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Synlett 2008(12): 1801-1804  
DOI: 10.1055/s-2008-1078504
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of (S)-(-)-Curvularin: A Ring-Closing-Metathesis-Based Construction of the Macrocyclic Framework

Debendra K. Mohapatra*, Hasibur Rahaman, Rita Pal, Mukund K. Gurjar
Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
Fax: +91(20)25902629; e-Mail: dk.mohapatra@ncl.res.in;
Further Information

Publication History

Received 25 April 2008
Publication Date:
19 June 2008 (online)

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Abstract

A convergent, flexible, and efficient approach to the synthesis of curvularin is described. Key step is the high-yielding macrocyclic ring formation by ring-closing metathesis (RCM) using the Grubbs second-generation catalyst.

Key words

curvularin - cytotoxic - ring-closing metathesis - Pinnick oxidation - Wittig reaction

18

Analytical and Spectral Data of 10
IR (neat): 3032, 2933, 1673, 1598, 1572, 1513, 1436, 1384, 1320, 1247, 1152, 1090, 1031, 820, 754, 698 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 3.21 (t, J = 6.6 Hz, 2 H), 3.59 (t, J = 6.6 Hz, 2 H), 3.67 (s, 3 H), 4.35 (s, 2 H), 4.95 (s, 2 H), 4.99 (s, 2 H), 6.40 (d, J = 2.2 Hz, 1 H), 6.42 (d, J = 2.2 Hz, 1 H), 6.73 (d, J = 8.6 Hz, 2 H), 7.12 (d, J = 8.7 Hz, 2 H), 7.22-7.32 (m, 10 H), 10.45 (s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl3): δ = 34.9, 55.2, 70.1, 70.2, 70.6, 72.3, 98.4, 110.1, 113.6, 117.4, 127.3, 127.6, 128.2, 128.3, 128.7, 129.2, 130.7, 135.9, 135.9, 145.3, 159.0, 163.4, 164.4, 190.3 ppm. Anal. Calcd for C31H30O5: C, 77.16; H, 6.27. Found: C, 77.46; H, 6.21.

19

Analytical and Spectral Data of 11
IR (neat): 3400, 2930, 1600, 1512, 1454, 1383, 1302, 1247, 1151, 1084, 1030, 822, 738, 698 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 2.42-2.55 (m, 1 H), 2.64-2.79 (m, 1 H), 2.84-3.03 (m, 2 H), 3.51-3.67 (m, 2 H), 3.77 (s, 3 H), 4.39 (d, J = 11.5 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.85-4.95 (m, 2 H), 4.97 (s, 2 H), 5.01-5.02 (m, 1 H), 5.05 (s, 2 H), 5.66-5.87 (m, 1 H), 6.42 (d, J = 2.4 Hz, 1 H), 6.51 (d, J = 2.4 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.33-7.41 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl3): δ 34.6, 55.2, 70.0, 70.1, 70.4, 72.6, 99.2, 108.2, 113.7, 114.3, 116.0, 118.7, 126.3, 126.9, 127.2, 127.6, 127.8, 128.0, 128.5, 128.6, 129.3, 130.4, 132.0, 134.0, 136.7, 136.8, 138.9, 139.3, 158.1, 158.3, 159.1. Anal. Calcd for C34H36O5: C, 77.84; H, 6.92. Found: C, 77.69; H, 6.82.

23

Analytical and Spectral Data of 6
IR (neat): 3065, 3031, 2927, 2855, 1730, 1602, 1454, 1385, 1254, 1105, 836, 756, 616 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = -0.11 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 2.40-2.54 (m, 1 H), 2.61-2.75 (m, 1 H), 3.96 (d, J = 16.7 Hz, 1 H), 4.45 (d, J = 16.7 Hz, 1 H), 4.97-5.08 (m, 6 H), 5.55-5.58 (m, 1 H), 5.68-5.89 (m, 1 H), 6.52-6.60 (m, 2 H), 7.30-7.48 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl3): δ = -3.7, 17.9, 25.6, 34.8, 40.2, 70.0, 70.2, 77.5, 99.1, 104.2, 114.3, 114.7, 119.3, 126.9, 127.1, 127.5, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 131.8, 132.4, 136.2, 136.3, 136.6, 136.9, 141.7, 154.9, 159.8, 170.4 ppm. Anal. Calcd for C32H40O5Si: C, 72.14; H, 7.57. Found: C, 72.31; H, 7.39.

