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Intermolecular Stacking-Instructed Chiral Preference in Covalent 2 + 2 Macrocyclization.

Zhen-Sheng Huang¹, Wen-Rong Wang¹, Fang-Hong Yang¹

¹Department of Chemistry, College of Chemistry and Chemical Engineering and the MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, Xiamen University, Xiamen 361005, China.

|February 27, 2026

Summary

This summary is machine-generated.

This study reveals unexpected chiral preferences in macrocyclization reactions. Using specific amino acid-based reactants, researchers achieved high yields of heterochiral macrocycles, driven by intermolecular stacking rather than intramolecular bonding.

Keywords:

anion receptor chiral self-sorting macrocycle stacking peptidomimetic macrocycles stereoselective macrocyclization

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Area of Science:

Supramolecular Chemistry
Organic Synthesis
Stereochemistry

Background:

Macrocyclization reactions are crucial for synthesizing complex molecules.
Chiral preferences in macrocyclization typically rely on intramolecular interactions and entropy-driven processes.
Controlling stereochemistry in macrocycle formation is a significant challenge in synthetic chemistry.

Purpose of the Study:

To investigate chiral preferences in 2 + 2 macrocyclization reactions.
To explore the role of intermolecular interactions in stereoselective macrocycle formation.
To establish a new strategy for catalyst-free, stereoselective macrocyclization.

Main Methods:

Reacting racemic or meso 2,6-pyridine-(dicarbonylamino-acid)-hydrazides with achiral 1,4-phenylenediisothiocyanate.
Utilizing alanine (A)-based and phenylalanine (F)-based dihydrazides.
Analyzing product yields and stereochemical outcomes using analytical techniques (implied).

Main Results:

Exclusive formation of heterochiral macrocycles (e.g., L,L,D,D-AAAA) in high yields (ca. 80%) from racemic starting materials.
Demonstrated heterochiral preference with phenylalanine and mixed amino acid-based dihydrazides.
Observed a preference for L,D,D,L-AAAA over L,D,L,D-AAAA from meso dihydrazides.
Identified enhanced intermacrocycle stacking as the driving force for chiral preference.
Favored macrocycles exhibited more symmetric conformations upon stacking, leading to increased thermal stability (30-40 °C higher decomposition temperature).

Conclusions:

Established a novel, catalyst-free method for stereoselective macrocyclization driven by intermolecular stacking.
Demonstrated that intermolecular interactions can be leveraged to control macrocycle stereochemistry, orthogonal to traditional entropy-driven homochiral preferences.
This work provides a new paradigm for designing stereoselective synthetic strategies for macrocyclic compounds.