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Synfacts 2015; 11(8): 0789
DOI: 10.1055/s-0034-1381028
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of an Atropisomeric HIV Integrase Inhibitor

Autor*innen

    Rezensent(en):

  • Philip Kocienski

Fandrick KR * et al. Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, USA and Boehringer Ingelheim (Canada) Ltd., Laval, Canada
Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.

Angew. Chem. Int. Ed. 2015;
54: 7144-7148
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Publikationsverlauf

Publikationsdatum:
20. Juli 2015 (online)

 
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Key words

HIV integrase inhibitor - transfer hydrogenation - Suzuki–Miyaura reaction - tert-butyl ethers

Significance

The target molecule is an atropisomeric integrase inhibitor that is of interest for the treatment of HIV. Noteworthy steps in the synthesis depicted include (1) a copper(I)-catalyzed acylation of quinoline A, (2) an asymmetric transfer hydrogenation of the α-keto ester C mediated by the ligand D, and (3) a ligand-controlled asymmetric Suzuki–Miyaura reaction mediated by the ligand F.


Comment

The installation of the tert-butyl ether group on the bis(quinoline) scaffold of I was challenging, because intermediate I contains two basic nitrogen atoms and the tert-butyl ether is buried within a very sterically crowded environment. Best results were obtained using the trichloro­acetimidate J together with bis(trifluoromethane)sulfonimide.





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