25

Analytical and Spectral Data of 5
[α]D ²5 +9.89 (c 1.1, CHCl3). IR (neat): 3435, 3019, 1598, 1403, 1215, 1118, 758, 669 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.17 (d, J = 6.2 Hz, 3 H), 1.46-1.58 (m, 2 H), 1.99 (br s, 1 H), 2.06-2.20 (m, 2 H), 3.79 (quin, J = 6.2 Hz, 1 H), 4.90-5.07 (m, 2 H), 5.71-5.91 (m, 1 H) ppm. ¹³C NMR (50 MHz, CDCl3): δ = 23.4, 30.1, 38.2, 67.4, 114.7, 138.4 ppm. Anal. Calcd for C6H12O: C, 71.95; H, 12.08. Found: C, 71.89; H, 12.11.

27

Analytical and Spectral Data of 4
[α]D ²5 +7.86 (c 1.5, CHCl3). IR (neat): 2929, 2371, 2361, 2341, 1730, 1604, 1383, 1257, 1146, 1068, 773, 696, 667 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = -0.16 (s, 3 H), 0.01 (s, 3 H), 0.86 (s, 9 H), 1.22 (d, J = 5.7 Hz, 1.5 H), 1.25 (d, J = 5.7 Hz, 1.5 H), 1.47-1.79 (m, 2 H), 1.99-2.16 (m, 2 H), 2.37-2.50 (m, 1 H), 2.61-2.75 (m, 1 H), 3.70-3.88 (m, 1 H), 4.37-4.50 (m, 1 H), 4.92-5.07 (m, 9 H), 5.50-5.56 (m, 1 H), 5.67-5.91 (m, 2 H), 6.48 (d, J = 2.3 Hz, 1 H), 6.53 (br s, 1 H), 7.31-7.42 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl3): δ = -5.2, -4.9, 18.2, 19.9, 20.0, 25.9, 29.6, 29.7, 35.1, 69.9, 70.2, 70.5, 70.6, 98.9, 108.5, 108.6, 115.0, 116.4, 124.2, 126.9, 127.2, 127.5, 127.7, 128.0, 128.4, 128.5, 128.6, 135.9, 136.8, 137.0, 137.7, 158.2, 158.3, 170.9, 171.9 ppm. Anal. Calcd for C38H50O5Si: C, 74.23; H, 8.20. Found: C, 74.01; H, 8.22.

29

Analytical and Spectral Data of 16
[α]D ²5 +45.05 (c 1.0, CHCl3). IR (neat): 3208, 2928, 1728, 1687, 1655, 1601, 1429, 1311, 1154, 1105, 754 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.09 (d, J = 6.3 Hz, 3 H), 1.47-1.62 (m, 2 H), 1.91-1.99 (m, 1 H), 2.14-2.26 (m, 1 H), 3.05-3.55 (m, 4 H), 4.94-5.02 (m, 5 H), 5.15-5.25 (m, 1 H), 5.38-5.51 (m, 1 H), 6.46 (d, J = 2.1 Hz, 1 H), 6.52 (s, 1 H), 7.22-7.36 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl3): δ = 20.9, 30.4, 33.7, 38.0, 49.0, 70.2, 70.6, 72.4, 99.6, 109.5, 120.1, 124.3, 127.2, 127.6, 128.0, 128.1, 128.6, 134.1, 136.2, 136.5, 137.2, 156.6, 160.2, 170.8, 204.6 ppm. Anal. Calcd for C30H30O5: C, 76.57; H, 6.43. Found: C, 76.42; H, 6.49.

30

Analytical and Spectral Data of 1
[α]D ²5 -31.89 (c 2.0, EtOH); lit [¹4] [α]D ²5 -33.0 (c 2.0, EtOH). IR (Nujol): 3419, 3176, 2933, 2869, 2254, 1719, 1661, 1607, 1589, 1463, 1316, 1264, 1105, 1006, 823, 616. cm-¹. ¹H NMR (500 MHz, acetone-d 6,): δ = 1.13 (d, J = 6.3 Hz, 3 H), 1.24-1.28 (m, 2 H), 1.40-1.50 (m, 3 H), 1.52-1.57 (m, 1 H), 1.59-1.64 (m, 1 H), 1.73-1.80 (m, 1 H), 2.78 (ddd, J = 2.9, 9.8, 15.5 Hz, 1 H), 3.12 (ddd, J = 2.9, 8.7, 15.5 Hz, 1 H), 3.71 (d, J = 15.7 Hz, 1 H), 3.79 (d, J = 15.6 Hz, 1 H), 4.90-4.96 (m, 1 H), 6.36 (d, J = 2.2 Hz, 1 H), 6.41 (d, J = 2.2 Hz, 1 H), 8.82 (br s, 1 H), 9.19 (br s, 1 H) ppm. ¹³C NMR (50 MHz, acetone-d 6): δ = 20.5, 23.4, 24.5, 27.4, 32.8, 39.6, 44.0, 72.6, 102.4, 112.2, 121.3, 136.9, 158.2, 160.1, 171.0, 206.7 ppm. Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.68; H, 6.91.