The Synthesis of α,α-Disubstituted α-Amino Acids via Ichikawa Rearrangement

J Org Chem. 2016 Feb 5;81(3):1057-74. doi: 10.1021/acs.joc.5b02628. Epub 2016 Jan 12.

Abstract

An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X7-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allyl Compounds / chemistry*
  • Amantadine / analogs & derivatives*
  • Amantadine / chemistry
  • Amino Acids / chemistry*
  • Biochemical Phenomena
  • Cyanates / chemistry*
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Indicators and Reagents / chemistry
  • Isocyanates / chemistry*
  • Molecular Structure
  • Pyrans / chemistry
  • Stereoisomerism

Substances

  • 4-amino-tetrahydropyranyl-4-carboxylic acid
  • Allyl Compounds
  • Amino Acids
  • Cyanates
  • Dipeptides
  • Indicators and Reagents
  • Isocyanates
  • Pyrans
  • allyl isocyanate
  • adamantanine
  • Amantadine
  • GSK-2793660