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Synlett 2008(15): 2275-2278  
DOI: 10.1055/s-2008-1078205
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

New Route to Natural Camptothecin through Isomünchnone Cycloaddition

Alice Kanazawa*, Mauro N. Muniz, Barbora Baumlová, Natalie Ljungdahl, Andrew E. Greene
Département de Chimie Moléculaire (SERCO), UMR 5250, ICMG FR 2650, CNRS Université Joseph Fourier, BP 53, 38041 Grenoble, France
Fax: +33(4)76635754; e-Mail: Alice.Kanazawa@ujf-grenoble.fr;
Further Information

Publication History

Received 23 May 2008
Publication Date:
21 August 2008 (online)

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Abstract

A novel approach to camptothecin by [3+2] cycloaddition of an isomünchnone intermediate is described.

Key words

camptothecin - antitumor natural product - isomünchnone cycloaddition - Suzuki coupling - cyanosilylation

    References and Notes

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  • 16a

    Compound 8b: mp 246-248 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.49 (t, J = 7.0 Hz, 3 H), 4.50 (q, J = 7.1 Hz, 2 H), 5.23 (s, 2 H), 7.03 (s, 1 H), 7.67 (pseudo t, J = 7.3 Hz, 1 H), 7.83 (pseudo t, J = 7.2 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 8.37 (s, 1 H). ¹³C NMR (75 MHz, CDCl3-MeOH, 4:1): δ = 14.1, 50.0, 61.9, 94.6, 128.0, 128.3, 128.4, 129.2, 129.3, 130.6, 131.4, 148.5, 149.7, 151.3, 155.9, 159.3, 171.5, 175.6. IR: 3447, 1660, 1616
    cm-¹. MS: m/z = 323 [M + H+]. Anal. Calcd for C18H14N2O4: C, 67.08; H, 4.38; N, 8.70. Found: C, 67.23; H, 4.37; N, 8.71.

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12

Compound 5: mp 215-216 ˚C (dec.). ¹H NMR (300 MHz, CD2Cl2): δ = 1.29 (t, J = 7.1 Hz, 3 H), 4.31 (q, J = 7.1 Hz, 2 H), 5.08 (s, 2 H), 7.69 (pseudo t, J = 7.5 Hz, 1 H), 7.82 (pseudo t, J = 7.2 Hz, 1 H), 7.93 (d, J = 7.9 Hz, 1 H), 8.36 (d, J = 7.2 Hz, 2 H). ¹³C NMR (75 MHz, CD2Cl2): δ = 14.6, 46.8, 62.5, 71.0, 128.6, 129.6, 130.0, 130.9, 131.2, 131.4, 132.2, 149.4, 150.1, 161.0, 161.5, 165.0. IR: 2142, 1736, 1717, 1655 cm-¹. MS: m/z = 325 [M + H+]. HRMS: m/z [M + H+] calcd for C16H13N4O4: 325.0937; found: 325.0952.

14

Compound 7: mp 169-170 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.14 (t, J = 7.1 Hz, 3 H), 4.17-4.29 (m, 3 H), 4.81-4.94 (m, 3 H), 5.01 (s, 2 H), 6.30 (d, J = 2.7 Hz, 1 H), 7.25-7.40 (m, 5 H), 7.58 (pseudo t, J = 8.0 Hz, 1 H), 7.75 (pseudo t,
J = 8.5 Hz, 1 H), 7.83 (d, J = 8.2 Hz, 1 H), 8.12-8.14 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.1, 48.4, 62.8, 73.1, 80.5, 81.1, 101.7, 127.5, 127.9, 128.0 (2 ×), 128.2, 128.5, 128.6, 129.7, 130.3, 130.8, 137.1, 137.9, 149.0, 152.4, 166.6, 168.6. IR: 3428, 1744, 1659 cm-¹. MS: m/z = 431 [M + H+]. Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.16; N, 6.51. Found: C, 69.48; H, 5.04; N, 6.41.

