First Total Synthesis of (3R,4S)-4-Hydroxylasiodiplodin: A Facile and Stereoselective Approach

Abstract

A first total synthesis of (3R,4S)-4-hydroxylasiodiplodin is described starting from methyl acetoacetate and a commonly available carbohydrate, d-mannitol, which is regularly used in organic synthesis. The facile and stereoselective approach involves the Barbier allylation and a ring-closing metathesis as key steps.

Key words

Hydroxylasiodiplodin - Barbier allylation - metathesis - carbohydrate - total synthesis - natural product

• References and Notes

• 1 Nozawa K, Nakajima S. J. Nat. Prod. 1979; 42: 374
• 2a Stob M, Baldwin RS, Tuite J, Andrews FN, Gillette KG. Nature (London) 1962; 196: 1318
• 2b Urry WH, Wehrmeister HL, Hodge EB, Hidy PH. Tetrahedron Lett. 1966; 7: 3109
• 3a Aldridge DC, Galt S, Giles D, Turner WB. J. Chem. Soc. C 1971; 1623
• 3b Li P, Takahashi K, Matsuura H, Yoshihara T. Biosci. Biotechnol. Biochem. 2005; 69: 1610
• 4 Oyama H, Sassa T, Ikeda M. Agric. Biol. Chem. 1978; 42: 2407
• 5a Ayer WA, Lee SP, Tsuneda A, Hiratsuka Y. Can. J. Microbiol. 1980; 26: 776
• 5b Matsuura H, Nakamori K, Omer EA, Hatakeyama C, Yoshihara T, Ichihara A. Phytochemistry 1998; 49: 579
• 5c Isaka M, Suyarnsestakorn C, Tanticharoen M. J. Org. Chem. 2002; 67: 1561
• 5d Hellwig V, Mayer-Bartschmid A, Müller H, Greif G, Kleymann G, Zitzmann W, Tichy H.-T, Stadler M. J. Nat. Prod. 2003; 66: 829
• 5e Isaka M, Yangchum A, Intamas S, Kocharin K, Jones EB. G, Kongsaeree P, Prabpai S. Tetrahedron 2009; 65: 4396
• 5f Ayers S, Graf TN, Adcock AF, Kroll DJ, Matthew S, Carcche de Blanco EJ, Shen Q, Swanson SM, Wani MC, Pearce CJ, Oberlies NH. J. Nat. Prod. 2011; 74: 1126
• 6 Xin-Sheng Y, Ebizuka Y, Noguchi H, Kiuchi F, Litaka Y, Sankawa U, Seto H. Tetrahedron Lett. 1983; 24: 2407
• 7 Lee K.-H, Hayashi N, Okhano M, Hall IH, Wu R.-Y, Mchail AT. Phytochemistry 1982; 21: 1119
• 8 Buayairaksa M, Kanokmedhakul S, Kanokmedhakul K, Moosophon P, Hahnvajanawong C, Soytong K. Arch. Pharm. Res. 2011; 34: 2037
• 9 Jiang C.-S, Zhou R, Gong J.-X, Chen L.-L, Kurtan T, Shen X, Guo Y.-W. Bioorg. Med. Chem. Lett. 2011; 21: 1171
• 10 Yang R-Y, Li C.-Y, Lin Y.-C, Peng G.-T, She Z.-G, Zhou S.-N. Bioorg. Med. Chem. Lett. 2006; 16: 4205
• 11 Veiga TA. M, Silva SC, Francisco A.-C, Filho ER, Vieira PC, Ferndes JB, Silva MF. G. F, Müller MW, Lotina-Hennsen B. J. Agric. Food. Chem. 2007; 55: 4217
• 12 Yang Q, Asai M, Matsuura H, Yoshihara T. Phytochemistry 2000; 54: 489
• 13a Yadav JS, Das S, Mishra AK. Tetrahedron: Asymmetry 2010; 21: 2443
• 13b Das S, Mishra AK, Kumar A, Ghamdi AA. K. A, Yadav JS. Carbohydr. Res. 2012; 358: 7
• 13c Yadav JS, Das S, Reddy JS, Thrimurtulu N, Prasad AR. Tetrahedron Lett. 2010; 51: 4050
