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Synfacts 2013; 9(2): 0119
DOI: 10.1055/s-0032-1318012
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Glucagon Receptor Antagonist

Contributor(s):
Philip Kocienski
Chung JY. L * et al. Merck Research Laboratories, Rahway, USA and Merck Sharp & Dohme Research Laboratories, Hoddesdon, UK
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of an Indole with Chiral α-Phenyl Benzyl Cation.

Org. Process Res. Dev. 2012;
16: 1832-1845
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Publication History

Publication Date:
18 January 2013 (online)

 
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Key words

glucagon receptor antagonists - Friedel–Crafts alkylation - palladium-catalyzed enolate arylation - Noyori asymmetric hydrogenation - dynamic kinetic resolution

Significance

The target glucagon receptor antagonist is a candidate for the treatment of type 2 diabetes. Key steps in the synthesis of the sterically congested 1,1,2-triarylalkane core are (1) the asymmetric Noyori hydrogenation of ketone C involving a dynamic kinetic resolution and (2) the anti-selective Friedel–Crafts alkylation of the ­fluoroindole F by chiral benzylic carbocation G.


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Comment

Optimal Friedel–Crafts diastereoselectivity and yield were achieved with nosyl-protected indole F using TFA as solvent and catalytic MsOH. A highly efficient, large-scale Larock-type synthesis of fluoroindole F from 2-bromoaniline was also developed. For the stereochemistry of the anti-selective Friedel–Crafts alkylation, see: J. Y. L. Chung et al. Org. Lett. 2008, 10, 3037.


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