Preparation of (-)-Nutlin-3 using enantioselective organocatalysis at decagram scale

J Org Chem. 2013 Nov 1;78(21):10605-16. doi: 10.1021/jo401321a. Epub 2013 Oct 15.

Abstract

Chiral nonracemic cis-4,5-bis(aryl)imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (-)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (-20 °C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (-)-Nutlin-3 in a 17 g batch and elimination of all but three chromatographic purifications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amidines / chemistry*
  • Animals
  • Catalysis
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazolines / chemistry*
  • Mice
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Stereoisomerism
  • Temperature
  • Tumor Cells, Cultured

Substances

  • Amidines
  • Imidazoles
  • Imidazolines
  • Piperazines
  • nutlin 3