Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation

Asymmetric synthesis of a novel non-benzodiazepine hypnotic drug Ramelteon (TAK-375) was accomplished via asymmetric hydrogenation. Development of the substrate design revealed that a novel class of substrate, allylic acylamine 4a, was hydrogenated with a Ru-BINAP catalyst in 95% ee and 98% yield. The effectiveness and robustness of the reaction were demonstrated on a 700-g scale.