近日，南方科技大学谭斌团队报道了不对称有机催化控制锥体氮手性。该研究于2025年11月12日发表在《自然》杂志上。

手性是生命体的核心特征，而控制一对镜像分子（对映异构体）中特定构型的生成更是合成化学的基本准则。尽管对手性碳、硅、磷和硫中心的控制已司空见惯，但胺类中氮中心的结构通常难以稳定维持。氮手性对映选择性构建的有限成果主要集中于构型受限的四级铵盐和桥联双环胺类。对于非桥联的锥形氮手性化合物，其不对称合成不仅需要超化学计量的手性源，且立体选择性控制效果欠佳。

研究组提出了一种通过手性布朗斯特酸催化的氯化反应，构建无环氮立体中心的催化对映选择性策略。他们设计了具有立体专一性的分子内反应，以克服氮氯羟胺的结构不稳定性与构型不稳定性。所得2-烷氧基-1,2-氧氮杂环戊烷展现出优良的对映纯度，密度泛函理论计算也证实了氯化过程中成功实现了氮手性的对映控制。进一步地，该策略被成功应用于构建具有构型稳定氮手性中心的N-氯氮丙啶的对映选择性合成。控制实验为分子内亲核取代遵循SN2路径提供了证据。

附：英文原文

Title: Controlling pyramidal nitrogen chirality by asymmetric organocatalysis

Author: Wu, San, Chen, Pengquan, Duan, Meng, Jiang, Peng-Ying, Zhou, Qingyang, Xiang, Shao-Hua, Houk, K. N., Tan, Bin

Issue&Volume: 2025-11-12

Abstract: Chirality is central to life, and controlling the formation of one of a pair of mirror-image molecules (enantiomers) is a central tenet of synthetic chemistry. Although controlling stereogenic carbon1,2,3, silicon4,5, phosphorus6,7 and sulfur8,9 centres is commonplace, nitrogen centres in amines are not typically stable. Limited achievements in the enantioselective construction of nitrogen chirality have primarily been established in quaternary ammonium salts10,11,12 and bridged bicyclic amines13,14,15,16,17, which have a restricted pyramidal configuration. The asymmetric synthesis of non-bridged pyramidal nitrogen-chirogenic compounds suffers from a super-stoichiometric chiral source and exhibits poor stereoselectivity18,19,20,21,22,23,24. Here we present a catalytic enantioselective strategy for construction of acyclic nitrogen stereocentres via a chiral Brnsted acid-catalysed chlorination reaction. We designed a stereospecific intramolecular reaction to overcome the structural and configurational instabilities of nitrogen-chlorinated hydroxylamines. The resulting 2-alkoxy-1,2-oxazolidines showed good enantiopurities, and density functional theory calculations confirmed successful enantiocontrol of nitrogen chirality during the chlorination process. Furthermore, this strategy has been applied successfully to synthesize the enantioselective N-chloroaziridines with a configurationally stable nitrogen stereogenic centre. Control experiments provide evidence for an SN2 pathway for the intramolecular nucleophilic substitution event.

DOI: 10.1038/s41586-025-09607-6

Source: https://www.nature.com/articles/s41586-025-09607-6