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Photocatalytic Oxygen-Atom Transmutation in Oxetanes

29 October 2025

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Recently, the research group of Ph.D. Ming Joo Koh at the National University of Singapore, in collaboration with Dr. Xinglong Zhang at the Chinese University of Hong Kong, published a paper in Nature entitled "Photocatalytic oxygen-atom transmutation of oxetanes"[1]. This work achieves a breakthrough in oxygen-atom replacement of oxetanes. Their developed photocatalytic strategy selectively substitutes the endocyclic oxygen atom, transforming it in a single step into diverse nitrogen-, sulfur-, or carbon-bridged four-membered and five-membered saturated cyclic systems. The mechanism involves a photocatalytic ring-opening process that forms a dihalide intermediate, followed by nucleophile-mediated ring closure to complete the "atom transmutation"(Fig. 1b). This method exhibits excellent functional group compatibility and chemoselectivity, is applicable for late-stage modification of complex bioactive molecules, and provides a more straightforward route for the synthesis of pharmaceuticals and their analogues.

Background

Four-membered saturated cyclic molecules such as azetidines, thietanes and cyclobutanes have garnered increasing attention in medicinal chemistry. These molecules often possess physicochemical properties relevant to drug discovery: potency, stability, metabolic stability and target specificity. However, the conventional retrosynthesis of four-membered cyclic compounds largely relies on multi-step cycloaddition or nucleophilic substitution reactions, which are often step-intensive, inefficient, and generate significant waste (Fig. 1a). The development of a method that enables direct replacement of the oxygen atom in readily accessible oxetanes with nitrogen, sulfur, or carbon moieties thus holds substantial synthetic value and application potential, particularly as a powerful tool for late-stage functionalization and structural diversification of drug-like molecules.

Fig. 1 | Synthetic logic based on atomic replacement of oxygen in oxetanes. [From Nature]

Mechanistic Hypothesis and Studies

Through DFT calculations and mechanistic experiments, the authors proposed a catalytic cycle involving four key steps and elucidated the origin of selectivity (Fig. 2a):

i) Photocatalytic Initiation: The photoexcited Ru catalyst transfers an electron to CBr₄, generating the ·CBr₃ radical and Ru(III).

ii) Key Reagent Generation: The ·CBr₃ radical reacts with the solvent DMF to form intermediate I, which is subsequently oxidized by Ru(III), efficiently generating the crucial electrophile – the Vilsmeier-Haack reagent (II). DFT calculations indicate this step has a very low activation barrier and is highly exergonic, ensuring efficient reaction initiation.

iii) Ring Deconstruction: Reagent II reacts with the oxetane, triggering ring-opening and ultimately leading to the linear dibromide intermediate (V). This step releases ring strain, which is a key driving force for the reaction.

iv) Ring Reconstruction: The dibromide intermediate V undergoes double nucleophilic substitution in the presence of nucleophiles (e.g., amines, thiols), leading to re-cyclization and completion of the oxygen-atom transmutation.

After condition screening, the optimal conditions were established as follows: using Ru(bpy)₃Cl₂·6H₂O (1 mol%) as the photocatalyst, CBr₄ (2 equiv.) as the bromine source and electron acceptor, in DMF solvent under irradiation with 456 nm blue LEDs and heating, followed by treatment with para-anisidine/Hünig's base at 50 °C. This one-pot procedure successfully afforded azetidine 9 in 85% yield.

Fig. 2 | Mechanistic hypothesis and studies. [From Nature]

Substrate scope

In the O→N transmutation reaction for synthesizing azetidines (Fig. 3), both 2- and 3-substituted oxetanes were successfully transformed, demonstrating excellent functional group tolerance towards groups such as arenes, thioethers, haloarenes (Cl/Br), esters, thiophene, phenol, and cyclic ethers (12–23). For substrates containing free aliphatic alcohols, competing bromination side reactions occurred, necessitating pre-protection. This strategy exhibited a broad scope concerning amine nucleophiles, with aromatic amines (31–33), alkylamines (34–37), and *p*-toluenesulfonamide 38 all participating efficiently in the reaction. Furthermore, the strategy demonstrated good generality and was successfully extended to larger ring systems and acyclic ethers: the five-membered tetrahydrofuran was converted to pyrrolidine 40, while the acyclic ether 41 yielded the tertiary amine 42 in 40% yield, proving that this atom-swapping strategy is not limited to four-membered ring systems.

Fig. 3 | Reaction scope of O-to-N swap. [From Nature]

Extension to other O-atom transmutations: This photocatalytic strategy extends far beyond O→N transmutation. Its broad applicability is demonstrated in O→S, O→C and dual-atom transmutation.

Fig. 4 | Extension to other O-atom transmutations. [From Nature]

Late-Stage Functionalization

Applicability with Complex Amines

The strategy successfully employed complex bioactive amines, such as aminoglutethimide and D-tryptophan methyl ester, as nucleophiles to efficiently generate the corresponding azetidine products (68, 69). This demonstrates its capability for linking complex pharmacophores.

Direct Drug Modification to Enhance Activity

Direct O→S atomic editing on a PDE4 inhibitor (70) yielded the thietane analog 71, which exhibited an IC₅₀ of 17 nM. This represents a threefold potency increase compared to the parent molecule (IC₅₀ = 52 nM).

Access to New Drug Candidates

The method successfully converted a Hepatitis B virus inhibitor (72) into its thio-analog 73, providing an efficient synthetic route to a potentially novel antiviral candidate molecule.

Synthesis of High-Value Drug Intermedials

The transformation of an oxetane into the 1,1-difluorocyclobutane bioisostere 7 exemplifies a route to access analogs with potentially improved metabolic stability.

Streamlined Synthesis of Drug Intermediates

• The synthesis of a key precursor for a respiratory syncytial virus inhibitor was achieved in a 5-step sequence (31% overall yield), representing a significant improvement in both efficiency and step-count over a previously reported 8-step route (<18% overall yield).

• The synthesis of the key CDK2 inhibitor precursor 2 was accomplished in just 4 steps, drastically shorter than the reported 12-step synthetic route. This streamlined process also avoided the use of explosive NaN₃, precious metal catalysts, and tedious protection/deprotection steps.

Fig. 5  Application to late-stage functionalization and complex molecule synthesis. [From Nature]

AmBeed's Products Support Related Research

Photocatalyst Ru(bpy)3Cl2·6H2O, oxetanes, and nitrogen/sulfur/carbon/dual-atom reagents were used in the above studies. At AmBeed, we offer a diverse catalog of high-purity reagents to support your research in this field:

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References

[1]Zhang Y Q, Li S H, Zhang X, et al. Photocatalytic oxygen-atom transmutation of oxetanes[J]. Nature, 2025.

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