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Synfacts 2014; 10(1): 0001
DOI: 10.1055/s-0033-1340328
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (–)-Nutlin-3

Contributor(s):
Philip Kocienski
Davis TA, Vilgelm AE, Richmond A, Johnston JN * Vanderbilt University, Nashville and Vanderbilt School of Medicine, Nashville, USA
Preparation of (–)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale.

J. Org. Chem. 2013;
78: 10605-10616
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Further Information

Publication History

Publication Date:
13 December 2013 (online)

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Key words

nutlin-3 - cis-imidazolines - organocatalysis - chiral bis(amidine) catalysts - asymmetric aza-Henry reaction

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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