Stereoselective Synthesis of (+)-Paeonilide and Confirmation of its Absolute Configuration

Chenying Wang; Hongbin Zhang; Jikai Liu; Yanhua Ji; Zhihui Shao; Liang Li

doi:10.1055/s-2006-939698

LETTER

Stereoselective Synthesis of (+)-Paeonilide and Confirmation of its Absolute Configuration

Chenying Wang^a,b, Hongbin Zhang*^b, Jikai Liu^a, Yanhua Ji^b, Zhihui Shao^b, Liang Li^b
^a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, Graduate School of Chinese Academy of Science, Beijing 100039, P. R. of China
^b Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, Yunnan 650091, P. R. of China
Fax: +86(871)5035538; e-Mail: zhanghb@ynu.edu.cn;

Abstract

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Abstract

The first diastereoselective synthesis of paeonilide, a novel anti-PAF-active monoterpenoid, starting from R-(-)-carvone was reported. The absolute configuration for paeonilide was also established.

Key words

diastereoselective synthesis - (+)-paeonilide - absolute configuration - monoterpenoid - carvone

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References

References and Notes

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<A NAME="RW00706ST-1B">1b</A> Rönn M. Andersson PG. Bäckvall JE. Acta Chem. Scand. 1998, 52: 524

<A NAME="RW00706ST-1C">1c</A> Jonasson C. Rönn M. Bäckvall JE. J. Org. Chem. 2000, 65: 2122

<A NAME="RW00706ST-2">2</A> Liu JK. Ma YB. Wu DG. Lu Y. Shen ZQ. Zheng QT. Chen ZH. Biosci. Biotechnol. Biochem. 2000, 64: 1511

<A NAME="RW00706ST-3A">3a</A> Hatakeyama S. Kawamura M. Takano S. Irie H. Tetrahedron Lett. 1994, 35: 7993

<A NAME="RW00706ST-3B">3b</A> Hatakeyama S. Kawamura M. Shimanuki E. Takano S. Tetrahedron Lett. 1992, 33: 333

<A NAME="RW00706ST-4A">4a</A> Srikrishna A. Hemamalini P. J. Org. Chem. 1990, 55: 4883

<A NAME="RW00706ST-4B">4b</A> For a high-yielding procedure leading to compound 6, see: Engel W. J. Agric. Food Chem. 2001, 49: 4069

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<A NAME="RW00706ST-7">7</A> Bajwa JS. Anderson RC. Tetrahedron Lett. 1991, 32: 3021

In the synthetic work published in ref. 3, discriminating between the two primary hydroxyl groups was achieved by an enzymatic acetylation towards substrate 3 and diastereoisomeric monoacetate of diol 3 was obtained with a ratio of 13: 1. In our case, bromoetherification of diol 3 led to only desired diastereisomer 15.

<A NAME="RW00706ST-9A">9a</A> Hoffmann RW. Synthesis 2004, 2075

<A NAME="RW00706ST-9B">9b</A> Studer A. Schleth F. Synlett 2005, 3033

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<A NAME="RW00706ST-11">11</A> More JD. Finney NS. Org. Lett. 2002, 4: 3001

Natural paeonilide was provided by professor J. K. Liu. The optical rotation of synthetic paeonilide compared well to the value of authentic sample.

