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. 2025 Aug 29;27(34):9364-9369.
doi: 10.1021/acs.orglett.5c02576. Epub 2025 Aug 18.

Enantioselective NHC-Catalyzed Annulation via Umpolung for the Construction of Hydroxylamine Architectures with Variable Ring Sizes

Izabela Barańska  1 , Monika Radosińska  1 , Liliana Dobrzańska  1 , Krzysztof Dzieszkowski  2 , Zbigniew Rafiński  1
Affiliations

Enantioselective NHC-Catalyzed Annulation via Umpolung for the Construction of Hydroxylamine Architectures with Variable Ring Sizes

Izabela Barańska et al. Org Lett. .

Abstract

An efficient and highly enantioselective organocatalytic annulation for the synthesis of chiral hydroxylamine-containing heterocycles is described. The N-heterocyclic carbene (NHC)-catalyzed reaction successfully engages traditionally inert keto-oxime ethers as electrophiles in an intramolecular cyclization with in situ generated Breslow intermediates. This protocol overcomes the inherent challenges of this substrate class, such as low C═N bond electrophilicity and potential N-O bond cleavage, to deliver diverse five- and six-membered N-O frameworks in excellent yields (up to 99%) and enantioselectivities (up to >99% ee). This work provides a powerful, metal-free strategy to access valuable chiral building blocks and significantly expands the reactivity scope of keto-oximes in asymmetric catalysis.

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Figures

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Importance of the functional N–O (hydroxylamino) group, synthesis challenges and strategies, and NHC-catalyzed annulation for N-alkoxyamine synthesis.
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1. Scope of Indole Substitution and Ether Oxime Substrates
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2. Scope of Salicylaldehyde-Derived Ether Oximes
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3. Deprotection of O-THP for Hydroxylamine Moiety Formation
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