Toward a Click-to-Click Strategy Enabled by Sequential Reverse Cope Cyclization and Strain-Promoted Alkyne-Nitrone
Vivien Herrscher1, Agathe Martinez1,2, Alexis Vallée1,2
1Université de Reims Champagne-Ardenne, CNRS, ICMR, Reims51687, France.
Organic Letters
|July 17, 2026
Summary
Primary hydroxylamines and strained cyclooctynes efficiently form nitrones under mild conditions. These nitrones enable sequential "click-to-click" ligations for complex molecule synthesis.
Area of Science:
- Organic Chemistry
- Chemical Biology
- Bioconjugation Chemistry
Background:
- Hydroxylamine derivatives are versatile building blocks in organic synthesis.
- Strained cyclooctynes are key components in bioorthogonal chemistry.
- Nitrones are reactive intermediates with diverse synthetic applications.
Purpose of the Study:
- To develop a mild and efficient method for synthesizing nitrones from primary hydroxylamines and strained cyclooctynes.
- To explore the scope and limitations of this reaction with various substrates.
- To demonstrate the utility of the generated nitrones in sequential click chemistry.
Main Methods:
- Reaction of primary hydroxylamines (RNHOH) with strained cyclooctynes (e.g., BCN, DBCO-acid).
- Characterization of the resulting nitrones using standard spectroscopic techniques.
- Strain-Promoted Alkyne-Nitrone Cycloaddition (SPANC) reactions for sequential ligation.
Main Results:
- Primary hydroxylamines react rapidly with strained cyclooctynes under mild conditions to yield nitrones.
- Diverse hydroxylamine derivatives, including amino-acid and carbohydrate-based ones, were successfully coupled.
- DBCO-acid exhibited the highest reactivity among tested cyclooctynes (k2 > 23 M-1 s-1).
- The synthesized nitrones effectively participated in SPANC reactions.
Conclusions:
- A robust method for nitrone synthesis using readily available hydroxylamines and strained cyclooctynes has been established.
- This methodology facilitates the creation of complex molecules through sequential "click-to-click" ligation strategies.
- The developed reaction expands the toolkit for bioconjugation and chemical biology applications.
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