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 (4)

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