Finn Moeller

The Giese-Reaction celebrates its 50. Birthday, it is a cyclic radical chain reaction centered around C,C-bond formation in a three component synthesis. This minireview speaks about the birth of the name-reaction, explains how the complete understanding of its reaction mechanism stimulates new methods in organic synthesis, and why it can proceed in living cells.

Abstract

50 years ago, a synthetic method was discovered, in which alkyl radical precursors, alkenes and hydrogen donors selectively yield 1:1:1-addition products in cyclic chain reactions. This paved the way for many variants of three-component syntheses, which became standard procedures for C,C-bond formation. For successful syntheses the different chain carrying radicals have to follow reactivity and selectivity rules. This requires knowledge of the substituent influence on substrate-, regio- and stereoselectivities of intermolecular radical reactions. These rules were experimentally elucidated, and the synthetic method was coined “Giese reaction”. 20 years after its discovery in the chemical laboratory, biologists observed that microorganisms use the same synthetic strategy, which triggered our studies on biological cells. Although chemical rules in laboratory vessels and biological cells are the same, their different set-ups lead to very different features. Syntheses in homogeneous solution of a laboratory vessel is driven by kinetic effects. In contrast, most reactions in biological cells occur at protein/water interfaces, where thermodynamic interactions with enzymatic amino acids establish close contact between the educts. In addition, biochemical processes often start with metallo-cofactors that generate the productive radicals at the interface by long-distance electron transfer.

Strained spirocyclic spiro[2.3]hexane and its heteroatom-containing derivatives, including previously underrepresented 5-oxa-1-azaspiro[2.3]hexanes and 1,5-diazaspiro[2.3]hexanes, were synthesized via a modular approach of insertion of cyclobutane-, oxetane-, and azetidine-containing sulfonium reagents into alkenes, carbonyls and imines. A combined in silico unsupervised learning and predictive analytics approach was used to investigate their potential as bioisosteres and our hypothesis was validated through in vitro studies.

Abstract

Molecular scaffolds with a high fraction of sp³ -hybridized centers have attracted considerable attention in medicinal chemistry as bioisosteres for a wide range of aromatic and nonstrained heterocycles. In particular, strained spiro-heterocycles have garnered popularity for this purpose, although access to spiro[2.3]hexane analogues is underrepresented. We herein report modular access to nine different spiro[2.3]hexane analogues, including previously underdeveloped 5-oxa-1-azaspiro[2.3]hexane and 1,5-diazaspiro[2.3]hexane motifs. Our synthetic approach leverages novel cyclobutane-, oxetane-, and azetidine-substituted sulfonium salts, which can undergo Johnson–Corey–Chaykovsky type reactions with alkenes, carbonyls and imines to provide access to the desired spiro[2.3]hexanes. Here, we also report the first comprehensive computational and predictive in silico evaluation of their bioisosteric potential, with validation provided by in vitro experiments.

Anodic oxidation unlocks C─N bond formation in electron-rich fluoroarenes. Spatial separation of redox events extends the lifetime of active intermediates, expands the scope of nucleophilic aromatic substitution reactions, and promotes a new mechanism for S_NAr reactions: uphill redox catalysis. Powered by voltage control, azolation occurs quickly and selectively; reactions proceed with catalytic charge and can be easily scaled in a batch setup.

Abstract

Nucleophilic aromatic substitution (S_NAr) reactions are critical methods for forming C─N bonds in synthetic campaigns, but limitations in electrophile electronics restrict access to a large portion of chemical space. Photochemical oxidation of fluoroarenes has emerged as an attractive strategy to activate fluoroarenes toward nucleophilic addition, but back-electron transfer to solution-phase reduced photocatalysts limit the scope and efficiency of these methods. Herein, we describe an electrochemical strategy to overcome this obstacle by spatially separating redox events at electrode surfaces, extending the lifetime of the activated electrophile and enabling the azolation of electron-rich alkoxyfluoroarenes. Through stabilization of the oxidized product with voltage control and HFIP solvent, the reaction proceeds with catalytic charge via a proposed uphill redox chain mechanism. A wide range of electron-rich fluoroarenes and azoles are tolerated—including those with orthogonal functional group handles. The redox catalytic nature of this e-S_NAr reaction enables energy and mass efficient syntheses and facile scaling in a simple batch setup.

