Application of Bis(AMidine) [BAM] Catalysis to the Synthesis of Therapeutics: Nutlins
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   The advances in stereoselective synthesis achieved by the development of Bis(AMidine) [BAM] catalysis are used to bring structurally and stereochemically complex small molecules into the reach of practical chemical synthesis. We have completed this cycle of discovery and development with the first enantioselective synthesis of (-)-Nutlin 3, the first potent small molecule inhibitor of p53/MDM2 binding. Through this mechanism, Nutlin 3 can restore apoptosis in cancerous cells with wild-type p53. The Nutlins and their biological activity were discovered and reported (Vassilev Lyubomir, T.; Vu Binh, T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu Emily, A. Science 2004, 303, 844) by Hoffmann-La Roche. Their synthetic route, as outlined in a series of patents, provided Nutlin 3 as a racemate, which was then separated into its enantiomeric forms using chromatography on a chiral stationary phase.
   Our discovery of a BAM catalyst that promoted the first highly diastereo- and enantioselective addition of aryl nitromethanes to aryl aldimines serves as the key step in our preparation of Nutlin 3. This development allows the conversion of all starting material into the more potent enantiomer of Nutlin 3.

Davis, T. A.; Johnston, J. N. Chemical Science 2011, 2, 1076
24 Aug 2016 09:19
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