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Synfacts 2019; 15(04): 0333
DOI: 10.1055/s-0037-1612292
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of an HIV-1 Integrase Allosteric Site Inhibitor

Contributor(s):
Philip Kocienski
Peese KM. * et al. Bristol-Myers Squibb Research & Development, Wallingford and GlaxoSmithKline, Collegeville, USA
5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors.

J. Med. Chem. 2019;
62: 1348-1361
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Further Information

Publication History

Publication Date:
19 March 2019 (online)

 
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Key words

5,6,7,8-tetrahydro-1,6-naphthyridines - Bode homologation - Corey–Itsuno asymmetric reduction - sulfur ylides - α-keto esters

Significance

Tetrahydronaphthyridine O inhibits HIV-1 integrase, one of the three enzymes encoded in the HIV-1 genome required for viral replication. A markworthy step in the small-scale synthesis depicted is the Bode homologation of carboxylic acid G to α-keto ester J via sulfur ylide I (L. Ju, A. R. Lippert, J. W. Bode J. Am. Chem. Soc. 2008, 130, 4253).


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Comment

Corey–Itsuno asymmetric reduction of α-keto ester J gave a 1:1 mixture of diastereoisomers from which the desired atropisomer L was isolated in 45% yield by column chromatography and crystallization. Tetrahydronaphthyridine F was constructed in four steps in 20% overall yield using a Hantzsch pyridine synthesis.


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