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Synfacts 2014; 10(8): 0786
DOI: 10.1055/s-0034-1378398
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of an HDM2 Inhibitor

Contributor(s):
Philip Kocienski
Ma Y, * Lahue BR, Gibeau CR, Shipps Jr. GW, Bogen SL, Wang Y, Guo Z, Guzi TJ. Merck Research Laboratories, Boston and Kenilworth, USA
Pivotal Role of an Aliphatic Side Chain in the Development of an HDM2 Inhibitor.

ACS Med. Chem. Lett. 2014;
5: 572-575
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Further Information

Publication History

Publication Date:
18 July 2014 (online)

 
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Key words

HDMs inhibitors - Bargellini reaction - α-aryloxy carboxylic acids

Significance

The target molecule inhibits the protein–protein interaction between the oncogene HDM2 and the p53 suppressor protein, thereby increasing levels of p53 with consequent decreased proliferation and increased apoptosis. The key feature of the synthesis depicted is the construction of the hindered α-aryloxy carboxylic acid C via a Bargellini reaction.


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Comment

The Bargellini reaction (G. Bargellini Gazz. Chim. Ital. 1906, 36, 329) entails the addition of a trichloromethide anion to the ketone A. The resultant adduct undergoes nucleophilic displacement of chloride ion to give a dichloro-substituted epoxide, which then reacts with phenoxide anion to give the α-aryloxy carboxylic acid C. For a previous use of the Bargellini reaction, see: R. J. Cvetovich et al. J. Org. Chem. 2005, 70, 8560.


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