An efficient, stereoselective synthesis of the hydroxyethylene dipeptide isostere core for the HIV protease inhibitor A-792611

J Org Chem. 2006 Jul 7;71(14):5369-72. doi: 10.1021/jo060737s.

Abstract

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.

MeSH terms

  • Crystallography, X-Ray
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Esters / chemical synthesis*
  • Esters / chemistry
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Stereoisomerism

Substances

  • Dipeptides
  • Esters
  • HIV Protease Inhibitors
  • Pyridines
  • methyl 1-(5-(2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate