Molecular-editing method trades oxygen for other atoms to diversify fragments on the fly

Catalytic methods to introduce fluorine into the backbone of small-ring heterocycles are challenging due to the problems of strain-induced ring cleavage and defluorination. Now, a copper catalyst medi...

Skeletal editing pushed beyond aromatic structures, sparking new opportunities in drug discovery

Nature Chemistry, Published online: 13 July 2026; doi:10.1038/s41557-026-02213-7Oxetane and azetidine scaffolds are important motifs in medicinal chemistry, yet their direct interconversion remains challenging. Now it has been shown that oxetanes can be converted into azetidines via a broadly applicable, non-redox skeletal editing strategy, enabling rapid access to structurally diverse azetidine analogues for drug discovery.

The compound (S)-oxetan-2-ylmethyl tosylate 1 was identified as a key synthetic fragment for the introduction of the 2-substituted oxetane functionality in potential drug candidates under development ...

Taxol is a potent drug used in various cancer treatments. Its complex structure has prompted extensive research into its biosynthesis. However, certain critical steps, such as the formation of the oxe...

Chiral spirocyclic oxetanes [2-oxo-spiro(3H-indole-3,2′-oxetanes)] were subjected to irradiation in the presence of a chiral thioxanthone catalyst (5 mol %) at λ = 398 nm. An efficient kinetic resolution was observed, which led to an enrichment of one oxetane enantiomer as the major enantiomer (15 examples, 37−50% yield, 93−99% ee). The minor enantiomer underwent decomposition, and the decomposition products were carefully analyzed. They arise from a photocycloreversion (retro-Paternò–Büchi reaction) into a carbonyl component and an olefin. The cycloreversion offers two cleavage pathways depending on whether a C−O bond scission or a C−C bond scission occurs at the spirocyclic carbon atom. The course of this reaction was elucidated by a suite of mechanistic, spectroscopic, and quantum chemical methods. In the absence of a catalyst, cleavage occurs exclusively by initial C−O bond scission, leading to formaldehyde and a tetrasubstituted olefin as cleavage products. Time-resolved spectroscopy on the femtosecond/picosecond time scale, synthetic experiments, and calculations suggest the reaction to occur from the first excited singlet state (S1). In the presence of a sensitizer, triplet states are populated, and the first excited triplet state (T1) is responsible for cleavage into an isatin and a 1,1-diarylethene by an initial C−C bond scission. The kinetic resolution is explained by the chiral catalyst recruiting predominantly one enantiomer of the spirocyclic oxindole. A two-point hydrogen-bonding interaction is responsible for the recognition of this enantiomer, as corroborated by NMR titration studies and quantum chemical calculations. Transient absorption studies on the nanosecond/microsecond time scale allowed for observing the quenching of the catalyst triplet by either one of the two oxetane enantiomers with a slight preference for the minor enantiomer. In a competing situation with both enantiomers present, energy transfer to the major enantiomer is suppressed initially by the better-binding minor enantiomer and─as the reaction progresses─by oxindole fragmentation products blocking the binding site of the catalyst.

Enantioselective amine-catalyzed conjugate additions of aldehydes to oxetane- and azetidine-containing nitroolefins afford γ-nitroaldehydes as key building blocks en route to spirocyclic oxetane/azetidine-pyrrolidines. The study provided insights into the stability and reactivity of these β,β-disubstituted nitroolefins and enabled the enantioselective synthesis of chiral oxetanes and azetidines in moderate-to-high yields and enantioselectivities. This approach expands synthetic access to medicinally relevant scaffolds and broadens the scope of enantioselective organocatalytic transformations.

Four-membered heterocycles such as oxetanes and azetidines represent attractive and emergent design options in medicinal chemistry due to their small and polar nature and potential to significantly im...

The compound (S)-oxetan-2-ylmethyl tosylate 1 was identified as a key synthetic fragment for the introduction of the 2-substituted oxetane functionality in potential drug candidates under development in our laboratories. The focus of this paper is to highlight methodologies evaluated in our quest for synthetic routes to 2-substituted oxetanes suitable for enabling manufacture. Of the five routes investigated, three (Route 1A, Route 2, and Route 3) were successfully demonstrated in the laboratory. Subsequently, Route 3 was executed at scale to deliver metric ton quantities of the oxetane tosylate 1 as a solution in EtOAc, which was integrated into the synthesis of 2 and aforementioned drug candidates.

Four-membered heterocycles such as oxetanes and azetidines represent attractive and emergent design options in medicinal chemistry due to their small and polar nature and potential to significantly impact the physiochemical properties of drug molecules. The challenging preparation of these derivatives, especially in a divergent manner, has severely limited their combination with other medicinally and biologically important groups. Consequently, there is a substantial demand for mild and effective synthetic strategies to access new oxetane and azetidine derivatives and molecular scaffolds. Here, we report the development and use of oxetane sulfonyl fluorides (OSFs) and azetidine sulfonyl fluorides (ASFs), which behave as precursors to carbocations in an unusual defluorosulfonylation reaction pathway (deFS). The small-ring sulfonyl fluorides are activated under mild thermal conditions (60 °C), and the generated reactive intermediates couple with a broad range of nucleophiles. Oxetane and azetidine heterocyclic, -sulfoximine, and -phosphonate derivatives are prepared, several of which do not have comparable carbonyl analogs, providing new chemical motifs and design elements for drug discovery. Alternatively, a SuFEx pathway under anionic conditions accesses oxetane-sulfur(VI) derivatives. We demonstrate the synthetic utility of novel OSF and ASF reagents through the synthesis of 11 drug analogs, showcasing their potential for subsequent diversification and facile inclusion into medicinal chemistry programs. Moreover, we propose the application of the OSF and ASF reagents as linker motifs and demonstrate the incorporation of pendant groups suitable for common conjugation reactions. Productive deFS reactions with E3 ligase recruiters such as pomalidomide and related derivatives provide new degrader motifs and potential PROTAC linkers.

Chiral spirocyclic oxetanes [2-oxo-spiro(3H-indole-3,2′-oxetanes)] were subjected to irradiation in the presence of a chiral thioxanthone catalyst (5 mol %) at λ = 398 nm. An efficient kinetic resolut...

Although biocatalysis offers complementary or alternative approaches to traditional synthetic methods, the limited range of available enzymatic reactions currently poses challenges in synthesizing a diverse array of desired compounds. Consequently, there is a significant demand for developing novel biocatalytic processes to enable reactions that were previously unattainable. Herein, we report the discovery and subsequent protein engineering of a unique halohydrin dehalogenase to develop a biocatalytic platform for enantioselective formation and ring-opening of oxetanes. This biocatalytic platform, exhibiting high efficiency, excellent enantioselectivity, and broad scopes, facilitates the preparative-scale synthesis of chiral oxetanes and a variety of chiral γ-substituted alcohols. Additionally, both the enantioselective oxetane formation and ring-opening processes are proven scalable for large-scale transformations at high substrate concentrations, and can be integrated efficiently in

The Paternò–Büchi reaction is the [2+2] photocycloaddition of a carbonyl with an alkene to afford oxetane products. Enantioselective catalysis of this classical photoreaction, however, has proven to b...

Chemists identify the enzyme that forms the molecule’s oxetane ring