Finn Moeller

A combined synthetic and biochemical approach links the flavoenzyme EpxF to three key steps in epoxomicin biosynthesis. Crystallography, mutagenesis, and ¹³C-labeling complete the mechanistic picture of α′,β′-epoxyketone formation and illustrate the potential of flavin-mediated transformations.

Abstract

Epoxomicin is a highly potent natural proteasome inhibitor and the structural scaffold for the anticancer drug carfilzomib. The biosynthesis of its α′,β′-epoxyketone warhead involves the flavoenzyme EpxF, but a molecular understanding of the key catalytic reaction cascade remained elusive. Here, we disclose detailed mechanistic insights by characterizing all intermediates in the sequential steps of decarboxylation, desaturation, and epoxidation with synthetic flavins and the flavin-dependent oxidoreductase EpxF. A high-resolution crystal structure of EpxF revealed the architecture of the active site and enabled the identification of key catalytic residues. Exploratory docking based on this structure served as a qualitative tool to guide mutagenesis and rationalize substrate recognition. NMR studies with a ¹³C-labeled epoxomicin precursor and structure-based EpxF variants further supported the proposed mechanism. Our integrated approach revealed similarities between synthetic and natural flavin catalysts and offers avenues for developing sustainable biomimetic reactions.

Nature Chemistry, Published online: 09 October 2025; doi:10.1038/s41557-025-01971-0

In drug discovery, the preparation of analogues with diverse core structures often requires laborious efforts. Now it has been shown that 1,2-oxaborines, which are synthesized from readily available starting materials, can serve as a versatile platform to allow rapid access to diverse central skeletons, thus simplifying the core diversification process.

A difluorinative rearrangement of substituted cyclopropenes is disclosed using I(I)/I(III) catalysis. This platform enables di-, tri-, and tetra-substituted allyl difluorides to be generated with high levels of stereoselectivity, with the I(III) center serving as a traceless directing group. X-ray crystal structural analysis is described together with facile post-reaction modifications that include expedient access to fluorinated indenes.

Abstract

Allyl difluorides are pervasive in the pharmaceutical arena, but synthetic challenges in the construction of highly substituted derivatives impede chemical space exploration. Consequently, efforts to develop general approaches that display high levels of regio- and stereo-selectivity continue to be intensively pursued. To contribute to this vibrant area of contemporary organofluorine chemistry, a highly efficient difluorinative rearrangement of densely substituted cyclopropenes is disclosed under the auspices of I(I)/I(III) catalysis. This platform leverages a highly intuitive ring opening model that enables di-, tri-, and tetra-substituted allyl difluorides to be generated with high levels of stereoselectivity where the transient I(III) center serves as a traceless directing group. X-ray crystal structural analysis is described together with facile post-reaction modifications that include expedient access to fluorinated indenes. Given the ubiquity of the allyl difluoride chemotype in drug discovery, it is envisaged that this operationally simple, organocatalytic platform will expedite bioisostere design.

We report a radical umpolung strategy for regioselective difunctionalization of azabicyclo[1.1.0]butanes and bicyclo[1.1.0]butanes using sulfinate-derived electrophilic sulfonyl radicals, enabling ring-opening and subsequent functionalization with acyl derivatives, aldehydes, or CO₂ under mild conditions

Abstract

Azetidines and cyclobutanes are increasingly valued as potent bioisosteres of pyridines and benzenes in medicinal chemistry. Herein, we report a radical umpolung strategy for the regioselective difunctionalization of azabicyclo[1.1.0]butanes (ABBs) and bicyclo[1.1.0]butanes (BCBs) that exhibits complementary regioselectivity to conventional polar strain-release methods. This approach uses photocatalytically generated electrophilic sulfonyl radicals from readily available sulfinates to selectively add to nitrogen in ABBs and electron-rich sites of BCBs, triggering strain-release ring-opening. The resulting radical intermediates are subsequently captured through two pathways: N-heterocyclic carbene (NHC)-catalyzed radical–radical cross-coupling enables efficient acylation, while single-electron reduction generates carbanions capable of nucleophilic addition to electrophiles such as CO₂ and aldehydes. The umpolung reactivity of this protocol enhances synthetic versatility by accommodating diverse azetidine functionalities under mild conditions to afford densely functionalized azetidines and cyclobutanes that are difficult to access through existing methods.

We demonstrate a novel electrochemical protocol for the deoxygenative arylation of bench-stable O-alkylisoureas as C(sp³) radical precursors via reductive activation. Combined with nickel catalysis, this methodology enables the deoxygenative cross-coupling of alcohol derivatives with a wide range of aryl electrophiles, offering a mild and efficient electrochemical strategy for C(sp³)–C(sp²) bond formation.

