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Synlett 2006(7): 1051-1054  
DOI: 10.1055/s-2006-939698
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Chenying Wanga,b, Hongbin Zhang*b, Jikai Liua, Yanhua Jib, Zhihui Shaob, Liang Lib
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;
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Publication History

Received 8 January 2006
Publication Date:
24 April 2006 (online)

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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

8

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.

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

13

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).