Compound 3: colorless solid; mp 84-85 °C; [α]_D ²⁰ -101.6 (c 0.993, CHCl₃). IR (film): 3424 (s), 2928 (m), 1632 (m), 1372 (m), 1297 (m), 1281 (m), 1237 (w), 1136 (s), 1099 (w), 1071 (w), 1034 (w) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 5.67 (1 H, dd, J = 3.9, 10.4 Hz), 5.58 (1 H, d, J = 10.4 Hz), 4.03 (1 H, br s), 3.92-3.74 (4 H, m), 3.12 (1 H, br s), 2.70 (1 H, br s), 2.49-2.20 (2 H, m), 1.96 (1 H, m), 1.91 (1 H, ddd, J = 2.8, 8.3, 15.6 Hz), 1.38 (3 H, s), 1.35 (3 H, s), 1.30 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 131.7 (d), 128.9 (d), 108.5 (s), 78.3 (d), 77.6 (s), 64.4 (t), 63.9 (t), 46.6 (d), 30.1 (d), 28.3 (q), 27.9 (q), 25.1 (q), 24.9 (t). MS (EI): m/z (%) = 242 (3) [M⁺], 227 (3), 211 (5), 191 (13), 167 (52), 149 (36), 105 (91), 57 (100). HRMS: m/z calcd for C₁₃H₂₂O₄Na [M + 23]⁺: 265.1415; found: 265.1416.
Compound 15: colorless oil; [α]_D ²⁰ -4.9 (c 0.745, CHCl₃). IR (KBr): 3443 (br s), 2985 (s), 2937 (s), 2876 (s), 1458 (s), 1380 (s), 1256 (s), 1215 (s), 1103 (s), 1071 (s), 1029 (s), 990 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.20-4.06 (4 H, m), 3.70-3.57 (3 H, m), 2.28-2.12 (4 H, m), 1.77-1.65 (1 H, m), 1.48 (3 H, s), 1.43 (3 H, s), 1.41 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 109.5 (s), 83.3 (d), 81.1 (s), 79.4 (d), 69.6 (t), 63.4 (t), 61.3 (d), 48.7 (d), 38.4 (d), 30.9 (t), 28.3 (q), 26.4 (q), 23.3 (q). MS (EI): m/z (%) = 322 (3) [M⁺], 320 (2) [M⁺], 307 (8), 305(7), 197 (7), 183 (10), 169 (12), 155 (16), 127 (27), 111 (27), 97 (38), 85 (64), 71 (100). HRMS: m/z calcd for C₁₃H₂₂O₄Na [M + 23]⁺: 343.0520; found: 343.0529.
Compound 16: colorless oil; [α]_D ²⁰ -5.7 (c 0.764, CHCl₃). IR (KBr): 2981 (s), 2953 (s), 2876 (s), 1724 (s), 1688 (s), 1602 (m), 1582 (m), 1453 (s), 1424 (s), 1380 (s), 1325 (s), 1285 (s), 1211 (s), 1180 (s), 1113 (s), 1056 (s), 934 (s), 708 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.98 (2 H, d, J = 7.5 Hz), 7.55 (1 H, t, J = 7.5 Hz), 7.43 (2 H, t, J = 7.5 Hz), 4.33-4.05 (6 H, m), 3.63 (1 H, dd, J = 6.9, 9.3 Hz), 2.44 (1 H, m), 2.26-2.17 (2 H, m), 1.72 (1 H, m), 1.45 (3 H, s), 1.40 (3 H, s), 1.37 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 166.7 (s), 133.7 (d), 130.1 (s), 129.9 (d), 128.9 (d), 109.9 (s), 83.6 (d), 81.4 (s), 79.7 (d), 69.9 (t), 65.4 (t), 61.2 (d), 46.2 (d), 39.5 (d), 31.3 (t), 28.7 (q), 26.8 (q), 23.7 (q). MS (EI): m/z (%) = 426 (14) [M⁺], 424 (15) [M⁺], 411 (30), 409 (32), 351 (5), 349 (5), 329 (3), 287 (4), 229 (13), 227 (15), 183 (6), 165 (19), 147 (22), 105(100). HRMS: m/z calcd for C₂₀H₂₅O₅NaBr [M + 23]⁺: 447.0783; found: 447.0774.