Catalytic self-assembling peptides (cSAPs) form fibrils that catalyze the retro-aldol reaction of Methodol. Co-assembly with inactive peptides tunes catalytic efficiency by altering substrate accessibility and the distance to the nucleophilic lysine. This approach enables precise engineering of catalytic domains and activities in peptide-based catalytic nanostructures.

Abstract

Short peptide sequences self-assemble into supramolecular structures through intermolecular interactions, creating a microenvironment in which chemical reactions can be catalyzed. In recent years, many peptide sequences have shown to demonstrate catalytic activity upon nanostructure formation, but the engineering of the catalytic microenvironment through co-assembly strategies have not been explored. We introduce a peptide sequence that gains retro-aldolase activity upon assembly to supramolecular peptide fibrils in aqueous buffer solution (pH 7.4). The catalytic activity is first optimized through synthetic sequence variation and the structure formation properties of the peptides are characterized. Co-assembly with inactive peptide sequences enables the up- or downregulation of the catalytic activity over a dynamic range, by modulating the likelihood for substrate interaction and thus the distance of the substrate to the nucleophilic lysine at the active site. It is observed that co-assemblies with positively charged sequences increase activity, whereas negatively charged peptide sequences decrease activity. We show that the emerging field of peptide-based catalysts can be further advanced by the engineering of the catalytic domain using heterogeneous supramolecular assembly.

We present a photoswitchable peptide conjugate which exhibits isomerism-dependent self-assembly: the planar trans-isomer assembles into well-ordered nanofibers while the non-planar cis-isomer yields disordered aggregates. Our study offers a direct visualization on the effects of structure formation inside living cells.

Abstract

Understanding how self-assembled structure formation affects cells remains a central challenge in supramolecular chemistry. However, chemical tools that allow access to both ordered and disordered intracellular assemblies from a single molecular scaffold are rare due to design complexity. Here, we present a photoswitchable isotripeptide incorporating an arylazopyrazole (AAP) unit, which undergoes intracellular cleavage to yield a self-assembling monomer. Upon photoisomerization, the planar trans-isomer forms β-sheet-rich nanofibers with strong aromatic interactions, while the non-planar cis-isomer assembles into disordered, random-coil aggregates lacking aromatic contribution. The structural dynamics of the assemblies are demonstrated by repeated photoswitching between the two states in buffered conditions. Notably, A549 cancer cell viability correlates with the isomer-dependent assembly behavior and critical aggregation concentrations (CACs): the trans-isomer, with higher aggregation propensity, exhibits greater cytotoxicity. This photoswitchable peptide system thus provides a powerful platform with fast, reversible and robust switching kinetics, long isomer half-lives, and high photostability to probe the intracellular consequences of supramolecular order and disorder using a single molecular scaffold.

An intramolecular Mannich reaction (A/B/E/F rings) and intermolecular Diels–Alder reactions (C/D rings) afforded a cage-like hexacyclic core skeleton of denudatine alkaloids. Derivatization of the hexacyclic intermediate enabled the first asymmetric total syntheses of four denudatine alkaloids: (–)-cochlearenine, (–)-macrocentrine, (–)-dictizine, and (–)-15-veratroyl-17-acetyl-19-oxodictizine (see scheme).

Abstract

The first asymmetric total syntheses of four denudatine alkaloids, cochlearenine, macrocentrine, dictizine, and 15-veratroyl-17-acetyl-19-oxodictizine, along with the asymmetric synthesis of the proposed structure of acochlearine, were accomplished in a divergent manner. Highly fused tetracyclic skeletons (A/B/E/F rings) with different N-alkyl groups (Me and Et) were constructed by Brønsted acid promoted intramolecular Mannich reactions. The bicyclo[2.2.2]octane C/D rings were constructed via two-fold intermolecular Diels–Alder reactions. By utilizing these key processes, the common intermediates, possessing the complex cage-like hexacyclic skeleton, were constructed. From these common intermediates, the four denudatine alkaloids were synthesized through late-stage, chemo- and stereoselective modifications around the A/C rings. The spectroscopic data of the proposed structure of acochlearine were inconsistent with those of natural acochlearine.

