Yan Xiaoyu, Pang Yubing, Zhou Yutong, Chang Rui, Ye Juntao
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
J Am Chem Soc. 2025 Jan 8;147(1):1186-1196. doi: 10.1021/jacs.4c14934. Epub 2024 Dec 18.
Photochemical deracemization has emerged as one of the most straightforward approaches to access highly enantioenriched compounds in recent years. While excited-state events such as energy transfer, single electron transfer, and ligand-to-metal charge transfer have been leveraged to promote stereoablation, approaches relying on hydrogen atom transfer, which circumvent the limitations imposed by the triplet energy and redox potential of racemic substrates, remain underexplored. Conceptually, the most attractive method for tertiary stereocenter deracemization might be hydrogen atom abstraction followed by hydrogen atom donation. However, implementing such a strategy poses significant challenges, primarily because the enantioenriched products are also reactive if the chiral catalyst is unable to differentiate between the two enantiomers. Herein we report a distinct dual hydrogen atom transfer strategy for photochemical deracemization of δ- and γ-lactams, achieving high enantioenrichment and deuterium incorporation despite the inherent reactivity of the products. Mechanistic studies reveal that benzophenone enables nonselective hydrogen atom abstraction while a tetrapeptide-derived thiol dictates the enantioselectivity of the hydrogen atom donation step. More importantly, a pyridine-based alcohol was found to play crucial roles in facilitating the hydrogen atom abstraction as well as enhancing the enantioselectivity of the hydrogen atom donation step.
近年来，光化学消旋化已成为获取高对映体富集化合物最直接的方法之一。虽然诸如能量转移、单电子转移和配体到金属的电荷转移等激发态事件已被用于促进立体消融，但依赖氢原子转移的方法仍未得到充分探索，这种方法规避了外消旋底物的三重态能量和氧化还原电位所带来的限制。从概念上讲，叔立体中心消旋化最具吸引力的方法可能是氢原子提取后再进行氢原子供体。然而，实施这样的策略面临重大挑战，主要是因为如果手性催化剂无法区分两种对映体，对映体富集产物也具有反应性。在此，我们报道了一种独特的双氢原子转移策略，用于δ-和γ-内酰胺的光化学消旋化，尽管产物具有固有反应性，但仍实现了高对映体富集和氘掺入。机理研究表明，二苯甲酮能够进行非选择性氢原子提取，而一种四肽衍生的硫醇决定了氢原子供体步骤的对映选择性。更重要的是，发现一种吡啶基醇在促进氢原子提取以及提高氢原子供体步骤的对映选择性方面发挥着关键作用。
