The Asymmetric Synthesis of an Acyclic N-Stereogenic Amine
Summary
Published: 19 November 2025
Authors: Chendan Zhu, Sayantani Das, Marie Sophie Sterling, Nobuya Tsuji, Spencer J. Léger, Frank Neese, Chandra Kanta De, Benjamin List et al.
Journal: Nature
This paper reports a catalytic asymmetric route to stable, acyclic N-stereogenic (nitrogen-centred) amines. The key transformation is the addition of enol silanes to nitronium ions that are ion-paired with a confined chiral anion, producing ‘anomeric amines’ whose nitrogen inversion is slowed by two N-oxy substituents. Computational studies accompany the experiments and provide insight into the origin of stereocontrol. The result is a practical way to access enantiopure anomeric amines that were previously elusive due to rapid pyramidal inversion.
Key Points
- First catalytic asymmetric synthesis of stable, acyclic N-stereogenic amines using enol silane addition to nitronium ions paired with a chiral anion.
- The products are ‘anomeric amines’ bearing two N-oxy substituents that slow nitrogen inversion and stabilise the stereocentre.
- The stereogenic step challenges conventional stereochemical descriptors used for enantiodifferentiation.
- Computational studies corroborate experimental stereocontrol and illuminate key transition states and ion-pairing interactions.
- Provides a new platform to explore enantiopure nitrogen-centred stereochemistry with potential impact on medicinal chemistry and asymmetric methodology.
- Supplementary information (methods, NMR, HPLC chromatograms) is available with the article.
Content Summary
The authors designed a catalytic system where nitronium ions, ion-paired to a confined chiral anion, react with enol silanes to forge N-stereogenic centres in acyclic amines. The resulting anomeric amines contain two N-oxy substituents that significantly impede the usual rapid pyramidal inversion of nitrogen, making the stereocentre configurationally stable at ambient conditions. Experimental data show high enantioselectivity; complementary computational analysis explores the stereocontrolling interactions and rationalises the observed selectivity. The study also notes that the stereochemistry-forming step does not fit neatly into previously established stereochemical descriptors, prompting fresh mechanistic thinking.
Context and Relevance
Carbon-centred stereochemistry is routine in synthesis, but nitrogen-centred stereochemistry—particularly in acyclic systems—has been scarce because nitrogen inverts rapidly. This work fills that gap by providing a catalytic, generalisable approach to stable N-stereogenic centres. That is important for fields such as drug discovery, where chiral amines are common pharmacophores; being able to access enantiopure nitrogen stereocentres could enable new molecular scaffolds and refined biological selectivity. The method also advances fundamental understanding of stereocontrol in ion-pairing and anomeric systems.
Author’s take
Punchy: This is a clear methodological step-change. The team gives chemists a tangible way to make acyclic N-stereogenic amines that won’t immediately racemise. If you work on asymmetric synthesis or medicinal chemistry, this paper matters.
Why should I read this?
Short and honest: If you want chiral amines that actually keep their chirality, this is the paper. It shows a clever catalytic trick to lock in nitrogen chirality, backs it up with computations and solid analytical data, and opens up new design possibilities for molecules where nitrogen stereochemistry matters. Handy time-saver — the authors did the heavy lifting so you don’t have to.