近日，瑞士苏黎世联邦理工学院Helma Wennemers团队研究了有机催化剂控制的立体选择性首尾大环化。该项研究成果发表在2026年2月26日出版的《科学》杂志上。

手性大环化合物是发现新药物的关键。然而，其合成极具挑战性，通常需要在线性前体中引入立体化学特征，而这一过程往往较为繁琐。

在该工作中，研究组报道了一种催化剂控制的选择性头尾成环反应。该方法利用双功能多肽催化剂对线性前体的末端官能团进行模板化，从而促进分子内反应而非分子间反应，并实现对新生立构中心立体化学的精准控制。从非手性线性前体出发，研究组获得了多种12至18元大环内酯和内酰胺。

即便在手性线性前体发生成环反应时，该有机催化剂仍能决定其立体化学结果。这种催化剂控制的选择性头尾成环反应为合成具有可预测立体化学结果的手性大环化合物提供了一条实用途径。通过合成天然产物robotnikinin（罗布特宁宁）的核心结构，进一步凸显了该方法的实用性。

附：英文原文

Title: Organocatalyst-controlled stereoselective head-to-tail macrocyclizations

Author: Jonas W. Rackl, Linus B. Boll, Helma Wennemers

Issue&Volume: 2026-02-26

Abstract: Chiral macrocycles are key to the discovery of new medicines. Their synthesis is, however, challenging and typically requires the often-cumbersome installation of stereochemical features in a linear precursor. In this study, we report a catalyst-controlled stereoselective head-to-tail macrocyclization. The method utilizes a bifunctional peptide catalyst to template the terminal functional groups of the linear precursor, thereby favoring intra- over intermolecular reaction and enabling exquisite control over the stereochemistry of the emerging stereogenic centers. Diverse 12- to 18‐membered macrocyclic lactones and lactams were obtained from achiral linear precursors. The organocatalyst even dictates the stereochemical outcome upon cyclizing a chiral linear precursor. This catalyst-controlled stereoselective head-to-tail macrocyclization provides a practical route to chiral macrocycles with predictable stereochemical outcomes. The utility was highlighted by synthesizing the core of the natural product robotnikinin.

DOI: aec8992

Source: https://www.science.org/doi/10.1126/science.aec8992