Download PDF
Synlett 2003(13): 2033-2036  
DOI: 10.1055/s-2003-42034
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Synthesis of 2,3-Dehydro-3-desoxy-10-oxa Epothilone D

Delphine Quintarda, Philippe Bertranda, Sophie Viellea, Eric Raimbaudb, Pierre Renardc, Bruno Pfeifferc, Jean-Pierre Gesson*a
a UMR 6514, Université de Poitiers et CNRS, 40, Avenue du Recteur Pineau, 86022 Poitiers, France
Fax: +33(5)49453501; e-Mail: jean-pierre.gesson@univ-poitiers.fr;
b Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France
c ADIR, 1 rue Carle Hébert, 92415 Courbevoie, France
Further Information

Publication History

Received 16 July 2003
Publication Date:
08 October 2003 (online)

    Permissions and Reprints All articles of this category

Abstract

A short and convergent synthesis of a 10-oxa epothilone analog is based on aldolisation of a β-methallyloxy aldehyde derived from methyl 3-hydroxy-2S-methyl propionate followed by ring-closing metathesis

Key words

epothilone - aldolisation - ring-closing metathesis - macrocycle

    References

  • 1 Höfle G. Bedorf N. Steinemetz H. Schomburg D. Gerth K. Reichenbach H. Angew. Chem., Int. Ed. Engl.  1996,  35:  1567 
    Google Scholar
  • 2a Bollag DM. McQueney PA. Zhu J. Hensens O. Koupal L. Liesch J. Goetz M. Lazarides E. Woods CM. Cancer Res.  1995,  55:  2325 
    CrossrefGoogle Scholar
  • 2b Bollag DM. Exp. Opin. Invest. Drugs  1997,  6:  867 
    CrossrefGoogle Scholar
  • 2c Kowalski RJ. Giannakakou P. Hamel E. J. Biol. Chem.  1997,  272:  2534 
    CrossrefGoogle Scholar
  • 3a Danishefsky SJ. Harris CR. J. Org. Chem.  1999,  64:  8434 
    Google Scholar
  • 3b Nicolaou KC. Roschangar F. Vourloumis D. Angew. Chem. Int. Ed.  1998,  37:  2014 
    Google Scholar
  • 3c Mulzer J. Chem. Mon.  2000,  131:  205 
    Google Scholar
  • 4 Chou TC. O’Connor OA. Tong WP. Guan Y. Zhang Z.-G. Stachel SJ. Lee C. Danishefsky SJ. Proc. Natl. Acad. Sci. U.S.A.  2001,  98:  8113 
    CrossrefGoogle Scholar
  • 5 Lee BC. Wu Z. Zhang XG. Chappell MD. Stachel SJ. Chou TC. Guan Y. Danishefsky SJ. J. Am. Chem. Soc.  2001,  123:  5249 
    CrossrefGoogle Scholar
  • 6 Nicolaou KC. Scapelli R. Bollbuck B. Werschkun B. Perreira MMA. Wartmann M. Altmann K.-H. Zaharevitz D. Gussio R. Giannakakou P. Chem. Biol.  2000,  7:  593 
    CrossrefGoogle Scholar
  • 7a Chou TC. Zhang XG. Harris CR. Kuduk SD. Balog A. Savin KA. Bertino JR. Danishefsky SJ. Proc. Natl. Acad. Sci. U.S.A.  1998,  96:  9642 
    CrossrefGoogle Scholar
  • 7b Schinzer D. Altmann KH. Stuhlmann F. Bauer A. Wartmn M. ChemBioChem  2000,  1:  67 
    CrossrefGoogle Scholar
  • 8 Hardt IH. Steinmetz H. Gerth K. Sasse F. Richenbach H. Höfle G. J. Nat. Prod.  2001,  64:  847 
    CrossrefGoogle Scholar
  • 9 Biswas K. Lin H. Njardarson JT. Chappell MD. Chou T.-C. Guan Y. Tong WP. He L. Horwitz SB. Danishefsky SJ. J. Am. Chem. Soc.  2002,  124:  9825 
    CrossrefGoogle Scholar
  • 10a White JD. Carter RG. Sundermann KF. J. Org. Chem.  1999,  64:  684 
    CrossrefGoogle Scholar
  • 10b White JD. Sundermann KF. Carter RG. Org. Lett.  1999,  1:  1431 
