Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale

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 gram batch, and elimination of all but three chromatographic purifications.

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

“…The first method entailed a radical bromination of para -chlorotoluene in order to prepare the corresponding benzyl bromide followed by the subsequent substitution of the bromide with a nitro group, an approach often referred to as Kornblum’s procedure. 23 Workup with phloroglucinol improved the yield by converting the nitrite (formed by O -alkylation) to alcohol. The resulting crude mixture could be purified by column chromatography to provide nitroalkane in 33% yield over 2 steps containing up to 2% of the corresponding aldehyde.…”

“…22 The original procedure 17 was refined 23 to provide the desired adduct 4 in 90% yield and with high stereoselectivity. During these studies we have discovered that to achieve consistent enantioselectivites on a larger scale, it was advantageous to add imine 1 slowly to the mixture of nitroalkane 2 and catalyst 3 in toluene at −20 °C.…”

“…23 Reduced cycle times on the order of 30–40 min would provide an opportunity for translation of these processes into an automated intermittent flow format.…”

Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells

“…Mutational status of TP53 was determined by direct exon sequencing with primers available from IARC TP53 Database (R16, November 2012). (−)-Nutlin-3 was synthesized as described previously (23) . MLN8237 was provided by Millennium Pharmaceuticals, Inc. At least 5 mice per treatment group were used.…”

Organocatalysts for enantioselective synthesis of fine chemicals: definitions, trends and developments

“…Many patents have already been disclosed on enantioselective organocatalytic transformations and this is a clear clue of the relevant potential of the technique [96][97][98][99]. Furthermore, a few organocatalytic procedures have recently been extended to industrial plants, even though the scale-up of a reaction is not straightforward [100]. For instance, the well-known L-proline-catalysed intramolecular aldol reaction (i.e., the Hajos-Parrish-Sauer-Wiechert process, see Figure 3, Chap.…”