₈H₁₈NaO₇: 369.0950; found: 369.0958. HPLC [CHIRALPAK IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (9:1), 1.0 mL/min, 20 °C, 254 nm]: t _R = 26.2 min [21.2 min for (S)-(–)-5a]
• 10 The yields refer to the chromatographically isolated pure products. Because each of the reactions was stopped at the time when the diol was detected by TLC monitoring, the yield of the monoacetate is approximately equal to the conversion (%) of the reaction. Moreover, the ee value virtually reflects the true selectivity that is not amplified by kinetic resolution of the monoacetate enantiomers.
• 11 The stereochemistries of monoacetates 5a–g were determined by correlation with stereodefined reference samples (S)-9–(S)-14, prepared from the iodobiphenyl (S)-7 (Scheme 8). See reference 12 and the Supporting Information.
• 12 The reactions of 3′-iodo derivative 4h were not sufficiently enantioselective. The use of ROL [pH 7 phosphate buffer–i-Pr₂O, 35 °C; 25% conversion of 4h] gave an 80:20-mixture of monoacetate (+)-5h and diol 6h, where the ee of (+)-5h was 87%. The use of PPL [pH 7 phosphate buffer–i-Pr₂O, 35 °C; 60% conversion of 4h] gave an 85:15-mixture of (–)-5h and 6h, where the ee of (–)-5h was 92%. However, enrichment of the ee through overhydrolysis to the diol 6h allowed us to obtain a 95% ee sample of (–)-5h at the cost of lowering the chemical yield, as shown in Scheme 9. The absolute stereochemistry of (–)-5h was determined to be R by X-ray analysis of the crystalline derivative (S)-7 (99% ee after repeated recrystallization; see ref. 15), which was then converted into compounds (S)-9–(S)-14 with definite configurations.
• 13 See ref. 10 for the yields of (S)-5a–(S)-5e (by the reactions with ROL) and of (R)-5a, (R)-5b (by the reaction with PPL). In the reactions of 4c–e with PPL, the monoacetates underwent overhydrolysis just as they were formed, so that they were obtained in only trace amounts irrespective of the reaction period and conditions.
• 14 (R)-3′-Acetyl-6-hydroxy-2′,6′-dimethoxybiphenyl-2-yl Acetate [(R)-(–)-5b]Colorless oil; yield: 89 mg (92%; >99% ee); [α]_D ²⁵ –1 (c 1.9, CHCl₃). IR (neat): 3405, 3010, 2940, 2840, 1765, 1660, 1582, 1458, 1400, 1360, 1275, 1200, 1135, 1090, 1025, 970 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.97 (s, 3 H), 2.63 (s, 3 H), 3.46 (s, 3 H), 3.82 (s, 3 H), 5.36 (s, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 7.34 (dd, J = 8.4, 8.0 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.7, 30.8, 56.3, 61.8, 107.0, 114.2, 114.4, 114.5, 115.2, 126.0, 129.6, 132.7, 149.4, 154.6, 159.7, 161.7, 168.6, 198.2. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₈H₁₈NaO₆: 353.1001; found, 353.0989. HPLC [CHIRALPAK IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (8:2), 1.0 mL/min, 20 °C, 294 nm]: t _R = 10.2 min [8.0 min for (S)-(+)-5b].(S)-6-Hydroxy-3′-isopropyl-2′,6′-dimethoxybiphenyl-2-yl Acetate [(S)-(+)-5c]Colorless oil; yield: 74 mg (83%; >99% ee); [α]_D ²⁵ +13 (c 1.2, CHCl₃). IR (neat): 3440, 2960, 2930, 2870, 2830, 1765, 1740, 1592, 1480, 1458, 1438, 1410, 1365, 1275, 1200, 1098, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (d, J = 6.8 Hz, 6 H), 1.95 (s, 3 H), 3.28 (sept, J = 6.8 Hz, 1 H), 3.35 (s, 3 H), 3.75 (s, 3 H), 5.62 (s, 1 H), 6.78 (d, J = 8.8 Hz, 1 H), 6.83 (dd, J = 8.4, 0.8 Hz, 1 H), 6.94 (dd, J = 8.0, 0.8 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.4, 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 23.6, 23.8, 26.6, 56.1, 61.3, 107.3, 113.7, 114.1, 115.0, 115.7, 127.5, 129.0, 134.6, 149.3, 154.6, 155.9, 156.6, 168.8. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₉H₂₂NaO₅: 353.1365; found, 353.1361. HPLC [CHIRALPAK IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (9:1), 1.0 mL/min, 20 °C, 275 nm]: t _R = 7.2 min [16.0 min for (R)-(–)-5c].