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Synlett 2002(1): 0097-0099
DOI: 10.1055/s-2002-19359
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the ABC Ring System of Paclitaxel: Formation of the 8-Membered B Ring by Intramolecular Alkylation

Shigeru Miyamoto, Takayuki Doi, Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, JAPAN
Fax: +81(3)57342884; e-Mail: ttakashi@o.cc.titech.ac.jp;
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Publication History

Received 5 November 2001
Publication Date:
01 February 2007 (online)

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Abstract

The formation of the B ring of the ABC ring system of paclitaxel was accomplished by intramolecular alkylation of the protected cyanohydrin ether in the presence of the 7-alkoxy group on the C ring. A significant effect of the protective groups at the 1,2-positions was observed in this alkylation. Acyclic protection provided the desired compound 3c and 3d in moderate yields, whereas cyclic protection led to 3a in low yield.

Key words

paclitaxel - intramolecular alkylations - cyanohydrins - terpenoids

    References

  • 1 For a recent review, see: Kingston DGI. Chem. Commun.  2001,  867 
    CrossrefGoogle Scholar
  • 2 Takahashi T. Iwamoto H. Nagashima K. Okabe T. Doi T. Angew. Chem. Int. Ed. Engl.  1997,  36:  1319 
    Google Scholar
  • 3 Nicolaou KC. Yang Z. Sorensen EJ. Nakada M. J. Chem. Soc., Chem. Commun.  1993,  1024 
    CrossrefGoogle Scholar
  • 4 DiGrandi MJ. Jung DK. Krol WJ. Danishefsky SJ. J. Org. Chem.  1993,  58:  4989 
    Google Scholar
  • 5a Nakai K. Miyamoto S. Sasuga D. Doi T. Takahashi T. Tetrahedron Lett.  2001,  42:  7859 
    Google Scholar
  • 5b Nakai K. Kamoshita M. Doi T. Yamada H. Takahashi T. Tetrahedron Lett.  2001,  42:  7855 
    Google Scholar
  • 11a Cyclic protection at 1,2-diol has been reported in previous reports (AC → ABC or ACD → ABCD), McMurry coupling at the 9,10 positions (cyclic carbonate): Nicolaou KC. Yang Z. Liu JJ. Ueno H. Nantermet PG. Guy RK. Claiborne CF. Renaud J. Couladouros EA. Paulvannan K. Sorensen EJ. Nature  1994,  367:  630 
    CrossrefGoogle Scholar
  • 11b Intramolecular aldol reaction closing at the 9,10 positions (cyclic silyl ether): Morihira K. Hara R. Kawahara S. Nishimori T. Nakamura N. Kusama H. Kuwajima I. J. Am. Chem. Soc.  1998,  120:  12980 
    CrossrefGoogle Scholar
  • 11c Mizoroki-Heck reaction at the 10,11-positions (cyclic carbonate): Masters JJ. Link JT. Snyder LB. Young WB. Danishefsky SJ. Angew. Chem. Int. Ed. Engl.  1995,  34:  1723 
    CrossrefGoogle Scholar
6

Calculation of coupling constants by Carplus equation based on conformational analysis using MM2 (macromodel 6.0, Monte Carlo) suggested J 2,3 = 0.9 Hz for the desired isomer and 10.1 Hz for the other. The observed J value was <1.0 Hz in 8.

7

Spectral data in agreement with the reported structures were obtained for all compounds in this paper.

8

It was observed that deprotection of the TBS ether at the 7-position is faster than at the 10-position when a free hydroxy group is at the 2-position.

9

The procedure of the formation of the protected cyanohydrin 4 from TBS ether 5 is as follows: i) TBAF, THF, r.t., 79-82%, ii) TPAP, NMO, CH2Cl2, 0 °C, 82-97%; iii) TMSCN, DC-18-crown-6 KCN, r.t.; iv) 1 M HCl, THF, 0 °C; v) EVE, CSA, CH2Cl2, 0 °C, 3 steps 72%-quant.

10

Transition state calculation by PC spartan (BP86/PM3) roughly estimated that the cyclization of 3c is preferable to that of 3a by 6.5 kcal/mol difference.

12

Cyclic protection at the 7,9-positions was necessary to represent dibenzylation at the 1,2-diol at the moment.

13

Spectral data of 2d: 1H NMR (270 MHz, CDCl3) δ 7.0-7.4 (m, 15 H, Ph), 5.05 (d, J = 1.3 Hz, 1 H, C20), 4.92 (d, J = 2.0 Hz, 1 H, C20), 4.83 (d, J = 6.9 Hz, 1 H, PhCH2 or OCH2O), 4.78 (d, J = 12.2 Hz, 1 H, PhCH2 or OCH2O), 4.74 (d, J = 6.9 Hz, 1 H, PhCH2 or OCH2O), 4.74 (d, J = 11.9 Hz, 1 H, PhCH2 or OCH2O), 4.69 (d, J = 12.2 Hz, 1 H, PhCH2 or OCH2O), 4.65 (d, J = 11.6 Hz, 1 H, PhCH2 or OCH2O), 4.61 (d, J = 11.9 Hz, 1 H, PhCH2 or OCH2O), 4.59 (d, J = 11.6 Hz, 1 H, PhCH2 or OCH2O), 3.99 (d, J = 4.6 Hz, 1 H, C2), 3.35 (dd, J = 5.3, 10.9 Hz, 1 H, C7), 3.03 (d, J = 4.6 Hz, 1 H, C3), 2.73 (d, J = 14.8 Hz, 1 H, C9), 2.65 (d, J = 14.8 Hz, 1 H, C9), 1.9-2.5 (m, 8 H, C5, C6, C13, C14), 1.70 (s, 3 H, C18), 1.38 (s, 3 H, Me), 1.17 (s, 3 H, Me), 1.10 (s, 3 H, Me). 13C NMR (CDCl3, 67.8 MHz) δ 206.4, 145.5, 144.3, 140.6, 138.9, 137.9, 137.5, 128.4, 128.0, 127.8, 127.6, 126.8, 126.6, 126.4, 112.8, 94.4, 85.3, 83.3, 80.9, 75.0, 69.8, 67.4, 53.8, 50.5, 44.4, 41.7, 33.4, 31.2, 28.6, 27.1, 22.6, 22.1, 20.7, 17.6. IR(neat) 2961, 2927, 2855, 1727, 1646, 1497, 1454, 1378, 1261, 1216. 1099, 1038 cm-1. MS (ESI-TOF) [C42H50O5 + H]+, calc. 635.3736, found 635.3736.