15

Compound 8a: mp 201-203 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.42 (q, J = 7.1 Hz, 2 H), 5.22 (s, 2 H), 5.35 (s, 2 H), 7.17 (s, 1 H), 7.30-7.50 (m, 5 H), 7.66 (pseudo t, J = 7.6 Hz, 1 H), 7.82 (pseudo t, J = 8.3 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.20 (d, J = 8.5 Hz, 1 H), 8.32 (s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.2, 49.2, 61.4, 71.1, 89.6, 109.6, 127.1, 128.1, 128.2, 128.31, 128.34, 128.7, 129.2, 129.6, 130.6, 131.2, 135.3, 147.8, 148.7, 152.0, 159.0, 164.9, 166.2. IR: 1718, 1651, 1602 cm-¹. MS: m/z = 413 [M + H+]. Anal. Calcd for C25H20N2O4: C, 72.81; H, 4.89; N, 6.80. Found: C, 72.70; H, 4.84; N, 6.59.

17

Compound 8c: mp 205-207 ˚C (dec.). ¹H NMR (300 MHz, CDCl3): δ = 1.42 (t, J = 7.2 Hz, 3 H), 4.46 (q, J = 7.2 Hz, 2 H), 5.28 (s, 2 H), 7.28 (s, 1 H), 7.70 (pseudo t, J = 8.1 Hz, 1 H), 7.85 (pseudo t, J = 8.4 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1 H), 8.41 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 13.7, 50.8, 62.5, 94.8, 115.7, 116.2, 120.5, 128.1, 128.5, 128.7, 129.5, 131.1, 131.6, 148.7, 149.0, 150.4, 156.9, 158.1, 161.6. IR: 1730, 1654, 1616
cm-¹. MS: m/z = 455 [M + H+]. Anal. Calcd for C19H13F3N2O6S: C, 50.23; H, 2.89; N, 6.17. Found: C, 50.11; H, 2.99; N, 6.10.

18

Compound 9: mp 261-263 ˚C (dec.). ¹H NMR (300 MHz, CDCl3): δ = 1.46 (t, J = 7.2 Hz, 3 H), 4.52 (q, J = 7.1 Hz, 2 H), 5.30 (s, 2 H), 7.20-7.70 (m, 9 H), 7.84 (pseudo t, J = 7.7 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 8.26 (d, J = 8.4 Hz, 1 H), 8.40 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.4, 49.9, 61.8, 97.1, 122.5, 122.9, 127.4, 127.9, 128.1, 128.2, 128.8, 129.0, 129.3, 129.5, 130.5, 131.0, 135.8, 136.8, 145.7, 147.1, 148.7, 152.4, 158.7, 166.3. IR: 1723, 1640, 1603
cm-¹. MS: m/z = 409 [M + H+]. Anal. Calcd for C26H20N2O3: C, 76.46; H, 4.94; N, 6.86. Found: C, 76.37; H, 4.99; N, 6.67.

19

Compound 10a: mp 261-263 ˚C (dec.). ¹H NMR (300 MHz, DMSO-d 6): δ = 4.74 (d, J = 5.1 Hz, 2 H), 4.99 (t, J = 5.1 Hz, 1 H), 5.25 (s, 2 H), 7.30-7.50 (m, 3 H), 7.60-7.90 (m, 7 H), 8.10-8.25 (m, 2 H), 8.67 (s, 1 H). ¹³C NMR (100 MHz, CDCl3-MeOH, 4:1): δ = 49.8, 55.9, 99.4, 122.5, 126.4, 127.1, 127.6, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 128.9, 130.5, 131.3, 135.8, 136.3, 143.5, 147.4, 148.2, 152.3, 161.9. IR: 3310, 1652, 1580, 1566 cm-¹. MS: m/z = 367 [M + H+]. HRMS: m/z [M + H+] calcd for C24H19N2O2: 367.1447; found: 367.1455.

20

Compound 10b: mp 247-248 ˚C (dec.). ¹H NMR (300 MHz, CDCl3): δ = 0.16 (s, 6 H), 0.93 (s, 9 H), 5.02 (s, 2 H), 5.27 (s, 2 H), 7.27-7.47 (m, 5 H), 7.59-7.73 (m, 4 H), 7.82 (pseudo t, J = 7.7 Hz, 1 H), 7.92 (d, J = 7.4 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 8.35 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = -5.1, 18.3, 26.0, 49.9, 56.6, 88.4, 98.4, 124.5, 127.2, 127.4, 127.5, 128.0, 128.1, 128.7, 128.8, 129.0, 129.6, 130.3, 130.9, 134.9, 136.6, 143.6, 147.7, 148.6, 153.2, 161.0. IR: 1656, 1651, 1593 cm-¹. MS: m/z = 481 [M + H+]. Anal. Calcd for C30H32N2O2Si: C, 74.87; H, 6.71; N, 5.83. Found: C, 74.87; H, 6.76; N, 5.89.

