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Dialkyl ether synthesis through heteroatom homolytic substitution
Nature
(2026) Cite this article
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The modular and selective synthesis of dialkyl ethers, particularly sterically congested variants, remains a longstanding challenge in drug discovery and medicinal chemistry.1,2 Hindered alkyl ethers are especially desirable given their prevalence in bioactive natural products and favorable physicochemical properties.3 Classically, dialkyl ether synthesis relies on nucleophilic substitution strategies; however, SN2 reactions are fundamentally limited by steric congestion at the transition state, while SN1 pathways proceed through promiscuous carbocation intermediates prone to elimination, rearrangement, and loss of stereogenic information.4–6 Herein, we report a radical-based paradigm for general dialkyl ether synthesis enabled by an underutilized heteroatom homolytic substitution (het-SH2) mechanism. This mechanistic paradigm overcomes the intrinsic limitations of classical polar substitution chemistry by leveraging carbon-centered radicals generated under mild conditions that are insensitive to steric congestion in the bond-forming transition state. Utilizing a titanium-based catalytic platform in combination with visible-light photoredox catalysis, we demonstrate the efficient coupling of carboxylic acid-derived redox-active esters with alcohols across a broad range of substitution patterns, including 3°–2°, 3°–1°, 2°–2°, and 2°–1° architectures. This strategy grants access to dialkyl ether chemical space largely inaccessible through conventional approaches, including sterically demanding BCP ether bioisosteres, and enables late-stage diversification of complex pharmaceutical scaffolds. This platform is expected to serve as a broadly applicable blueprint for radical-mediated heteroatom bond formation.
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These authors contributed equally: Johannes J. Großkopf, Johnny Z. Wang
Merck Center for Catalysis at Princeton University, Princeton, New Jersey, USA
Johannes J. Großkopf, Johnny Z. Wang, Jacqueline W. Gu & David W. C. MacMillan