One-pot synthesis of (-)-oseltamivir and mechanistic insights into the organocatalyzed Michael reaction

Takasuke Mukaiyama, Hayato Ishikawa, Hiroyuki Koshino, Yujiro Hayashi

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2- nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone. (-)-Oseltamivir, a neuraminidase inhibitor, was synthesized in a one-pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E-Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine.

Original languageEnglish
Pages (from-to)17789-17800
Number of pages12
JournalChemistry - A European Journal
Volume19
Issue number52
DOIs
Publication statusPublished - 2013 Dec 23

Keywords

  • Michael addition
  • Tamiflu
  • asymmetric synthesis
  • one-pot reaction
  • organocatalysis

ASJC Scopus subject areas

  • Chemistry(all)

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