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DOI: 10.1055/a-2601-4351
Stereodivergent Synthesis of Cyanocyclopropanes via Asymmetric Nitrogen Insertion
Nitrogen Insertion via Asymmetric Condensation and Chirality Transfer: A Stereodivergent Entry to Cyanocyclopropanes.
Angew. Chem. Int. Ed. 2025;
DOI: 10.1002/anie.202503056
Significance
Nitriles are highly common functional groups in a variety of biologically active natural products and pharmaceutical compounds. While their synthesis from oxime esters is well established, this work is the first to present an asymmetric method to access enantiomerically enriched cyanocyclopropanes through axially chiral oxime esters. The synthesis of these nitrile precursors is enabled using a catalytic chiral phosphoric acid. The significance of this work is demonstrated by the formal synthesis of Tasimelteon, an FDA-approved drug used for the treatment of non-24-hour sleep-wake disorder.
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Comment
This work showcased a novel method to access enantioenriched cyanocyclopropanes from readily available prochiral cyclobutanones. Condensation with diphenylphosphinyl hydroxylamine (DPPH) affords the corresponding oxime ester, which is also isolable. Treatment with lithium bis(trimethylsilyl)amide (LiHMDS) then triggers the ring contraction, which proceeds through a Beckmann fragmentation followed by C–C bond formation. Both the cis- and trans-cyanocyclopropanes can be obtained in good enantioselectivities and moderate yields by changing the temperature and LiHMDS stoichiometry.
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Publication History
Article published online:
23 June 2025
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