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

Davis TA, Vilgelm AE, Richmond A, Johnston JN
J Org Chem. 2013 78 (21): 10605-16

PMID: 24127627 · PMCID: PMC3880828 · DOI:10.1021/jo401321a

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.

MeSH Terms (11)

Amidines Animals Catalysis Humans Imidazoles Imidazolines Mice Piperazines Stereoisomerism Temperature Tumor Cells, Cultured

Connections (3)

This publication is referenced by other Labnodes entities:

Links