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

Chemistry. 2010 Nov 8;16(42):12616-26. doi: 10.1002/chem.201001108.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Catalysis
  • Combinatorial Chemistry Techniques
  • Ethers / chemistry
  • Humans
  • Molecular Structure
  • Neuraminidase / antagonists & inhibitors*
  • Oseltamivir / chemical synthesis*
  • Oseltamivir / chemistry
  • Oseltamivir / pharmacology*
  • Proline / analogs & derivatives
  • Proline / chemistry
  • Stereoisomerism

Substances

  • Antiviral Agents
  • Ethers
  • diphenylprolinol silyl ether
  • Oseltamivir
  • Proline
  • Neuraminidase