Enantioselective Total Synthesis of 5-Phenylmorphans and Cis-Octahydroisoquinolines

Modifications of morphine have delivered novel opioid scaffolds, such as 5-phenylmorphans and cis-octahydroisoquinolines, that exhibit various pharmacological profiles. Herein, we disclose the first enantioselective total syntheses of both scaffolds. These syntheses exploit an enantioselective conjugate addition, followed by conver-sion of the ester to a common amine intermediate. Subsequently, a diastereoselective aza-Michael reaction generates 5-phenylmorphans, while a γ-regio- and diastereoselective Mannich reaction generates cis-octahydroisoquinolines.