High-yielding synthesis of the anti-influenza neuraminidase inhibitor (-)-oseltamivir by two "one-pot" sequences

Hayato Ishikawa, Takaki Suzuki, Hideo Orita, Tadafumi Uchimaru, Yujiro Hayashi

Research output: Contribution to journalArticlepeer-review

127 Citations (Scopus)

Abstract

The efficient asymmetric total synthesis of (-)-oseltamivir, an antiviral reagent, has been accomplished by using two "one-pot" reaction sequences, with excellent overall yield (60%) and only one required purification by column chromatography. The first one-pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner-Wadsworth-Emmons reaction combined with retro-aldol/Horner-Wadsworth-Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base-catalyzed isomerization. Six reactions can be successfully conducted in the second one-pot reaction sequence; these are deprotection of a tert-butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column-free synthesis of (-)-oseltamivir has also been established. Fighting the flu: Two "one-pot" and column-free asymmetric sequences are used to accomplish the synthesis of (-)-oseltamivir, known as the anti-influenza drug Tamiflu (see scheme; TMS: trimethylsilyl). This high-yielding synthesis takes advantage of a diphenylprolinol silyl ether as an organocatalyst and single-pot domino operations.

Original languageEnglish
Pages (from-to)12616-12626
Number of pages11
JournalChemistry - A European Journal
Volume16
Issue number42
DOIs
Publication statusPublished - 2010 Nov 8
Externally publishedYes

Keywords

  • Tamiflu
  • asymmetric synthesis
  • domino reactions
  • organocatalysis

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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