Dialkyl ether synthesis through heteroatom homolytic substitution.

Authors

Johannes J Großkopf, Johnny Z Wang, Jacqueline W Gu, Cheng Bi, Sarah N Dishman, Xiaoshen Ma, Yu-Hong Lam, David W C MacMillan

Published in

Nature. Aug 20, 2026. Epub Aug 20, 2026.

Abstract

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, S_N2 reactions are fundamentally limited by steric congestion at the transition state, while S_N1 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-S_H2) 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.

PMID:
42742172
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

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