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

doi:10.1055/s-2008-1078504

LETTER

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;

Abstract

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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

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References

References and Notes

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Previous syntheses:

<A NAME="RG15008ST-13A">13a</A> Baker PM. Bycroft BW. Roberts JC. J. Chem. Soc. C 1967, 913

<A NAME="RG15008ST-13B">13b</A> Gerlach H. Helv. Chim. Acta 1977, 60: 3039

<A NAME="RG15008ST-13C">13c</A> Takahashi T. Ikeda H. Tsuji J. Tetrahedron Lett. 1980, 3885

<A NAME="RG15008ST-13D">13d</A> Wasserman HH. Gambale RJ. Pulwer MJ. Tetrahedron Lett. 1981, 1737

<A NAME="RG15008ST-13E">13e</A> Birch AJ. Mani NS. Rao GSRS. J. Chem. Soc., Perkin Trans. 1 1990, 1423

<A NAME="RG15008ST-13F">13f</A> Kasar RA. Khan RA. Desphande VH. Ayyangar NR. Tetrahedron Lett. 1991, 32: 1599

<A NAME="RG15008ST-13G">13g</A> Bracher F. Schulte B. Liebigs Ann./Recl. 1997, 1979

<A NAME="RG15008ST-13H">13h</A> Liang Q. Sun Y. Yu B. She X. Pan X. J. Org. Chem. 2007, 72: 9846

<A NAME="RG15008ST-13I">13i</A> Miyagi T. Kuwahara S. Biosci. Biotechnol. Biochem. 2007, 71: 1592

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<A NAME="RG15008ST-14">14</A> Venkatachalam TK. Huang H. Yu G. Uckun FM. Synth. Commun. 2004, 34: 1489

<A NAME="RG15008ST-15A">15a</A> Díez-Barra E. González-Verdú P. Tolosa J. Tetrahedron 2004, 60: 1563

<A NAME="RG15008ST-15B">15b</A> Hawker CJ. Fréchet JMJ. J. Am. Chem. Soc. 1990, 112: 7638

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<A NAME="RG15008ST-17">17</A> Makara GM. Klubek K. Anderson WK. Synth. Commun. 1996, 26: 1935

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.

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.

<A NAME="RG15008ST-20">20</A> Corey EJ. Venkateswarlu A. J. Am. Chem. Soc. 1972, 94: 6190

<A NAME="RG15008ST-21">21</A> Solsona JG. Romea P. Urpi F. Org. Lett. 2003, 5: 4681

<A NAME="RG15008ST-22">22</A> Pinnick HW. Balkrishna SB. Childers WE. Tetrahedron 1981, 37: 2091

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.

<A NAME="RG15008ST-24">24</A> Poppe L. Recseg K. Novak L. Synth. Commun. 1995, 25: 3993

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.

<A NAME="RG15008ST-26">26</A> Boden EP. Keck GE. J. Org. Chem. 1985, 50: 2394

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.

For general reviews on RCM, see:

<A NAME="RG15008ST-28A">28a</A> Grubbs RH. Angew. Chem. Int. Ed. 2006, 45: 3760

<A NAME="RG15008ST-28B">28b</A> Chauvin Y. Angew. Chem. Int. Ed. 2006, 45: 3741

<A NAME="RG15008ST-28C">28c</A> Schrock RR. Angew. Chem. Int. Ed. 2006, 45: 3748

<A NAME="RG15008ST-28E">28e</A> Fürstner A. Müller C. Chem. Commun. 2005, 5583

<A NAME="RG15008ST-28F">28f</A> Deiters A. Martin SF. Chem. Rev. 2004, 104: 2199

<A NAME="RG15008ST-28G">28g</A> Fürstner A. Angew. Chem. Int. Ed. 2000, 39: 3012

<A NAME="RG15008ST-28H">28h</A> Grubbs RH. Chang S. Tetrahedron 1998, 54: 4413

<A NAME="RG15008ST-28I">28i</A> Fürstner A. Langemann K. Synthesis 1997, 792

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.

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.