Rhodium catalyzed tunable amide homologation through a hook-and-slide strategy

• 成果类型: Article
• 署名作者: Zhang, Rui; Yu, Tingting; Dong, Guangbin
• 署名单位: University of Chicago
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13492
• DOI: 10.1126/science.adk1001
• 发表日期: 2023-11-24
• 页码: 951-957
• 关键词: molecular-orbital methods; carbon-carbon bonds; gaussian-type basis; c-c bonds; basis-sets; carboxylic-acids; split-valence; isomerization; activation; complexes

摘要

Preparation of diverse homologs from lead compounds has been a common and important practice in medicinal chemistry. However, homologation of carboxylic acid derivatives, particularly amides, remains challenging. Here we report a hook-and-slide strategy for homologation of tertiary amides with tunable lengths of the inserted carbon chain. Alkylation at the alpha-position of the amide (hook) is followed by highly selective branched-to-linear isomerization (slide) to effect amide migration to the end of the newly introduced alkyl chain; thus, the choice of alkylation reagent sets the homologation length. The key step involves a carbon-carbon bond activation process by a carbene-coordinated rhodium complex with assistance from a removable directing group. The approach is demonstrated for introduction of chains as long as 16 carbons and is applicable to derivatized carboxylic acids in complex bioactive molecules.