American Chemical Society
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Two Asymmetric Syntheses of AMG 221, an Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1

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journal contribution
posted on 2009-05-15, 00:00 authored by Seb Caille, Sheng Cui, Tsang-Lin Hwang, Xiang Wang, Margaret M. Faul
Two asymmetric syntheses of AMG 221 (2), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) discovered in our laboratories, are reported. One of the syntheses utilizes chiral trimethylsilyl cyanohydrin 12 as starting material and the other utilizes its enantiomer ent-12. The displacement approach involves the conversion of 12 to 2 via a six-step sequence, occurs with net inversion of configuration, and employs amine 6 as starting material. This route features a novel approach toward chiral dialkylsubstituted α-mercaptoacids. The cyclization approach entails the synthesis of 2 from ent-12 in 2 steps, takes place with net retention of configuration, and uses thiourea 8 as starting material. The final step of this route exemplifies a novel synthesis of chiral C-5 dialkylsubstituted 2-aminothiazolones from chiral α-hydroxyacids and thioureas. Insights into the mechanism of this transformation and study of the effect of the medium on the stereochemical outcome of the reaction are presented.