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亚胺与环丙醇的形式环丙烷化反应:立体控制合成构象受限的γ-氨基醇

Formal Cyclopropylation of Imines with Cyclopropanols: Stereocontrolled Access to Conformationally Constrained γ-Amino Alcohols.

作者信息

Tsukiji Kento, Kanemoto Kazuya, Kwon Eunsang, Yoshikai Naohiko

机构信息

Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Sendai, 980-8578, Japan.

Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan.

出版信息

Angew Chem Int Ed Engl. 2025 Sep 22;64(39):e202511646. doi: 10.1002/anie.202511646. Epub 2025 Aug 11.

Abstract

γ-Amino alcohols are essential motifs in bioactive compounds and chiral catalysts, yet the synthesis of their conformationally constrained variants remains challenging due to the lack of suitable methodologies. Here, we report a formal cyclopropylation of imines with cyclopropanols, enabling the construction of previously inaccessible cyclopropane-embedded γ-amino alcohols. This transformation leverages the unique reactivity of enolized zinc homoenolates, which effectively act as a β-hydroxycyclopropyl anions and engage imines through a sequence of Mannich addition and ring closure. The key to this reactivity lies in the use of bulky N-heterocyclic carbene (NHC) ligands, which promote efficient coupling with N-sulfonyl aldimines as well as chiral N-sulfinyl trifluoromethyl-ketimines while ensuring excellent diastereocontrol over three contiguous stereocenters. Furthermore, the resulting γ-amino alcohols can be transformed into β- or γ-aminofunctionalized ketones via homoenolate or β-keto radical intermediates, offering versatile platforms for downstream derivatization.

摘要

γ-氨基醇是生物活性化合物和手性催化剂中的重要结构单元,然而由于缺乏合适的方法,其构象受限变体的合成仍然具有挑战性。在此,我们报道了一种亚胺与环丙醇的形式环丙烷化反应,能够构建此前难以获得的含环丙烷的γ-氨基醇。这种转化利用了烯醇化锌均烯醇盐的独特反应性,其有效地作为β-羟基环丙基阴离子,并通过一系列曼尼希加成和闭环反应与亚胺发生反应。这种反应性的关键在于使用大位阻的N-杂环卡宾(NHC)配体,其促进与N-磺酰基醛亚胺以及手性N-亚磺酰基三氟甲基酮亚胺的有效偶联,同时确保对三个相邻立体中心具有出色的非对映选择性控制。此外,所得的γ-氨基醇可通过均烯醇盐或β-酮基自由基中间体转化为β-或γ-氨基官能化酮,为下游衍生化提供了通用平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0e9/12455443/124f3198d4f6/ANIE-64-e202511646-g007.jpg

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