title: Two asymmetric syntheses of AMG 221, an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1.
abstract: Two asymmetric syntheses of AMG 221 (2), an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 alpha-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 alpha-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.
authors.affiliation: Chemical Process R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. scaille@amgen.com
authors.forename: Seb
authors.initials: S
authors.lastname: Caille
authors.forename: Sheng
authors.initials: S
authors.lastname: Cui
authors.forename: Tsang-Lin
authors.initials: TL
authors.lastname: Hwang
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Faul
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000438:Alcohols / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C541878:AMG 221; D000438:Alcohols; D002712:Chlorides; D004791:Enzyme Inhibitors; D012997:Solvents; D013844:Thiazoles; C031363:2-aminothiazoline; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1