Diastereoselective arylithium addition to an alpha-trifluoromethyl imine. Practical synthesis of a potent cathepsin K inhibitor

J Org Chem. 2006 May 26;71(11):4320-3. doi: 10.1021/jo052430j.

Abstract

A practical, chromatography-free synthesis of potent cathepsin K inhibitor 1 is described. The addition of 4-bromophenyllithium to an alpha-trifluoromethylimine derived from commercially available (S)-leucinol was accomplished in a highly diastereoselective manner (97.6% de, 91% yield). Subsequent Suzuki cross-coupling afforded biaryl 7. Oxidation of the alcohol and sulfide functionalities led to the formation of carboxylic acid 8. Crystallization of 7 and acid 8 as its dicyclohexylamine salt gave excellent impurity rejection. The final amide coupling with commercially available aminoacetonitrile hydrochloride afforded 1 in excellent purity (99.6A% by HPLC, 100% de, <3 ppm Pd, W, Cr).

MeSH terms

  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Imines / chemistry*
  • Lithium / chemistry*
  • Molecular Structure

Substances

  • Imines
  • Lithium
  • Cathepsins
  • Cathepsin K