Total Synthesis of (±)-Gephyrotoxin by Amide-Selective Reductive Nucleophilic Addition

A chemoselective approach for the total synthesis of (+/-)-gephyrotoxin has been developed. The key to success was the utilization of N-methoxyamides, which enabled the direct coupling of the amide with an aldehyde and selective reductive nucleophilic addition to the amide in the presence of a variety of sensitive and electrophilic functional groups, such as a methyl ester. This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (+/-)-gephyrotoxin described to date.