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Synlett 2004(8): 1428-1430  
DOI: 10.1055/s-2004-825625
LETTER
© Georg Thieme Verlag Stuttgart · New York

Two Concise Syntheses of Cialis via the N-Acyliminium Pictet-Spengler Reaction

Jefferson D. Revell, Natarajan Srinivasan, A. Ganesan*
Combinatorial Centre of Excellence, School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Fax: +44(2380)596805; e-Mail: ganesan@soton.ac.uk;
Further Information

Publication History

Received 8 March 2004
Publication Date:
08 June 2004 (online)

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Abstract

The imine derived from piperonal and d-tryptophan ­methyl ester underwent N-acyliminium Pictet-Spengler reaction with either Fmoc-sarcosyl chloride or chloroacetyl chloride. The products were readily converted to the drug Cialis.

Key words

imine acylations - Pictet-Spengler reactions - indoles - diketopiperazines - drugs

    References

  • 1 Stamford AW. In Annual Reports in Medicinal Chemistry   Vol. 37:  Doherty AM. Academic; San Diego: 2002.  p.53 
    Google Scholar
  • 2 Daugan AC.-M, and Gellibert F. inventors; US patent  6143746. 
  • For reviews, see:
  • 3a Whaley WM. Govindachari TR. Org. React.  1951,  6:  151 
    Google Scholar
  • 3b Cox ED. Cook JM. Chem. Rev.  1995,  95:  1797 
    Google Scholar
  • 3c Nielsen TE. Diness F. Meldal M. Curr. Opin. Drug Discovery  2003,  6:  801 
    Google Scholar
  • 4 Srinivasan N. Ganesan A. Chem. Commun.  2003,  916 
    CrossrefGoogle Scholar
  • 5 Wang H. Ganesan A. Tetrahedron Lett.  1997,  38:  4327 
    CrossrefGoogle Scholar
  • 6 Wang H. Ganesan A. Org. Lett.  1999,  1:  1647 
    CrossrefGoogle Scholar
  • 7 Wang H. Ganesan A. J. Org. Chem.  2000,  65:  4685 
    CrossrefGoogle Scholar
  • 8 Bonnet D., Ganesan A.; J. Comb. Chem.; 2002, 4: 546
  • 9 Sivanandaiah KM. Babu VVS. Shankaramma SC. Int. J. Pept. Protein Res.  1994,  44:  24 
    Google Scholar
  • 10 Chan TH. Villeneuve GB. Tetrahedron Lett.  1997,  38:  6489 
    CrossrefGoogle Scholar
  • 11 Ungemach F. Soerens D. Weber R. DiPierro M. Campos O. Mokry P. Cook JM. Silverton JV. J. Am. Chem. Soc.  1980,  102:  6976 
    CrossrefGoogle Scholar
  • 12 Wang H. Usui T. Osada H. Ganesan A. J. Med. Chem.  2000,  43:  1577 
    CrossrefGoogle Scholar

Note added in proof

The large-scale process for Lilly’s synthesis of Cialis has now appeared in the patent literature (Chelius, E. C.; Martinelli, M. J.; Pawlak, J. M.; Orme, M. W.; Doecke, C. W.; WO patent 011463, 2004). By carrying out the acid-catalyzed Pictet-Spengler reaction in an appropriate solvent where the cis diastereomer 1 is less soluble than the trans diastereomer 2, a nearly quantitative yield of 1 is ­elegantly obtained.