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)

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.

    References

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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.