Advertisement

Practical Synthesis of Tamiflu and Beyond

  • Motomu Kanai
Conference paper

Abstract

Influenza viruses pose a serious threat to world public health. In particular, the currently spreading avian H5N1 virus strain is a great menace because of its high lethality rate, and strains of this virus have already spread to many countries in Asia, Europe, and Africa. There are now increasing concerns that this virus might acquire infectious ability among humans, leading to a worldwide pandemic. Two of the drugs currently used to treat influenza patients are Tamiflu [(−)-oseltamivir phosphate; Fig. 1, 1] [1] and Relenza (zanamivir) [2], both of which inhibit viral neuraminidase. Tamiflu is an orally active prodrug, whereas Relenza has low bioavailability and is administered by inhalation. Because neuraminidase is a fundamental enzyme for the life cycle of general influenza viruses, the neuraminidase inhibitors are effective against all influenza virus types including H5N1.

Keywords

Influenza Virus Shikimic Acid Alder Reaction Dimethyl Fumarate Allyl Ester 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

I thank Professor Masakatsu Shibasaki for his kind support and guidance of this project. I also thank Drs. Kenzo Yamatsugu, Liang Yin, Shin Kamijo, Mr. Yasuaki Kimura, and Kenta Saito of The University of Tokyo for their contribution. Professor Takashi Kuzuhara and Dr. Noriko Echigo are acknowledged for collaboration. This work was partly supported by the Uehara Memorial Foundation.

References

  1. 1.
    Kim CU, Lew W, Williams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver G, Stevens RC (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119:681–690PubMedCrossRefGoogle Scholar
  2. 2.
    Itzstein MV, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Phan TV, Smythe ML, White HF, Oliver SW, Colman PM, Varghese JN, Ryan DM, Woods JM, Bethell RC, Hotham VJ, Cameron JM, Penn CR (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature (Lond) 363:418–423CrossRefGoogle Scholar
  3. 3.
    Abrecht S, Harrington P, Iding H, Karpf M, Trussardi R, Wirz B, Zutter U (2004) The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu®): a challenge for synthesis & process research. Chimia 58:621–629CrossRefGoogle Scholar
  4. 4.
    Abrecht S, Federspiel MC, Estermann H, Fisher R, Karpf M, Mair HJ, Oberhauser T, Rimmler G, Trussardi R, Zutter U (2007) The synthetic-technical development of oseltamivir phosphate Tamiflu™: a race against time. Chimia 61:93–99CrossRefGoogle Scholar
  5. 5.
    Shibasaki M, Kanai M (2008) Synthetic strategies for oseltamivir phosphate. Eur J Org Chem 2008:1839–1850CrossRefGoogle Scholar
  6. 6.
    Shibasaki M, Kanai M, Yamatsugu K (2011) Recent development in synthetic strategies for oseltamivir phosphate. Isr J Chem 51:316–328CrossRefGoogle Scholar
  7. 7.
    Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KH, Pham ND, Ngyen HH, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y (2005) Avian flu: isolation of drug-resistant H5N1 virus. Nature (Lond) 437:1108CrossRefGoogle Scholar
  8. 8.
    Fukuta Y, Mita T, Fukuda N, Kanai M, Shibasaki M (2006) De novo synthesis of Tamiflu via a catalytic asymmetric ring-opening of meso-aziridines with TMSN3. J Am Chem Soc 128:6312–6313PubMedCrossRefGoogle Scholar
  9. 9.
    Mita T, Fukuda N, Roca FX, Kanai M, Shibasaki M (2007) Second generation catalytic asymmetric synthesis of Tamiflu: allylic substitution route. Org Lett 9:259–262PubMedCrossRefGoogle Scholar
  10. 10.
    Yamatsugu Y, Yin L, Kamijo S, Kimura Y, Kanai M, Shibasaki M (2009) A synthesis of Tamiflu by using a barium-catalyzed asymmetric Diels–Alder-type reaction. Angew Chem Int Ed 48:1070–1076CrossRefGoogle Scholar
  11. 11.
    Nemoto H, Li X, Ma R, Suzuki I, Shibuya M (2003) A three-step preparation of MAC reagents from malononitrile. Tetrahedron Lett 44:73–75CrossRefGoogle Scholar
  12. 12.
    Yamatsugu K, Kanai M, Shibasaki M (2009) An alternative synthesis of Tamiflu®: a synthetic challenge and the identification of a ruthenium-catalyzed dihydroxylation route. Tetrahedron 65:6017–6024CrossRefGoogle Scholar
  13. 13.
    Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ (2008) Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature (Lond) 453:1258–1262CrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  1. 1.Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan

Personalised recommendations