He Jiayan, Yokoi Kenta, Wixted Breanna, Zhang Benxiang, Kawamata Yu, Renata Hans, Baran Phil S
Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, USA.
Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, TX, USA.
Science. 2024 Dec 20;386(6728):1421-1427. doi: 10.1126/science.adr9368. Epub 2024 Dec 19.
Modern medicinal chemists are targeting more complex molecules to address challenging biological targets, which leads to synthesizing structures with higher sp character (Fsp) to enhance specificity as well as physiochemical properties. Although traditional flat, high-fraction sp 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.
现代药物化学家致力于针对更复杂的分子以攻克具有挑战性的生物学靶点，这导致合成具有更高sp特征（Fsp）的结构，以提高特异性以及物理化学性质。尽管传统的平面、高比例sp分子，如吡啶，可以通过亲电芳香取代和基于钯（Pd）的交叉偶联进行修饰，但衍生化三维（3D）饱和分子的通用策略却远未得到充分发展。在这项工作中，我们提出了一种对哌啶（吡啶的饱和类似物）进行快速、模块化、对映体特异性和非对映选择性官能化的方法，该方法将强大的生物催化碳-氢氧化与自由基交叉偶联相结合。这种组合直接类似于平面分子的亲电芳香取代后接Pd偶联，简化了3D分子的合成。这项研究为构建复杂结构提供了一种可推广的策略，对药物化学家和工艺化学家都具有吸引力。
