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Synthesis 2010(12): 2039-2042  
DOI: 10.1055/s-0029-1218771
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical and Convenient Synthesis of the Protease Inhibitor Epibestatin

Anja Richter, Christian Hedberg*
Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Fax: +49(231)1332498; e-Mail: Christian.Hedberg@mpi-dortmund.mpg.de;
Further Information

Publication History

Received 14 January 2010
Publication Date:
05 May 2010 (online)

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Abstract

A convenient synthesis of the protease inhibitor epibestatin, a useful component in protease inhibition cocktails for use in proteomics research, is described. The synthesis sequence consists of seven steps, starting from phenylacetaldehyde, yielding enantiopure epibestatin in 8% overall yield. A regioselective Mitsunobu­ transformation of a diol is the key step in the sequence.

Key words

amino acids - asymmetric synthesis - osmium - dihydroxylation - Mitsunobu reaction

    References

  • 1a Aprotenine is also known as Trasylol (Bayer). For a recent reference, see: Diniz CM. Xavier LP. Santoro MM. Figueiredo AFS. Curr. Enzyme Inhib.  2009,  5:  163 
    Google Scholar
  • 1b Aoyagi T. Takeuchi T. Matsuzaki A. Kawamura K. Kondo S. Hamada M. Maeda K. Umezawa H. J. Antibiot.  1969,  22:  283 
    Google Scholar
  • 1c Umezawa H. Aoyagi T. Suda H. Hamada M. Takeuchi T. J. Antibiot.  1976,  29:  97 
    Google Scholar
  • 1d Umezawa H. Aoyagi T. Morishima H. Matsuzaki M. Hamada M. Takeuchi T. J. Antibiot.  1970,  23:  259 
    Google Scholar
  • 1e

    For general application information, see: Sigma technical bulletin on protease inhibition cocktails INHIB1.

  • 1f For information on epibestatin as peptidase inhibitor, see: Rich DH. Moon BJ. Harbeson S. J. Med. Chem.  1984,  27:  417 
    Google Scholar
  • 1g For the original description of epibestatin, see: Nishizawa R. Saino T. J. Med. Chem.  1977,  20:  510 
    Google Scholar
  • 2a

    Epibestatin is available in very limited quantities from Sigma, ordering number E0381.

  • 2b Lee JH. Kim JH. Lee BW. Seo WD. Yang MS. Park KH. Bull. Korean Chem. Soc.  2006,  27:  1211 
    Google Scholar
  • 3 Ko S. J. Org. Chem.  2002,  67:  2689 
    CrossrefPubMedGoogle Scholar
  • 4a Wadsworth W. Emmons W. J. Am. Chem. Soc.  1961,  83:  1733 
    Google Scholar
  • 4b Claridge TDW. Davies SG. Lee JA. Nicholson RL. Roberts PM. Russell AJ. Smith AD. Toms SM. Org. Lett.  2008,  10:  5437 
    Google Scholar
  • 5a Jacobsen E. Marko I. Mungall W. Schroder G. Sharpless K. J. Am. Chem. Soc.  1988,  110:  1968 
    Google Scholar
  • 5b Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong KS. Kwong HL. Morikawa K. Wang ZM. Xu DQ. Zhang XL. J. Org. Chem.  1992,  57:  2768 
    Google Scholar
  • 6 Swamy KCK. Kumar NNB. Balaraman E. Kumar KVPP. Chem. Rev.  2009,  109:  2551 
    CrossrefGoogle Scholar
  • 8 Compound 9 and its enantiomer have been reported previously in literature. For a recent synthesis, see: Masaya K. Matsumoto J. Yukifumi N. Tetrahedron: Asymmetry  2002,  13:  1201 
    CrossrefGoogle Scholar
  • 9 Montalbetti C. Falque V. Tetrahedron  2005,  61:  10827 
    CrossrefGoogle Scholar
7

The structural verification of 5 was based on the characteristic 2D NMR cross peaks (COSY, HMBC) after conversion of the azide functionality into the corresponding N-acetamide derivative.