The aviation sector's reliance on fossil kerosene is a major source of CO₂ emissions, while wood waste represents an abundant, renewable carbon resource that can help reduce its footprint. Hemicellulose and lignin are catalytically converted into kerosene-like naphthenes via Friedel–Crafts alkylation and hydrodeoxygenation, enabling sustainable drop-in aviation fuels compatible with existing engines and infrastructure.

Abstract

To address the aviation sector's growing carbon footprint, this study presents a novel route for producing sustainable aviation fuel precursors via acid-catalyzed Friedel–Crafts alkylation of wood-derived lignin monomers with furfuryl alcohol. Using guaiacol as a model compound, key catalytic requirements were investigated in batch mode. Although heterogeneous zeolites showed initial promise, pore blocking by oligomerized furfuryl alcohol limited performance, leading to the selection of para-toluenesulfonic acid as an effective homogeneous catalyst. A fed-batch strategy was employed to suppress oligomerization by controlling furfuryl alcohol concentration. The resulting alkylated products, structurally aligned with conventional kerosene, were further upgraded via metal-catalyzed hydrodeoxygenation, achieving final overall yields up to 92 C%.

A convergent radical annulation strategy for the synthesis of complex terpenoids is disclosed. A 1,3-diradical synthon enabled rapid C-ring annulations through sequential radical couplings to synthesize serratene and cyclodammarane scaffolds from sclareolide. These concise routes feature unique hydrogen atom transfer-initiated (HAT) radical cascades including a 7-endo-trig cycloisomerization and a radical/polar crossover (RPC) bicyclization.

Abstract

The development of a convergent radical annulation strategy for the synthesis of complex terpenoids from sclareolide is disclosed. This approach employs a 1,3-diradical synthon to enable rapid C-ring annulation through inter- and intramolecular radical couplings, exemplified in the concise syntheses of serratene and cyclodammarane scaffolds from a common intermediate. Key features include a rapid alternating polarity (rAP) Kolbe electrolysis for onoceradiene assembly, a Co-electrocatalytic metal-catalyzed hydrogen atom transfer (MHAT) 7-endo-trig cycloisomerization─the first of its kind─to form the serratene core, and a tandem Fe-mediated reductive olefin coupling/enolate alkylation cascade─also unprecedented─to forge the [4.3.1] propellane motif of cyclodammaranes with complete diastereocontrol over three contiguous quaternary centers. These routes, completed in 5–9 steps, maximize skeletal bond-forming efficiency, feature unique radical cascades, and highlight the advantages of radical-based disconnections in terpenoid synthesis.

Catalysts generated from the halogen-bridged methylnaphthyl-palladium dimer [Pd(1-MeNAP)Br]₂ and biarylphosphine ligands in combination with the base LiHMDS promote Buchwald-Hartwig type aminations and para-C─H arylations of non-activated aryl fluorides already at 60 °C. Their enabling performance is attributed to the efficient generation of monoligated Pd(0)-species.

Abstract

The C─F bond is among the strongest in organic molecules and can be cleaved only by few transition metal catalysts under harsh conditions or with highly reactive nucleophiles. We herein report that a methyl naphthyl (MeNAP) palladium bromide / BrettPhos catalyst with lithium bis(trimethylsilyl)amide (LiHMDS) as the base promotes aminations of non-activated aryl fluorides already at 40–60 °C to give primary, secondary, and tertiary anilines. A related catalyst system further enables para-C─H arylations of tritylated anilines with aryl fluorides, yielding biarylamines.

Nature Chemistry, Published online: 17 November 2025; doi:10.1038/s41557-025-02001-9

Dearomative functionalization is an extraordinary approach for transforming inert, two-dimensional arenes into three-dimensional architectures. Now it has been shown that electrolysis could facilitate dearomative syn-1,4-hydroalkylation and para-selective C(sp2)–H alkylation of electron-deficient (hetero)arenes. Mechanistic studies indicate that the chemoselectivity is primarily governed by the choice of supporting electrolyte and electrode.