21

Compound 10c: mp 262-265 ˚C (dec.). ¹H NMR (300 MHz, CDCl3): δ = 0.14 (s, 6 H), 0.90 (s, 9 H), 5.15 (s, 2 H), 5.27 (s, 2 H), 7.63-7.66 (m, 2 H), 7.80 (pseudo t, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H), 8.20 (d, J = 8.5 Hz, 1 H), 8.34 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = -5.4, 18.3, 25.7, 50.3, 57.2, 97.4, 127.8, 127.9, 128.5, 129.8, 130.4, 130.9, 134.6, 143.5, 145.1, 149.0, 152.6, 160.7, 192.2. IR: 1697, 1651, 1600 cm-¹. MS: m/z = 407 [M + H+]. Anal. Calcd for C23H26N2O3Si: C, 67.95; H, 6.45; N, 6.90. Found: C, 68.12; H, 6.43; N, 6.89.

22

Compound 11: mp 200-201 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 0.12 (s, 6 H), 0.91 (s, 9 H), 1.22 (t, J = 7.2 Hz, 3 H), 2.91 (q, J = 7.2 Hz, 2 H), 4.91 (s, 2 H), 5.28 (s, 2 H), 7.16 (s, 1 H), 7.65 (pseudo t, J = 7.0 Hz, 1 H), 7.81 (pseudo t, J = 7.7 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 8.37 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = -5.6, 7.6, 18.6, 25.8, 36.2, 50.3, 58.5, 98.5, 127.7, 127.8, 127.9, 128.0, 128.6, 129.6, 130.4, 130.9, 144.5, 148.7, 150.3, 152.5, 159.9, 205.6. IR: 1708, 1649, 1596 cm-¹. MS: m/z = 435 [M + H+]. Anal. Calcd for C25H30N2O3Si: C, 69.10; H, 6.96; N, 6.45. Found: C, 69.19; H, 7.07; N, 6.55.

25

Compound (-)-12: mp 228-231 ˚C (dec.); [α]D ²² -18 (c 1.3, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 0.19 (s, 3 H), 0.20 (s, 3 H), 0.28 (s, 9 H), 0.93 (s, 9 H), 1.09 (t, J = 7.3 Hz, 3 H), 2.37 (q, J = 7.3 Hz, 2 H), 5.05 (ABq, J = 10.8 Hz, 1 H), 5.21 (ABq, J = 10.8 Hz, 1 H), 5.26 (s, 2 H), 7.58-7.66 (m, 2 H), 7.80 (pseudo t, J = 7.7 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1 H), 8.34 (s, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = -5.4, -5.3, 1.0, 8.5, 18.5, 25.9, 37.2, 50.2, 56.6, 76.0, 99.1, 120.0, 127.5, 127.7, 128.0, 128.7, 129.8, 130.3, 130.7, 144.4, 148.9, 151.2, 152.7, 161.2. IR: 1652, 1598 cm-¹. MS: m/z = 534 [M + H+]. HRMS: m/z [M + H+] calcd for C29H40N3O3Si2: 534.2608; found: 534.2616.

26

Dichloromethane was used as the solvent for this reaction instead of a more usual one (THF or EtCN) because of solubility problems. The reaction was performed at -20 ˚C for the same reason.

27

Analytical HPLC of 12 was performed on a Chiralpak® IA column (250 × 4.6 mm) using hexane-i-PrOH (9:1) as the eluent with a flow rate of 1.0 mL/min and UV monitoring at λ = 254 nm [t R (+)-12 = 10.2 min; t R (-)-12 = 7.5 min]. The separation was performed using the same chiral support (250 × 10 mm) and eluent with a flow rate of 5 mL/min.

28

(20S)-Camptothecin was purchased from Sigma-Aldrich.