Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key ste...

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Bibliographic Details
Published in:	Organic process research & development Vol. 16; no. 11; pp. 1832 - 1845
Main Authors:	Chung, John Y. L, Steinhuebel, Dietrich, Krska, Shane W, Hartner, Fred W, Cai, Chaoxian, Rosen, Jonathan, Mancheno, Danny E, Pei, Tao, DiMichele, Lisa, Ball, Richard G, Chen, Cheng-yi, Tan, Lushi, Alorati, Antony D, Brewer, Sarah E, Scott, Jeremy P
Format:	Journal Article
Language:	English
Published:	American Chemical Society 16-11-2012
Online Access:	Get full text
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Summary:	Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.
ISSN:	1083-6160 1520-586X
DOI:	10.1021/op300249q