(S)-3′-Cyclopentyl-6-hydroxy-2′,6′-dimethoxybiphenyl-2-yl Acetate [(S)-(+)-5d]Colorless oil; yield: 73 mg (82%; 99% ee); [α]_D ²⁵ +6 (c 1.5, CHCl₃). IR (neat): 3440, 2950, 2870, 2830, 1765, 1740, 1595, 1580, 1480, 1460, 1438, 1412, 1365, 1272, 1202, 1100, 1082, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.49–1.87 (m, 6 H), 1.96 (s, 3 H), 1.99–2.08 (m 2 H), 3.26–3.32 (m, 1 H), 3.35 (s, 3 H), 3.74 (s, 3 H), 5.66 (s, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.83 (dd, J = 8.0, 1.2 Hz, 1 H), 6.94 (dd, J = 8.0, 1.2 Hz, 1 H), 7.29 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.0, 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 25.51, 25.55, 34.2, 34.5, 38.4, 56.1, 61.3, 107.2, 113.6, 114.1, 115.0, 115.6, 128.1, 129.0, 132.1, 149.3, 154.6, 155.9, 157.2, 168.8. ; HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₁H₂₄NaO₅: 379.1521; found, 379.1518; HPLC [CHIRALPAK IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (8:2), 1.0 mL/min, 20 °C, 274 nm]: t _R = 5.6 min [8.8 min for (R)-(–)-5d].(S)-3′-Cyclopent-1-en-1-yl-6-hydroxy-2′,6′-dimethoxybiphenyl-2-yl Acetate [(S)-(+)-5e]Colorless oil; yield: 87 mg (92%; >99% ee); [α]_D ²⁵ +12 (c 1.4, CHCl₃). IR (neat): 3440, 3010, 2940, 2840, 1765, 1740, 1590, 1580, 1560, 1438, 1402, 1285, 1205, 1120, 1085, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.97 (s, 3 H), 1.97 (quin, J = 7.2 Hz, 2 H), 2.50–2.55 (m, 2 H), 2.72–2.76 (m, 2 H), 3.35 (s, 3 H), 3.75 (s, 3 H), 5.58 (s, 1 H), 6.26–6.28 (m, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 6.83 (dd, J = 8.0, 1.2 Hz, 1 H), 6.94 (dd, J = 8.0, 1.2 Hz, 1 H), 7.31 (dd, J = 8.0, 8.0 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 23.1, 33.7, 35.3, 56.1, 60.2, 106.8, 114.1, 114.5, 115.0, 115.3, 124.4, 129.06, 129.11, 130.0, 138.7, 149.3, 154.6, 156.8, 157.0, 168.8. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₁H₂₂NaO₅: 377.1365; found, 377.1371. HPLC [CHIRALPAK^® IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (8:2), 1.0 mL/min, 20 °C, 274 nm]: t _R = 6.0 min [7.5 min for (R)-(–)-5e].(R)-3′-(2-Furyl)-6-hydroxy-2′,6′-dimethoxybiphenyl-2-yl Acetate [(R)-(–)-5f]Colorless oil; yield: 73 mg (89%; >99% ee); [α]_D ²⁵ –35 (c 2.1, CHCl₃). IR (neat): 3446, 2937, 2838, 1764, 1736, 1586, 1457, 1435, 1416, 1367, 1276, 1197, 1084, 1021, 1003 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.97 (s, 3 H), 3.40 (s, 3 H), 3.81 (s, 3 H), 5.50 (s, 1 H), 6.49 (dd, J = 3.6, 1.6 Hz, 1 H), 6.84 (dd, J = 3.6, 0.8 Hz, 1 H), 6.86 (dd, J = 8.0, 0.8 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.97 (dd, J = 8.0, 0.8 Hz, 1 H), 7.34 (dd, J = 8.0, 8.0 Hz, 1 H), 7.47 (dd, J = 1.6, 0.8 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 56.2, 60.2, 107.5, 108.2, 111.9, 114.2, 114.7, 114.8, 115.2, 118.3, 127.6, 129.3, 141.1, 149.3, 149.8, 154.6, 155.3, 157.3, 168.8. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₁₈NaO₆: 377.1001; found, 377.0991. HPLC [CHIRALPAK IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (8:2), 1.0 mL/min, 20 °C, 305 nm]: t _R = 9.9 min [7.4 min for (S)-(+)-5f].(R)-6-Hydroxy-2′,6′-dimethoxy-3′-(2-thienyl)biphenyl-2-yl Acetate [(R)-(–)-5g]Colorless oil; yield: 77 mg (89%; >99% ee); [α]_D ²⁵ –44 (c 1.5, CHCl₃). IR (neat): 3428, 2934, 2836, 1763, 1734, 1591, 1457, 1405, 1367, 1277, 1195, 1112, 1084, 1022 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.00 (s, 3 H), 3.35 (s, 3 H), 3.80 (s, 3 H), 5.52 (s, 1 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.87 (dd, J = 8.0, 1.2 Hz, 1 H), 6.96 (dd, J = 8.4, 1.2 Hz, 1 H), 7.08 (dd, J = 5.2, 3.6 Hz, 1 H), 7.31 (dd, J = 5.2, 1.2 Hz, 1 H), 7.34 (dd, J = 8.4, 8.0 Hz, 1 H), 7.41 (dd, J = 3.6, 1.2 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.9, 56.2, 60.6, 107.6, 114.2, 114.8, 114.9, 115.2, 121.4, 124.5, 125.4, 126.9, 129.3, 129.8, 138.7, 149.3, 154.6, 155.6, 157.3, 168.8. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₁₈NaO₅S: 393.0773; found, 393.0773. HPLC [CHIRALPAK IA (Daicel), 0.46 × 25 cm, hexane–2-propanol (8:2), 1.0 mL/min, 20 °C, 305 nm]: t _R = 12.0 min [8.5 min for (S)-(+)-5g].
• 15 CCDC 1817942 contains the supplementary crystallographic data for compound (S)-7. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.