Biocatalytic C-H oxidation meets radical cross-coupling: Simplifying complex piperidine synthesis

• 成果类型: Article
• 署名作者: He, Jiayan; Yokoi, Kenta; Wixted, Breanna; Zhang, Benxiang; Kawamata, Yu; Renata, Hans; Baran, Phil S.
• 署名单位: Scripps Research Institute; Rice University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8928
• DOI: 10.1126/science.adr9368
• 发表日期: 2024-12-20
• 页码: 1421-1427
• 关键词: asymmetric-synthesis; enantioselective synthesis; reagents; ACID; efficient; analogs; moiety; esters

摘要

Modern medicinal chemists are targeting more complex molecules to address challenging biological targets, which leads to synthesizing structures with higher sp3 character (Fsp3) to enhance specificity as well as physiochemical properties. Although traditional flat, high-fraction sp2 molecules, such as pyridine, can be decorated through electrophilic aromatic substitution and palladium (Pd)-based cross-couplings, general strategies to derivatize three-dimensional (3D) saturated molecules are far less developed. In this work, we present an approach for the rapid, modular, enantiospecific, and diastereoselective functionalization of piperidine (saturated analog of pyridine), combining robust biocatalytic carbon-hydrogen oxidation with radical cross-coupling. This combination is directly analogous to electrophilic aromatic substitution followed by Pd-couplings for flat molecules, streamlining synthesis of 3D molecules. This study offers a generalizable strategy for accessing complex architectures, appealing to both medicinal and process chemists.