Remote desymmetrization of tetraoxacalix[2]arene[2]triazines enables the asymmetric synthesis of inherently chiral heteracalix[4]aromatics
- 1Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University Guangzhou 510006 China
- 2School of Pharmacy, Shenzhen University Medical School, Shenzhen University Shenzhen 518055 China
Abstract
The catalytic enantioselective synthesis of inherently chiral macrocycles remains a major challenge, particularly through non-cyclization strategies. Herein, we report a chiral phosphoric acid (CPA)-catalyzed remote desymmetrization of tetraoxacalix[2]arene[2]triazines, enabling access to inherently chiral heteracalix[4]aromatics. The strategy relies on sequential SNAr aminations, in which the first amination installs an aniline N–H unit as a “control handle” that both creates a hydrogen-bonding recognition site for the catalyst and suppresses macrocyclic ring inversion. In the subsequent CPA-catalyzed step, the monoaminated intermediate undergoes kinetic resolution, allowing asymmetric differentiation of two remote enantiotopic sites within a flexible macrocyclic scaffold. The method affords a broad range of inherently chiral heteracalix[4]aromatics in good yields and high to excellent enantioselectivities (up to 99% ee), and is further applicable to disubstituted products and diverse derivatizations. Mechanistic studies indicate that hydrogen-bond-assisted catalyst recognition and steric inhibition of conformational inversion are both crucial for enantiocontrol. This work establishes a practical asymmetric strategy for inherently chiral macrocycles and expands the scope of remote desymmetrization in flexible supramolecular scaffolds.
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BibTeX
@article{lin2026remote,
title = {{Remote desymmetrization of tetraoxacalix[2]arene[2]triazines enables the asymmetric synthesis of inherently chiral heteracalix[4]aromatics}},
author = {Zhanpeng Lin and Xinjie Wu and Xinyi Li and Yuanxing Kuang and Zhen Huang and Guofeng Li and Ming Zhang and Liang Hong},
journal = {Chemical Science},
year = {2026},
month = sep,
doi = {10.1039/d6sc03931f},
url = {https://doi.org/10.1039/d6sc03931f},
note = {CC BY 3.0},
}
RIS
TY - JOUR
TI - Remote desymmetrization of tetraoxacalix[2]arene[2]triazines enables the asymmetric synthesis of inherently chiral heteracalix[4]aromatics
AU - Zhanpeng Lin
AU - Xinjie Wu
AU - Xinyi Li
AU - Yuanxing Kuang
AU - Zhen Huang
AU - Guofeng Li
AU - Ming Zhang
AU - Liang Hong
PY - 2026
DA - 2026/09/09
JO - Chemical Science
DO - 10.1039/d6sc03931f
UR - https://doi.org/10.1039/d6sc03931f
AB - The catalytic enantioselective synthesis of inherently chiral macrocycles remains a major challenge, particularly through non-cyclization strategies. Herein, we report a chiral phosphoric acid (CPA)-catalyzed remote desymmetrization of tetraoxacalix[2]arene[2]triazines, enabling access to inherently chiral heteracalix[4]aromatics. The strategy relies on sequential SNAr aminations, in which the first amination installs an aniline N–H unit as a “control handle” that both creates a hydrogen-bonding recognition site for the catalyst and suppresses macrocyclic ring inversion. In the subsequent CPA-catalyzed step, the monoaminated intermediate undergoes kinetic resolution, allowing asymmetric differentiation of two remote enantiotopic sites within a flexible macrocyclic scaffold. The method affords a broad range of inherently chiral heteracalix[4]aromatics in good yields and high to excellent enantioselectivities (up to 99% ee), and is further applicable to disubstituted products and diverse derivatizations. Mechanistic studies indicate that hydrogen-bond-assisted catalyst recognition and steric inhibition of conformational inversion are both crucial for enantiocontrol. This work establishes a practical asymmetric strategy for inherently chiral macrocycles and expands the scope of remote desymmetrization in flexible supramolecular scaffolds.
SN - 2041-6520
SN - 2041-6539
ER -