Enantioselective synthesis of antiinfluenza compound A-315675

J Org Chem. 2002 Aug 9;67(16):5445-53. doi: 10.1021/jo0162890.

Abstract

Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Humans
  • Influenza, Human
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Neuraminidase / antagonists & inhibitors*
  • Orthomyxoviridae / drug effects*
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacology
  • Stereoisomerism

Substances

  • A 315675
  • Antiviral Agents
  • Pyrrolidines
  • Neuraminidase