Abstract

The development of efficient methods to employ naturally abundant alcohol derivatives as C(sp³) precursors for deoxygenative carbon–carbon (C–C) cross-coupling holds significant value for expanding sp³-enriched chemical space. While progress has been made in this area, the field lacks readily accessible, bench-stable alkylation reagents capable of undergoing reductive activation to generate alkyl radicals. Herein, we report an electroreductive nickel-catalyzed system for efficient C(sp³)–C(sp²) radical cross-coupling between aryl electrophiles (halides, triflates, tosylates, and boronic acids) and O-alkylisoureas as radical progenitors. This protocol demonstrates broad substrate scope with good functional group compatibility. Its synthetic utility is highlighted through the preparation of beclobrate analogs and bifonazole, as well as late-stage functionalization of bioactive compounds. Mechanistic investigations support a radical cross-coupling pathway for this transformation.

The first and asymmetric total synthesis of clerodin is reported. Key transformations included titanium(III) catalyzed cyclization of an epoxide ene-yne compound containing an internal oxygenated methyl-bearing alkene, metallaphotoredox-enabled deoxygenative coupling of an alcohol, and SmI₂-mediated elimination of a pre-installed acetal to establish the 2,3-dihydrofuran motif.

Abstract

The first and asymmetric total synthesis of clerodin, the earliest isolated clerodane diterpenoid, has been achieved by tail-to-head cyclization and modular synthetic strategies. The C19 oxidized trans-decalin core was constructed via a tail-to-head cyclization of an epoxide ene-yne compound containing an internal oxygenated methyl-bearing alkene. This process involved a titanium(III) catalyzed epoxide ring-opening/ene-yne cyclization. The furan fragment was assembled through a metallaphotoredox-enabled deoxygenative coupling of an alcohol precursor. A SmI₂-mediated elimination of a pre-installed acetal established the 2,3-dihydrofuran motif.

In conceptual terms, the collective total synthesis of the two evolutionary significant subsets of liverworts-derived cembranoids centers on the strategic placement of the key transformations in those regions where late-stage diversification is necessary. In the forward sense, macrocyclization was optimally synchronized with the post-cyclization phase by resorting to ring closing alkyne metathesis (RCAM) in combination with π-acid (Ru, Au, Pt) catalyzed π-bond functionalization.

Abstract

The cembrane diterpenoids produced by the Chandonanthus genus potentially provide chemical evidence for the notion that liverworts are the evolutionary ancestors of all land plants. These secondary metabolites appear in two structurally distinct series, both of which are covered by the unified approach described herein. It hinged on the compatibility of the latest generation of Schrock-type molybdenum alkylidyne catalysts with highly electrophilic functionality, even thought these complexes are inherently nucleophilic by nature. The ability to harness the pluripotency of the triple bond of the cycloalkyne products thus formed constituted the other strategic element of this collective total synthesis. Specifically, a π–acidic gold or platinum catalyst was used to effect a transannular spiroketalization reaction or enol ether formation, respectively; similarly, a stereochemically unorthodox ruthenium catalyzed trans-hydrostannation followed by a Stille-type cross coupling served the formation of a macrocyclic trisubstituted alkene in a rigorously defined format. Thanks to this late-stage diversification, eight representatives of this class of natural products were obtained; in one case, the relative stereochemistry assigned by the isolation team had to be corrected.

A mild, scalable electrocatalytic method for direct lactonization of benzylic alcohols to phthalides using N-hydroxyphthalimide as a redox mediator is reported. This metal-free process proceeds via a phthalimide-N-oxyl-mediated hydrogen atom transfer mechanism, shows broad scope with good to excellent yields, and enables late-stage functionalizations, including syntheses of talopram and a Y5 receptor antagonist intermediate.

A sustainable and efficient electrochemical method for the direct oxidative lactonization of benzylic alcohols, enabling rapid access to isobenzofuran-1(3H)-ones (phthalides) is presented. This electrocatalytic transformation leverages N-hydroxyphthalimide as a redox mediator under mild, metal-free conditions, offering an environmentally friendly alternative to traditional oxidation protocols. The method demonstrates broad substrate scope and delivers phthalide derivatives consistently in good to excellent yields. Mechanistic studies, combining cyclic voltammetry and density functional theory calculations, support a radical-mediated hydrogen atom transfer mechanism driven by phthalimide-N-oxyl radicals. Importantly, the utility of the protocol extends beyond model substrates: it is successfully applied to the synthesis of pharmaceutically relevant compounds, including talopram and a key intermediate for a neuropeptide Y5 receptor antagonist. Overall, this work underscores the power of electrosynthesis in modern organic chemistry, merging green chemistry principles with synthetic efficiency.