Compound 17: colorless oil; [α]_D ²⁰ +23.4 (c 1.161, CHCl₃). IR (KBr): 3453 (br s), 2977 (s), 2940 (s), 2889 (s), 1719 (s), 1601 (w), 1451 (s), 1394 (s), 1376 (s), 1274 (s), 1117 (s), 1069 (s), 1026 (s), 756 (s), 713 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.01 (2 H, d, J = 7.5 Hz), 7.57 (1 H, t, J = 7.5 Hz), 7.44 (2 H, t, J = 7.5 Hz), 4.43 (1 H, d, J = 7.5 Hz), 4.39 (1 H, dd, J = 5.7, 11.2 Hz), 4.29 (1 H, dd, J = 4.4, 6.7 Hz), 4.23 (1 H, d, J = 9.2 Hz), 4.21 (1 H, d, J = 9.3 Hz), 3.94 (1 H, t, J = 4.5 Hz), 3.73 (1 H, dd, J = 7.2, 9.0 Hz), 3.37 (1 H, br s), 2.98 (1 H, m), 2.37 (1 H, m), 2.01-1.90 (2 H, m), 1.33 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 166.5 (s), 133.2 (d), 129.8 (s), 129.6 (d), 128.4 (d), 82.5 (d), 74.2 (d), 72.3 (s), 69.6 (t), 65.2 (t), 42.5 (d), 39.6 (d), 28.2 (t), 22.8 (q), 14.2 (q). MS (EI): m/z (%) = 323 (1), 305(3), 287 (30), 264 (10), 262 (11), 217 (7), 183 (13), 165 (86), 147 (36), 138 (26), 123 (26), 105 (100). HRMS: m/z calcd for C₁₇H₂₁O₅NaBr [M + 23]⁺: 407.0470; found: 407.0463.
Compound 18: colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 9.82 (1 H, d, J = 1.5 Hz), 8.03 (2 H, d, J = 7.8 Hz), 7.58 (1 H, t, J = 7.9 Hz), 7.45 (2 H, t, J = 7.9 Hz), 4.82 (1 H, dd, J = 6.3, 8.6 Hz), 4.31-4.20 (2 H, m), 4.00-3.86 (3 H, m), 3.25 (1 H, ddd, J = 3.0, 8.9, 9.0 Hz), 2.52-2.33 (3 H, m), 1.48 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 200.4 (s), 166.8 (s), 133.6 (d), 130.2 (s), 130.0 (d), 128.9 (d), 90.4 (d), 82.1 (s), 70.5 (t), 65.3 (t), 65.0 (d), 62.1 (d), 45.1 (d), 44.2 (d), 24.6 (q).
Compound 22: colorless oil; [α]_D ²⁰ +50.7 (c 0.725, CHCl₃). IR (KBr): 3442 (br s), 2949 (w), 2892 (w), 1721 (s), 1601 (w), 1451 (w), 1275 (s), 1112 (s), 1071 (w), 1045 (w), 713 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.98 (2 H, d, J = 8.4 Hz), 7.56 (1 H, t, J = 7.5 Hz), 7.44 (2 H, dd, J = 7.5, 8.4 Hz), 4.51 (1 H, dd, J = 7.1, 8.3 Hz), 4.33 (2 H, d, J = 6.0 Hz), 4.22 (1 H, t, J = 9.0 Hz), 4.08 (1 H, d, J = 9.0 Hz), 3.79 (1 H, dd, J = 8.0, 9.1 Hz), 2.93 (1 H, dd, J = 8.0, 16.5 Hz), 2.80-2.67 (2 H, m), 2.49-2.37 (1 H, m), 1.43 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 208.0 (s), 166.4 (s), 133.5 (d), 129.8 (s), 129.7 (d), 128.7 (d), 82.2 (d), 76.6 (s), 69.5 (t), 64.4 (t), 59.9 (d), 43.5 (t), 41.3 (d), 36.6 (q), 22.5 (q). MS (EI): m/z (%) = 303 (15), 285 (4), 274 (5), 257 (3), 189 (8), 181 (48), 163 (13), 153 (14), 138 (20), 121 (11), 105 (100), 95 (13), 77 (24). HRMS: m/z calcd for C₁₇H₁₉O₅NaBr [M + 23]⁺: 405.0313; found: 405.0322.
