New Route to Natural Camptothecin
through Isomünchnone Cycloaddition

Alice Kanazawa; Mauro N. Muniz; Barbora Baumlová; Natalie Ljungdahl; Andrew E. Greene

doi:10.1055/s-2008-1078205

LETTER

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;

Abstract

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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

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References

References and Notes

1 Wall ME. Wani MC. Cook CE. Palmer KH. McPhail AT. Sim GA. J. Am. Chem. Soc. 1966, 88: 3888

2 Hsiang Y.-H. Hertzberg R. Hecht S. Liu L. J. Biol. Chem. 1985, 260: 14873

3 Saltz LB. Cox JV. Blanke C. Rosen LS. Fehrenbacher L. Moore MJ. Maroun JA. Ackland SP. Locker PK. Pirotta N. Elfring GL. Miller LL.
N. Engl. J. Med. 2000, 343: 905

4 Gore M. ten Bokkel Huinink W. Carmichael J. Gordon A. Davidson N. Coleman R. Spaczynski M. Heron JF. Bolis G. Malmstrom H. Malfetano J. Scarabelli C. Vennin P. Ross G. Fields SZ. J. Clin. Oncol. 2001, 19: 1893

5a Butler MS. Nat. Prod. Rep. 2008, 25: 475

5b Butler MS. Nat. Prod. Rep. 2005, 22: 162

5c Cragg GM. Newman DJ. J. Nat. Prod. 2004, 67: 332

For reviews on camptothecin and its derivatives, see:

6a Cuendet M. Pezzuto JM. In Modern Alkaloids: Structure, Isolation, Synthesis and Biology Fattorusso E. Taglialatela-Scafati O. Wiley-VCH; Weinheim: 2008. Chap. 2. p.29-33

6b Lorence A. Nessler CI. Phytochemistry 2004, 65: 2735

6c Thomas CJ. Rahier NJ. Hecht SM. Bioorg. Med. Chem. 2004, 12: 1585

6d Pizzolato JF. Saltz LB. Lancet 2003, 361: 2235

6e Du W. Tetrahedron 2003, 59: 8649

6f Lansiaux A. Bailly C. Bull. Cancer 2003, 90: 239

6g Torck M. Pinkas M. J. Pharm. Belg. 1996, 51: 200

6h Camptothecins: New Anticancer Agents Potmesil M. Pinedo H. CRC Press; Boca Raton: 1995.

6i Sawada S. Yokokura T. Miyasaka T. Curr. Pharm. Des. 1995, 1: 113

6j Hutchinson CR. Tetrahedron 1981, 37: 1047

For recent syntheses of (20S)-camptothecin, see:

7a Zhou H.-B. Liu G.-S. Yao Z.-J. Org. Lett. 2007, 9: 2003

7b Chavan SP. Pathak AB. Kalkote UR. Synlett 2007, 2635

7c Peters R. Althaus M. Nagy A.-L. Org. Biomol. Chem. 2006, 4: 498

7d Chavan SP. Venkatraman MS. ARKIVOC 2005, (iii): 165

8a Raolji GB. Garçon S. Greene AE. Kanazawa A. Angew. Chem. Int. Ed. 2003, 42: 5059

8b Anderson RJ. Raolji GB. Kanazawa A. Greene AE. Org. Lett. 2005, 7: 2989

8c Babjak M. Kanazawa A. Andersen RJ. Greene AE. Org. Biomol. Chem. 2006, 4: 407

8d Tang C.-J. Babjak M. Anderson RJ. Greene AE. Kanazawa A. Org. Biomol. Chem. 2006, 4: 3557

9a Danishefsky S. Bryson TA. Puthenpurayil J. J. Org. Chem. 1975, 40: 796

9b Boger DL. Hong J. J. Am. Chem. Soc. 1998, 120: 1218

For reviews on isomünchnone cycloadditions, see:

10a McMills MC. Wright D. In The Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products Padwa A. Pearson WH. John Wiley and Sons; New York: 2002. p.253-314

10b Mehta G. Muthusamy S. Tetrahedron 2002, 58: 9477

10c Padwa A. Top. Curr. Chem. 1997, 189: 121

10d Padwa A. Weingarten MD. Chem. Rev. 1996, 96: 223

10e Osterhout MH. Nadler WR. Padwa A. Synthesis 1994, 123

11a Marino JP. Osterhout MH. Price AT. Sheehan SM. Padwa A. Tetrahedron Lett. 1994, 35: 849

11b For the use of this reagent for similar cyclizations, see: Padwa A. Prein M. J. Org. Chem. 1997, 62: 6842

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.

13 Guy RK. DiPietro RA. Synth. Commun. 1992, 22: 687

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.

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.

16b For an alternative synthesis, see: Liao TK. Nyberg WH. Cheng CC. J. Heterocycl. Chem. 1971, 8: 373

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.

23 Warner CR. Walsh EJ. Smith RF. J. Chem. Soc. 1962, 1232

24a Yabu K. Masumoto S. Yamasaki S. Hamashima Y. Kanai M. Du W. Curran DP. Shibasaki M. J. Am. Chem. Soc. 2001, 123: 9908

24b Yabu K. Masumoto S. Kanai M. Shibasaki M. Heterocycles 2003, 59: 369

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.