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
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.
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.
