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Synthesis 2008(23): 3801-3804  
DOI: 10.1055/s-0028-1087226
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Nonclassical Stereoselective Semi-Synthesis of Drospirenone via Cross-Metathesis Reaction

Marco Bandini*a, Michele Contentoa, Andrea Garellia, Magda Monaria, Alessandra Tolomellia, Achille Umani-Ronchi*a, Erika Andriolob, Mauro Montorsib
a Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax: +39(51)2099456; e-Mail: marco.bandini@unibo.it; e-Mail: achille.umanironchi@unibo.it;
b NEWCHEM S.p.A., via Roveggia 47, 37136 Verona, Italy
Further Information

Publication History

Received 29 July 2008
Publication Date:
06 November 2008 (online)

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Abstract

A new synthetic approach for the construction of the spirolactone moiety of the progestin drospirenone is presented. A highly efficient cross-metathesis reaction catalyzed by Grubbs-Hoveyda second-generation catalyst (6 mol%) is employed as the key step for the introduction of the ester moiety on to the vinyl group at C17. No protecting groups are required and harmful heavy-metal-based oxidants are not used and this means that this route constitutes a valuable synthetic alternative to existing approaches.

Key words

cross-metathesis - drospirenone - stereoselection - steroids - synthesis

    References

  • 1a Elger W. Beier S. Pollow K. Garfield R. Shi SQ. Hillisch A. Steroids  2003,  68:  891 
    Google Scholar
  • 1b Wiechert R. In Analogue-based Drug Discovery   Fischer J. Ganellin CR. Wiley-VCH; Berlin: 2006.  Chap. 20. p.395 
    Google Scholar
  • 1c Costantino F, Lenna R, and Piuri S. inventors; WO  2006,061,309. 
  • 1d Seilz C, and Seba H. inventors; WO  2007,009,821. 
  • 2 Gálik G, Horváth J, Sörös B, Mahó S, Tuba Z, and Balogh G. inventors; WO  2006,059,168. 
  • 3a Sam KM. Auger S. Luu-The V. Poirier D. J. Med. Chem.  1995,  38:  4518 
    Google Scholar
  • 3b Bittler D. Hofmeister H. Laurent H. Nickisch K. Nickolson R. Petzoldt K. Wiechert R. Angew. Chem., Int. Ed. Engl.  1982,  21:  696 ; Angew. Chem. 1982, 94, 718
    Google Scholar
  • 3c Mohr J.-Y, and Nickisch K. inventors; US  6,933,395. 
  • 4 Waldemar A. Chantu RS.-M. Pralhad AG. Chem. Rev.  2001,  101:  3499 
    CrossrefPubMedGoogle Scholar
  • 5 Crabtree RH. Science  2007,  318:  756 
    CrossrefPubMedGoogle Scholar
  • 6a Handbook of Metathesis   Grubbs RH. Wiley-VCH; Weinheim: 2003. 
    Google Scholar
  • 6b Schrock RR. Hoveyda AH. Angew. Chem. Int. Ed.  2003,  42:  4592 
    Google Scholar
  • 6c Connon SJ. Blechert S. Angew. Chem. Int. Ed.  2003,  42:  1900 
    Google Scholar
  • 6d Astruc D. New J. Chem.  2005,  29:  42 
    Google Scholar
  • 6e Clavier H. Grela K. Kirschning A. Mauduit M. Nolan SP. Angew. Chem. Int. Ed.  2007,  46:  6786 
    Google Scholar
  • 6f Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4490 
    Google Scholar
  • 6g Schrodi Y. Pedersen RL. Aldrichimica Acta  2007,  2:  45 ; and references therein
    Google Scholar
  • 7 Hoveyda AH. Gillingham DG. Van Veldhuizen JJ. Kataoka O. Garber SB. Kingsbury JS. Harrity JPA. Org. Biomol. Chem.  2004,  2:  8 
    CrossrefGoogle Scholar
  • 8 Nickisch K. Bittler D. Laurent H. Wiechert R. Tetrahedron Lett.  1986,  27:  5463 
    CrossrefGoogle Scholar