Synthesis of 7,9-nitrogen-substituted paclitaxel derivatives

Tetrahedron Letters

Volumn 37, Issue 43, 1996, Pages 7837-7840

  Appendino, Giovanni ^a   Jakupovic, Jasmin ^b   Varese, Marcella ^a   Belloro, Emanuela ^a   Danieli, Bruno ^c   Bombardelli, Ezio ^d  

^a UNIVERSITY OF TURIN   (Italy)

^b TECHNISCHE UNIVERSITÄT BERLIN   (Germany)

^c Dipto di Chim Organ e Industriale   (Italy)

^d INDENA S P A   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; TAXANE DERIVATIVE;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS;

EID: 16044371986     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)01744-3     Document Type: Article

References (20)

1. 1. Part XXVII in the series: The Chemistry and Occurrence of Taxane Derivatives. For part XXVI, see: Torregiani, E.; Barboni, L.; Rafaiani, G.; Lambertucci, C.; Appendino, G. Gazz. Chim. Ital. (in press)
2. 2. Chen, S.-H.; Farina, V. "Paclitaxel (Taxol®) Chemistry and Structure-Activity Relationships" in The Chemistry and Pharmacology of Taxol® and its Derivatives F:arina, V. Ed.; Elsevier, 1995, pp. 165-253.
3. 3. Bouchard, H.; Pulicani, J.-P.; Vuilhorgne, M.; Bourzat, J.-D.; Commerco̧n, A. Tetrahedron Lett. 1994, 9713-9716.
4. 4. Chen, S.-H.; Huang, S.; Wei, J.; Farina, V. J. Org. Chem. 1993, 58, 4520-4521.
5. 5. Johnson, R.A.; Nidy, E.G.; Dobrowolski, P.J.; Gebhard, I.; Qualls, S.J.; Wicnienski, N.A.; Kelly, R.C. Tetrahedron Lett. 1994, 7893-7896.
6. 6. Menichincheri, M.; Botta, M.; Ceccarelli, W.; Ciomei, M.; Corelli, F.; D'Anello, M.; Fusar-Bassini, D.; Mongelli, N.; Pesenti, E.; Pinciroli, V.; Tafi, A.; Vanotti, E. Med. Chem. Res. 1995, 5, 534-555.
7. 7. Miller, R.W., Powell, R.G.; Smith Jr., C.R.; Arnold, E.; Clardy, J. J. Org. Chem. 1981, 46, 1469-1474.
8. 8. Appendino, G.; Jakupovic, J.; Cravotto, G.; Enriù, R.; Varese, M.; Bombardelli, E. Tetrahedron Lett. 1995, 3233-3236.
9. 9. Appendino, G.; Jakupovic, J.; Varese, M.; Bombardelli, E. Tetrahedron Lett. 1996, 727-730.
10. 3, TMS as reference, 60° C): δ 7.93 (br d, J=7.7 Hz, Bz), 7.82 (d, J=9.5 Hz, H-7), 7.51 (t, J=7.7 Hz, Bz), ca 7.40 (m, Bnz), 7.33 (br t, J=7.7 Hz, Bz), 6.32 (s, 9-OH), 6.20 (d, J=17,0 Hz, H-5), 6.05 (dd, J=17.0, 9.5 Hz, H-6), 5.55 (d, J=8.0 Hz, H-2), 5.12 (d, J=12.0 Hz, H-20a), 5.10 (d, J=12.0Hz, H-20b), 4.92 (m, H-13), 4.33 (d, J=8.0 Hz, H-3), 4.06 (d, J=11.5 Hz, Bnz), 3.96 (d, J=11.5 Hz, Bnz), 2.60 (dd, J=16,0, 6.0 Hz, H-14a), 2.48 (dd, J=16.0, 6.5 Hz, H-14b), 2.16 (s, Ac), 1.92 (s, H-19), 1.91 (d, J=1.5 Hz, H-18), 1.14, 1.06 (s, H-16 and H-17).
11. 11. a) Magri, N.F.; Kingston, D.G.I. J. Org. Chem. 1986, 51, 797-802.
12. b) Appendino, G.; Fenoglio, I.; Cravotto, G.; Varese, M.; Gariboldi, P.; Gabetta, B. Gazz. Chim. Ital. 1994, 124, 253-257.
13. 13C NMR spectra were assigned with the aid of NOE-inspection and the HMBC spectra.
14. 2 The importance of pyrazoline ring closure is highlighted by the observation that no reaction occurred when 1 was treated with tosylhydrazine, phenylhydrazine or N,N-dimethylhydrazine.
15. 14. Deprotection of the pyrazoline nitrogen could be effected with wet silica gel (EtOAc, RT, 12 h, 92%).
16. 15. Prepared by reaction of the 10-acetates with hydrazine in ethanol (see reference 5).
17. 16. Ojima, L; Duclos, O.; Kuduk, S.D.; Sun, C.-M.; Slater, J.C.; Lavelle, F.; Veith, J.M.; Bernacki, R.J. Bioorg. Med. Chem. Lett. 1994, 4, 2631-2634.
18. 3, TMS as reference): δ 8.13 (br d, J=8.1 Hz, Bz), 7.62 (br t, J=8.1 Hz, Bz), 7.49 (br t, J=8.1 Hz, Bz), 6.18 (br d, J=2.5 Hz, 7-NH), 6.11 (d, J=6.0 Hz, H-2), 6.01 (br dd, J=9.0, 7.5 Hz, H-13), 5.01 (br d, J=4.0 Hz, H-5), 4.68 (br d, J=10 Hz, Boc-NH), 4.43 (dd, J=13.0, 4.0 Hz, H-7), 4.37 (br s, H-20a + H-20b), 4.24 (dd, J=4.5, 2.0 Hz, H-2'), 4.15 (m, H-3'), 3.76 (br s, 2'-OH), 3.59 (d, J=6.0 Hz, H-3), 2.51 (dd, J=15.0, 9.0 Hz, H-14a), 2.34 (s, Ac), 2.16 (dd, J=15.0, 7.0 Hz, H-14b), 2.10 (ddd, J=14.0, 13.0, 1.5 Hz, H-6a), 1.84 (ddd, J=14.0, 4.0, 4.0 Hz, H-6b), 1.80-1.70 (m H-5'), 1.66 (d, J=1.5 Hz, H-18), 1.65-1.55 (m, H-4'a), 1.45-1.35 (m, H-4'b), 1.39 (s, Boc), 1.37, 1.35, 1.32 (s, H-16, H-17, H-19), 0.97 (d, J=7.0 Hz, 5'-Me), 0.96 (d, J=7.0 Hz, 5'-Me).
19. 18. The lower yield compared to 1 was due to the hydrolytic loss of the C-13 side chain, with formation of variable amounts of 4a,b.
20. 50 values, measured on MDA-MB231 cells, were: 1.4, 7.6 and 2.6 nM, respectively. Under these conditions, the corresponding values for docetaxel, paclitaxel and N-debenzoyl-N-Boc-3'-dephenyl-3'-isobutyltaxo1 were 0.8, 2.4 and 4.7 nM, respectively.