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

• Published in: Angewandte Chemie International Edition 2014-01, Vol.53 (2), p.512-516
• Main Authors: Shirokane, Kenji, Wada, Takamasa, Yoritate, Makoto, Minamikawa, Ryo, Takayama, Nobuaki, Sato, Takaaki, Chida, Noritaka
• Format: Article
• Language: English
• Subjects: Aldehydes; Alkaloids - chemical synthesis; Alkaloids - chemistry; Amides; Amides - chemistry; Catalysis; chemoselectivity; Esters; Functional groups; gephyrotoxin; Joining; Mesylates - chemistry; Molecular Structure; nucleophilic addition; Oxidation-Reduction; Redox reactions; Scandium - chemistry; Stereoisomerism; Synthesis; total synthesis; Trialkyltin Compounds - chemistry; Utilization
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201308905

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. Aim for selectivity: A chemoselective approach that utilizes N‐methoxyamides has been developed for the total synthesis of (±)‐gephyrotoxin. The N‐methoxy group enabled the direct coupling of the amide with an aldehyde and amide‐selective reductive allylation in the presence of a more electrophilic methyl ester, which resulted in the most concise and efficient total synthesis of (±)‐gephyrotoxin described to date.