• 14 Chiarello J, Joullie MM. Tetrahedron 1988; 44: 41
• 15 Harris EM, Roberson JS, Harris TM. J. Am. Chem. Soc. 1976; 17: 5380
• 16 Vu NQ, Chai CL. L, Lim KP, Chia SC, Chen A. Tetrahedron 2007; 63: 7053
• 17 For a general review of benzylic anions, see: Clark RD, Jahangin A. Org. React. 1995; 47: 1
• 18 Chattopadhyay A, Mamdapur VR. J. Org. Chem. 1995; 60: 585
• 19 Chattopadhyay A. J. Org. Chem. 1996; 61: 6104
• 20 Barrero FA, Alvarez-Manzaneda JE, Chahboun R. Tetrahedron Lett. 2000; 41: 1959
• 21 Selles P, Lett R. Tetrahedron Lett. 2002; 43: 4621
• 22 Fürstner A, Kindler N. Tetrahedron Lett. 1996; 37: 7005
• 23 Spectral Data for Representative Compounds Methyl 2-Hydroxy-4-(methoxymethoxy)-6-methyl-benzoate(7) Mp 55–58 °C. IR (KBr): 2956, 2855, 2831, 1726, 1657, 1618, 1579, 1446, 1422, 1369, 1324, 1261, 1215, 1152, 1111, 1080, 1062, 1020, 942, 845, 803, 770, 700, 673, 606, 578, 528 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 11.65 (s, 1 H), 6.47 (d, J = 3.0 Hz, 1 H), 6.36 (s, J = 2.3 Hz, 1 H), 5.15 (s, 2 H), 3.90 (s, 3 H), 3.45 (s, 3 H), 2.48 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.1, 165.2, 161.4, 143.3, 111.8, 101.5, 93.8, 56.3, 51.9, 29.7, 24.4. ESI-MS: m/z = 227 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₁H₁₈O₆Na: 269.1001; found: 269.0992. Methyl 2-Methoxy-4-(methoxymethoxy)-6-methyl-benzoate (8) IR (neat): 2944, 2846, 1727, 1602, 1585, 1459, 1434, 1321, 1268, 1231, 1189, 1149, 1096, 1078, 1026, 962, 928, 836, 814, 773 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.47 (d, J = 1.7 Hz, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 5.17 (s, 2 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.48 (s,3 H), 2.27 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.5, 158.9, 157.9, 138.0, 117.3, 109.2, 94.2, 97.7, 55.9, 55.8, 51.9, 19.7. ESI-MS: m/z = 241 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₂H₁₆O₅Na: 263.0890; found: 263.0894. Methyl 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-enyl)benzoate (9) IR (neat): 2951, 3004, 2907, 2838, 1739, 1709, 1615, 1577, 1431, 1297, 1219, 1137, 1103, 1037, 966, 930, 823, 772, 640 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.48 (m, 2 H), 5.89–5.71 (m, 1 H), 5.17 (s, 2 H), 5.07–4.87 (m, 2 H), 3.88 (s, 3 H), 3.47 (s, 3 H), 2.62–2.50 (m, 2 H), 2.15–2.07 (ABq, J = 14.0, 6.8 Hz, 2 H), 1.74–1.62 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.7, 158.9, 157.8, 142.5, 138.3, 125.5, 114.8, 108.4, 97.8, 94.3, 56.0, 55.9, 33.4, 33.1, 30.2. ESI-MS: m/z = 295 [M + H]⁺. 