Compound 23: colorless oil, mixture of α-bromoketones. ¹H NMR (300 MHz, CDCl₃): δ = 8.05-8.01 (4 H, m), 7.58 (2 H, t, J = 7.5 Hz), 7.48-7.43 (4 H, m), 4.53-4.27 (8 H, m), 4.18 (1 H, dd, J = 7.8, 9.0 Hz), 3.97 (1 H, d, J = 10.2 Hz), 3.76-3.70 (2 H, m), 3.68 (3 H, s), 3.65 (3 H, s), 2.85-2.62 (4 H, m), 2.50-2.39 (2 H, m), 2.42 (3 H, s), 2.36 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 200.9/200.2 (s), 172.4 (s), 166.7 (s), 133.6 (d), 130.0 (s), 130.0 (d), 128.9 (d), 80.4/80.0 (d), 70.9/70.4 (t), 65.7/65.6 (t), 54.5/49.3 (d), 52.4 (q), 44.6/43.7 (d), 41.3/40.9 (d), 33.8/33.4 (t), 27.7/26.1 (q). MS (EI): m/z (%) = 333 (25), 277 (20), 259 (6), 211 (30), 179 (15), 155 (35), 151 (29), 105(100). HRMS: m/z calcd for C₁₈H₂₁O₆NaBr [M + 23]⁺: 435.0419; found: 435.0421.
Compound 1 (R = Me): colorless oil, [α]_D ²⁰ +58.8 (c 1.822, acetone). ¹H NMR (300 MHz, CDCl₃): δ = 8. 01 (2 H, d, J = 7.2 Hz), 7.56 (1 H, t, J = 7.5 Hz), 7.43 (2 H, dd, J = 7.2, 7.5 Hz), 5.82 (1 H, s), 4.39 (1 H, dd, J = 6.0, 9.6 Hz), 4.32-4.21 (3 H, m), 3.93 (1 H, dd, J = 3.0, 11.7 Hz), 3.67 (3 H, s), 2.93 (1 H, dd, J = 3.0, 16.5 Hz), 2.78 (1 H, q, J = 6.0 Hz), 2.48 (1 H, dd, J = 10.8, 16.5 Hz), 2.12 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 197.3 (s), 177.5 (s), 172.2 (s), 166.7 (s), 133.6 (d), 130.1 (s), 130.0 (d), 128.8 (d), 99.7 (d), 72.4 (t), 65.8 (t), 52.3 (q), 42.6 (d), 42.1 (d), 35.6 (t), 31.7 (q). MS (EI): m/z (%) = 333 (1) [M⁺ + 1], 290 (2), 259 (5), 247 (5), 210 (22), 193 (12), 137 (15), 105(100). HRMS: m/z calcd for C₁₈H₂₀O₆Na [M + 23]⁺: 355.1157; found: 355.1152.
Paeonilide: colorless needles; [α]_D ²⁰ +50.6 (c 0.775, acetone). Authentic sample: [α]_D ²⁰ +53.5 (c 0.340, acetone). IR (KBr): 3438 (s), 1763 (s), 1709 (s), 1281 (s), 1119 (s), 1041 (m), 949 (m), 922 (m), 717 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.01 (2 H, d, J = 7.5 Hz), 7.59 (1 H, t, J = 7.5 Hz), 7.44 (2 H, t, J = 7.5 Hz), 4.29 (1 H, dd, J = 7.2, 11.1 Hz), 4.17 (1 H, dd, J = 8.1, 11.1 Hz), 4.02 (2 H, m), 3.41 (1 H, d, J = 17.8 Hz), 3.34 (1 H, dd, J = 10.5, 18.5 Hz),* 2.96 (1 H, d, J = 18.4 Hz), 2.94 (1 H, m), 2.54 (1 H, dd, J = 2.8, 18.4 Hz),* 2.54 (1 H, m), 2.19 (3 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 204.5 (s), 174.6 (s), 166.5 (s), 133.6 (d), 129.8 (s), 129.7 (d), 128.7 (d), 115.1 (s), 68.1 (t), 65.1 (t), 49.7 (t), 46.9 (d), 44.5 (d), 36.8 (t), 31.1 (q). MS (EI): m/z (%) = 196 (15), 178 (9), 152 (52), 139 (12), 105(100), 94 (53). HRMS: m/z calcd for C₁₇H₁₈O₆Na [M + 23]⁺: 341.1001; found: 341.1001. *A few typing errors were found for the assignment of protons at C₁₃ position in the original paper published in Biosci. Biotechnol. Biochem. (see ref. 2). It should be corrected as 3.34 (1 H, dd, J = 10.5, 18.5 Hz) and 2.55 (1 H, dd, J = 2.8, 18.5 Hz).