    CrossrefGoogle Scholar
  • 10c White JD. Carter RG. Sundermann KF. Wartmann M. J. Am. Chem. Soc.  2001,  123:  5407 
    CrossrefGoogle Scholar
  • 11 Ermolenko MS. Potier P. Tetrahedron Lett.  2002,  43:  2895 
    CrossrefGoogle Scholar
  • 12a EpoA series: Nicolaou KC. Sarabia F. Ninkovic S. Finlay MRV. Boddy CNC. Angew. Chem. Int. Ed.  1998,  37:  81 
    CrossrefGoogle Scholar
  • 12b EpoB series: Rivkin A. Njardarson JT. Biswas K. Chou T.-C. Danishefsky SJ. J. Org. Chem.  2002,  67:  7737 
    CrossrefGoogle Scholar
  • 13 Taylor RE. Zajicek J. J. Org. Chem.  1999,  64:  7224 
    CrossrefGoogle Scholar
  • 14 Taylor RE. Chen Y. Beatty A. J. Am. Chem. Soc.  2003,  125:  26 
    CrossrefGoogle Scholar
  • 15 Schwede W., Klar U., Skuballa W., Buchmann B., Hoffmann J., Lichtner R.; Ger. Offen. DE 10020899, 2001
  • 16 Buchmann B, Klar U, Skuballa W, Schwede W, Hoffmann J, and Lichtner R. inventors; Ger. Offen. DE  10020517. 
  • 17 Structures discussed in this study were modeled using standard bond lengths and angles, using the molecular modeling software SYBYL® 6.41, Tripos Inc., 1699 South Hanley Road, Saint-Louis, Missouri 63144, USA, running on an Indigo2 R4400 Extreme Silicon Graphics workstation. Geometries and energies were obtained by AM1 semi-empirical calculations with the Gaussian92® package (Gaussian 92/DFT, Revision F.3, M. J. Frisch, G. W. Trucks, H. B. Schlegel, P. M. W. Gill, B. G. Johnson, M. W. Wong, J. B. Foresman, M. A. Robb, M. Head-Gordon, E. S. Replogle, R. Gomperts, J. L. Andres, K. Raghavachari, J. S. Binkley, C. Gonzalez, R. L. Martin, D. J. Fox, D. J. Defrees, J. Baker, J. J. P. Stewart, and J. A. Pople, Gaussian, Inc., Pittsburgh PA, 1993): Dewar MJS. Zoebish EG. Healy EF. Stewart JP. J. Am. Chem. Soc.  1985,  107:  3902 
    CrossrefGoogle Scholar
  • 18 Meng D. Bertinato P. Balog A. Su D.-S. Kamenecka T. Sorensen EJ. Danishefsky SJ. J. Am. Chem. Soc.  1997,  119:  10073 
    CrossrefGoogle Scholar
  • 19 Nicolaou KC. Ninkovic S. Sarabia F. Vourloumis D. He Y. Vallberg H. Finlay MRV. Yang Z. J. Am. Chem. Soc.  1997,  119:  7974 
    CrossrefGoogle Scholar
  • 20 Dirat O. Kouklovsky C. Langlois Y. Lesot P. Courtieu J. Tetrahedron: Asymmetry  1999,  10:  3197 
    CrossrefGoogle Scholar
  • 21 Nicolaou KC. He Y. Vourloumis D. Vallberg H. Roschangar F. Sarabia F. Ninkovic S. Yang Z. Trujillo JI. J. Am. Chem. Soc.  1997,  119:  7960 
    CrossrefGoogle Scholar
  • 22a Winckler JD. Holland JM. Kasparec J. Axelsen PH. Tetrahedron  1999,  55:  8199 
    CrossrefGoogle Scholar
  • 22b Chou T.-C. Zhang X.-G. Harris CR. Kuduk SK. Balog A. Savin KA. Bertino JR. Danishefsky SJ. Proc. Natl. Acad. Sci. U.S.A.  1998,  95:  15798 
    CrossrefGoogle Scholar
  • 23 Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 
    Google Scholar
  • 25a May SA. Grieco P. Chem. Commun.  1998,  1597 
    Google Scholar
  • 25b Schinzer D. Bauer A. Schieber J. Chem.-Eur. J.  1999,  5:  2492 
    Google Scholar
  • 26 Harris CR. Kuduk SD. Balog A. Savin K. Glunz PW. Danishefsky SJ. J. Am. Chem. Soc.  1999,  121:  7050 
    CrossrefGoogle Scholar
24