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-enyl)benzoic Acid (10) IR (neat): 3076, 2932, 1697, 1603, 1460, 1425, 1297, 1218, 1193, 1151, 1113, 1081, 1021, 918, 837, 772 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.58 (d, J = 1.8 Hz, 1 H), 6.53 (d, J = 2.1 Hz 1 H), 5.93–5.76 (m, 1 H), 5.50–5.40 (m, 1 H), 5.21 (s, 2 H), 5.08–4.92 (m, 1 H), 3.93 (s, 3 H), 3.49 (s, 3 H), 2.92–2.80 (m, 2 H), 2.12 (ABq, J = 14.2, 7.17 Hz, 2 H), 1.79–1.64 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 159.4, 158.4, 144.4, 138.3, 115.3, 114.7, 109.3, 97.8, 94.1, 55.9, 33.5, 33.4, 30.3. ESI-MS: m/z = 281 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₅H₂₁O₅Na: 281.1384; found: 281.1369. (R)-2-[(S)-1-(Benzyloxy)but-3-enyl]oxirane (15) [α]_D ³⁰ +5.40 (c 1, CHCl₃). IR (neat): 3032, 3065, 2989, 2925, 2867, 1955, 1824, 1642, 1495, 1454, 1434, 1391, 1344, 1306, 1252, 1207, 1159, 1098, 1074, 1028, 995, 917, 851, 739, 698, 609, 2982, 2933, 1647, 1608, 1574, 1445, 1376, 1357, 1319, 1257, 1211, 1159, 1103, 1034, 967, 864, 757 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.32–7.20 (m, 5 H), 5.94–5.82 (m, 1 H), 5.17–5.06 (m, 2 H), 4.62–4.52 (m, 2 H), 3.32–3.28 (m, 1 H), 2.92–2.88 (m, 1 H), 2.73–2.70 (m, 1 H), 2.68–2.65 (m, 1 H), 2.47–2.35 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 138.3, 133.9, 128.3, 127.6, 117.4, 77.7, 72.1, 53.1, 45.6, 37.2. ESI-MS: m/z = 227[M + Na]⁺. ESI-HRMS: m/z calcd for C₁₃H₁₆O₂Na: 227.1402; found: 227.1402. (2R,3S)-3-(Benzyloxy)hex-5-en-2-ol (16) [α]_D ³⁰ +3.8 (c 0.3, CHCl₃). IR (neat): 3432, 3070, 3031, 2977, 2931, 2874, 1718, 1641, 1496, 1453, 1396, 1370, 1258, 1215, 1092, 1070, 1028,996, 913, 772, 738, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.36–7.20 (m, 5 H), 5.96–5.76 (m, 1 H), 5.18–5.05 (m, 2 H), 4.65 (m, 2 H), 3.98–3.89 (m, 1 H), 3.46–3.39 (m, 1 H), 2.48–2.37 (m, 1 H), 2.33–2.23 (m, 1 H), 1.18 (d, J = 6.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 138.4, 135.1, 127.7, 128.4, 127.8, 116.9, 82.4, 72.1, 68.2, 34.0, 17.8. ESI-MS: m/z = 229 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₃H₁₈O₂Na: 229.1199; found: 229.1199. (2R,3S)-3-(Benzyloxy)hex-5-en-2-yl 2-Methoxy-4-(methoxymethoxy)-6-(pent-4-en-1-yl)benzoate (17) [α]_D ³⁰ –7.0 (c 0.3, CHCl₃). IR (neat): 3073, 2927, 2855, 1725, 1640, 1604, 1588, 1458, 1426, 1317, 1261, 1216, 1191, 1150, 1085, 1023, 966, 917, 838, 772, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.38–7.28 (m, 5 H), 6.49 (d, J = 2.1 Hz, 1 H), 6.45 (d, J = 2.1 Hz, 1 H), 5.98–5.70 (m, 2 H), 5.45–5.22 (m, 2 H), 5.17 (s, 2 H), 5.12–4.91 (m, 3 H), 4.63 (m, 2 H), 3.81–3.74 (m, 3 H), 3.69–3.62 (m, 1 H), 3.48 (s, 3 H), 2.64–2.54 (m, 2 H), 2.44–2.35 (m, 2 H), 2.06 (ABq, J = 7.0, 14.1 Hz, 2 H), 1.73–1.64 (m, 2 H), 1.38 (d, J = 6.