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DOI: 10.1055/s-0033-1340328
Synthesis of (–)-Nutlin-3
Publication History
Publication Date:
13 December 2013 (online)
Key words
nutlin-3 - cis-imidazolines - organocatalysis - chiral bis(amidine) catalysts - asymmetric aza-Henry reaction![](https://www.thieme-connect.de/media/synfacts/201401/i_k074_s1_10-1055_s-0033-1340328.gif)
Significance
Nutlin-3 inhibits the interaction between proteins p53 and MDM2. It is of interest as an investigative tool in cancer biology. The key step in the decagram-scale synthesis depicted is an enantioselective aza-Henry reaction catalyzed by the novel bis(amidine) C that provides high enantioselectivity at higher temperatures and lower catalyst loadings than previously possible (T. A. Davis, J. Johnston Chem. Sci. 2011, 2, 1076).
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Comment
The optimized conditions of the aza-Henry reaction include the following: 0.5 mol% catalyst loading, slow addition of imine (ca. 0.06 equiv aliquots over 8 h), essentially stoichiometric amounts of the two partners A and B, a relatively high reaction concentration (0.4 M in PhMe), and exclusive precipitation of the desired diastereoisomer. A 90% yield of product D was produced after filtration in 91% ee and a dr > 200:1.
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![](https://www.thieme-connect.de/media/synfacts/201401/i_k074_s1_10-1055_s-0033-1340328.gif)