All new compounds have been characterized by 1H and 13C NMR, and HRMS. Selected data for E- 3b: oil, [α]D +82 (c 0., CHCl3). 1H NMR (300 MHz, CDCl3): δ (ppm) = 7.00 (s, 1 H), 6.77 (d, J = 15.8 Hz, 1 H), 6.64 (s, 1 H), 6.09 (d, J = 15.8 Hz, 1 H), 5.62 (d, J = 10.5 Hz, 1 H), 5.48 (dd, J = 10.7 and 5.0 Hz, 1 H), 4.18 (d, J = 12.2 Hz, 1 H), 3.70 (ddd, J = 9.5, 2.4 and 1.9 Hz, 1 H), 3.70 (m, 1 H), 3.56 (d, J = 12.2 Hz, 1 H), 3.48 (m, 1 H), 2.97 (qd, J = 6.7 and 9.5 Hz, 1 H), 2.90 (dd, J = 9.8 and 2.4 Hz, 1 H), 2.72 (s, 3 H), 2.70 (dd, J = 10.5 and 11.6 Hz, 1 H), 2.40 (dd, J = 3.4 and 11.6 Hz, 1 H), 2.16 (s, 3 H), 1.70 (s, 3 H), 1.40 (s, 3 H), 1.28 (d, J = 6.7 Hz, 3 H), 1.28 (s, 3 H) and 1.18 (d, J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ (ppm) 213.7, 164.9, 164.8, 152.3, 151.4, 137.5, 135.1, 125.6, 122.4, 120.0, 116.3, 78.4, 77.4, 76.3, 70.1, 52.5, 46.3, 34.9, 29.6, 23.2, 22.8, 19.2, 17.5, 16.7, 15.5, 13.2. HRMS: [M + Na]+ m/z calcd 476.2471. Found: 476.2470. Z- 3b: oil, [α]D -44 (c 0.2, CHCl3). 1H NMR (CDCl3): δ (ppm) = 7.12 (d, J = 15.8 Hz, 1 H), 6.98 (s, 1 H), 6.58 (s, 1 H), 6.00 (d, J = 15.8 Hz, 1 H), 5.47 (m, 2 H), 3.82 (d, J = 12.1 Hz, 1 H), 3.78 (d, J = 12.1 Hz, 1 H), 3.74 (dd, J = 8.9 and 2.8 Hz, 1 H), 3.72 (dd, J = 7.1 and 2.7 Hz, 1 H), 3.29 (dd, J = 9.1 and 4.1 Hz, 1 H), 3.10 (qd, J = 6.9 and 2.7 Hz, 1 H), 2.95 (broad s, 1 H), 2.71 (s, 3 H), 2.51 (dd, J = 6.9 and 6.8 Hz, 2 H), 2.16 (s, 3 H), 1.74 (m, 1 H), 1.60 (s, 3 H), 1.37 (s, 3 H), 1.27 (s, 3 H), 1.08 (d, J = 6.9 Hz, 3 H) and 0.94 (d, J = 7.2 Hz, 3 H). 13C NMR (CDCl3): δ (ppm) = 214.8, 165.2, 164.7, 152.4, 150.7, 137.8, 134.1, 122.1, 120.1, 119.6 116.1, 78.0, 75.3, 72.1, 72.0, 51.2, 43.2, 36.9, 31.6, 24.0, 22.5, 19.2, 15.4, 14.3 (2 ×), 10.6. HRMS: [M + Na]+ m/z calcd 476.2471. Found: 476.2474.