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.6, 158.8, 157.7, 142.2, 138.3, 134.6, 128.2, 127.7, 127.4, 117.3, 108.3, 97.7, 94.3, 80.4, 72.6, 72.5, 56.0, 55.6, 35.5, 33.5, 33.0, 30.3, 15.0. ESI-MS: m/z = 491 [M + Na]⁺. ESI-HRMS: m/z calcd for C₂₈H₃₆O₆Na: 491.2404; found: 491.2405. (3R,4S)-4-(Benzyloxy)-14-methoxy-12-(methoxymethoxy)-3-methyl-3,4,5,8,9,10-hexahydro-1H-benzo[c][1]oxacyclododecin-1-one (18) Mp 86–90 °C. [α]_D ³⁰ 32 (c 1, CHCl₃). IR (KBr): 2925, 2854, 1724, 1604, 1586, 1456, 1373, 1346, 1311, 1261, 1230, 1212, 1191, 1149, 1091, 1070, 1017, 964, 932, 830, 738, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.40–7.27 (m, 5 H), 6.51 (d, J = 1.9 Hz, 1 H), 6.42 (d, J = 1.9 Hz, 1 H), 5.70–5.51 (m, 1 H), 5.42–5.24 (m, 2 H), 5.16 (d, J = 1.3 Hz, 2 H), 4.82–4.44 (m, 2 H), 3.75 (s, 3 H), 3.62–3.53 (m, 1 H), 3.50 (s, 3 H), 2.62–2.49 (m, 2 H), 2.32–2.19 (m, 2 H), 2.15–1.96 (m, 2 H), 1.91–1.77 (m, 2 H), 1.43 (d, J = 5.9 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.4, 158.8, 157.2, 142.1, 138.3, 132.6, 128.7, 128.4, 128.3, 127.7, 127.6, 124.8, 108.3, 107.3, 97.7, 94.4, 80.5, 73.6, 71.3, 55.9, 56.1, 30.9, 31.8, 29.7, 29.5, 17.7. ESI-MS: m/z = 463 [M + Na]⁺. ESI-HRMS: m/z calcd for C₂₆H₃₂O₆Na: 463.2091; found: 463.2091. (3R,4S)-4-Hydroxy-14-(methoxymethoxy)-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-benzo[c][1]oxacyclo-dodecin-1-one (19) Mp 105–107 °C. [α]_D ³⁰ +7(c 1, CHCl₃). IR (KBr): 3422, 2950, 2853, 2923, 1718, 1604, 1587, 1462, 1377, 1265, 1218, 1150, 1088, 1023, 771, 722 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.47 (m, 2 H), 5.17 (s, 2 H), 5.05–4.84 (m, 1 H), 3.78–3.80 (m, 4 H), 3.48 (s, 3 H), 2.83–2.69 (m, 1 H), 2.62–2.51 (m, 1 H), 1.93–1.83 (m, 1 H), 1.74–1.56 (m, 5 H), 1.48 (d, J = 6.0 Hz, 3 H), 1.45–1.36 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.3, 158.9, 157.6, 142.6, 118.4, 108.7, 97.7, 94.3, 74.3, 73.9, 56.1, 55.9, 33.6, 31.9, 29.9, 25.9, 24.8, 21.4, 17.9. ESI-MS: m/z = 375 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₉H₂₈O₆Na: 375.1778; found: 375.1776. (3R,4S)-4-Hydoxylasiodiplodin (1) Mp 213–215 °C. [α]_D ³⁰ +3.5 (c 0.7, MeOH). IR (KBr): 3355, 2924, 2853, 1691, 1603, 1462, 1263, 1219, 1162, 1093, 1026, 772 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.28 (d, J = 2.0 Hz, 1 H), 6.23 (d, J = 2.0 Hz 1 H), 4.76–4.71 (m, 1 H), 3.75 (s, 3 H), 3.66–3.61 (m, 1 H), 2.68 (ddd, J = 13.9, 7.9, 3.9 Hz, 1 H), 2.51 (ABq, J = 12.9, 7.0 Hz, 1 H), 1.85–1.78 (m, 1 H), 1.74–1.67 (m, 1 H), 1.67–1.58 (m, 2 H), 1.57–1.50 (m, 2 H), 1.42 (d, J = 6.0 Hz, 3 H), 1.37–1.32 (m, 2 H), 1.31–1.27 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.5, 160.9, 159.5, 143.7, 117.4, 109.4, 97.9, 75.0, 74.9, 56.3, 31.4, 31.3, 31.2, 27.3, 25.6, 22.5, 18.5. ESI-MS: m/z = 331 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₂₄O₅Na: 331.1516; found: 331.1518.