Simple Enantioselective Syntheses of (2R,6R)-Hydroxynorketamine and Related Potential Rapid-Onset Antidepressants

A novel strategy for accessing cyclic alpha-amino ketones enantioselectively has opened a simple synthetic route to the antidepressant (2R,6R)-hydroxynorketamine and numerous analogues. Mechanistically guided catalyst selection was essential in an initial olefin epoxidation step. In a second crucial step, the epoxide was subjected to a novel O -> N displacement that occurred with retention of configuration through the use of Al- or Ti-based azides, which promote epoxide activation and internal cis delivery of N-3 to carbon.