Precise Radical Transfer

Welcome to this week’s Organic Synthesis Newsletter.

Monday 10^th February – Sunday 16^th February 2025 | Volume 2, Issue 6

HIGHLIGHT OF THE WEEK
Taming Distonic Radical Cations for Precise γ-C–H Functionalization of Alkylamines

T. Kinoshita,^† K. Hirate,^† K. Hamawaki,^† S. Chiba,^† K. Terada, Y. Sakakibara* & K. Murakami*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-srlvk) 🔓

While remote functionalization of primary and secondary alkylamines is well established, the analogous transformation of tertiary amines remains highly challenging, despite their prevalence in 60% of alkylamine-containing pharmaceuticals. This study utilises α-ammonio radicals, a class of distonic radical cations, to achieve γ-selective functionalization of tertiary amines. The approach leverages halomethylammonium salts as precursors to α-ammonio radicals, facilitating precise radical transfer to the γ-position. The resulting γ-radicals enable a diverse range of γ-selective functionalizations, including thioetherification, amination, alkylation, (hetero)arylation and alkenylation.

NATURE
σ-Bond Insertion Reactions of Two Strained Diradicaloids

A. T. Meza, C. A. Rivera, H. Shao, A. V. Kelleghan, K. N. Houk* & N. K. Garg*

Nature 2025 (DOI: 10.1038/s41586-025-08745-1)

The authors report a new synthetic method that furnishes bicyclo[2.1.1]hexanes using mild reaction conditions and an operationally-simple protocol. The methodology proceeds via the uncommon coupling of two strained fragments: transiently-generated cyclic allenes and bicyclo[1.1.0]butanes, which possess considerable strain energies of ~30 kcal/mol and ~60 kcal/mol, respectively. The reaction is thought to proceed via a σ-bond insertion through a diradical pathway. However, rather than requiring an external stimulus to generate radical species, reactivity is thought to arise as a result of innate diradical character present in each reactant.

NATURE CATALYSIS
Enantioconvergent Nucleophilic Substitution via Synergistic Phase-Transfer Catalysis

C. Dooley, F. Ibba, B. B. Botlik, C. Palladino, C. A. Goult, Y. Gao, A. Lister, R. S. Paton,* G. C. Lloyd-Jones* & V. Gouverneur*

Nat. Catal. 2025 (DOI: 10.1038/s41929-024-01288-0) 🔓

Catalytic enantioconvergent nucleophilic substitution reactions of alkyl halides are highly valuable transformations but are notoriously difficult to implement. Specifically, nucleophilic fluorination is a renowned challenge, especially when inexpensive alkali metal fluorides are used as fluorinating reagents due to their low solubility, high hygroscopicity and Brønsted basicity. Here, the authors report a solution by developing the concept of synergistic hydrogen bonding phase-transfer catalysis. Key to this strategy is the combination of a chiral bis-urea hydrogen bond donor (HBD) and an onium salt—two phase-transfer catalysts essential for the solubilization of potassium fluoride—as a well-characterized ternary HBD–onium fluoride complex.

NATURE COMMUNICATIONS
Enantioselective Total Synthesis of Lycoposerramine Congeners Through Late-Stage Nitrogen Deletion

K. Yokoi & H. Renata*

Nat. Commun. 2025, 16, 1659 (DOI: 10.1038/s41467-025-56956-x) 🔓

A concise total synthesis of lycoposerramine congeners is accomplished through the use of a nitrogen deletion strategy (N-deletion) to combine two fully elaborated piperidine and tetrahydroquinoline fragments. Specifically, two natural congeners, lycoposerramine V and W, previously accessible only in 18–23 steps, are each synthesized in 10 steps or less. To further highlight its modular nature, the strategy is applied in the synthesis of two unnatural epimers of lycoposerramine V and W.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Development of a Thioetherification of Heteroarene Electrophiles with Broad Scope via a Proton Transfer Dual Ionization Mechanism

C. R. Zwick III,* M. Eckhoff, J. J. Henle, A. V. Bay, R. Swiatowiec, S. Shekhar, C. Yang, Y. Zhou, A. L. Wall, R. F. Henry, J. N. Hoskins & M. S. Sigman*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18304)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-0bjgp-v2) 🔓

While studying photochemical thioetherification reactions, the authors uncovered a remarkably mild condition that does not require light, transition metals, or exogenous bases. An array of thiols and halogenated heterocycles were coupled to produce >70 diverse products. Reaction progress kinetic analysis and computational studies support a unique mechanism termed proton transfer dual ionization (PTDI) S_NAr. Finally, a predictive statistical model was constructed aided by high-throughput experimentation to understand when the PTDI processes are successful, resulting in the completion of ten target-oriented syntheses.

Bioinspired Copper/Amine Cooperative Catalysis Enables Asymmetric Radical Azidation

R. Wang,^† Y.-J. Liang,^† K.-J. Bian,^† J. Xu,^† S.-Y. Zhou, R.-X. Jin, W. Guan* & X.-S. Wang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15840)

Asymmetric radical transformations (ARTs) are vital for constructing chiral drugs and materials; however, the highly reactive nature of radicals often imposes a challenge in controlling the selectivity of these processes. Inspired by the principles of enzyme-cofactor cooperation to enhance stereochemical induction in enantioselective radical transformations, the authors developed an enantioselective asymmetric radical azidation via cooperative organo- and transition metal catalysis. This approach enabled the synthesis of functionalized tertiary azides from readily available aldehydes.

Reduction-Interrupted Tandem Reaction for General Synthesis of Functional Amino Acids by a Heterogeneous Cobalt Catalyst

H. Hua,^† C. Ci,^† P. H. Dixneuf & M. Zhang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15284)

Despite their importance, the direct and diverse synthesis of γ-amino-α-hydroxybutyric acids (AHBAs) remains challenging. Here, by preparation of a N-doped carbon-supported bifunctional cobalt catalyst (Co-DAPhen/C), a reductive tandem reaction was developed for the general synthesis of AHBA derivatives from cheap and abundant nitroarenes, formaldehyde and acrylates. This catalytic three-component reaction features a broad substrate scope, an easily accessible and reusable catalyst, and high step and atom economy.

ACS CATALYSIS
Catalytic Deoxygenation of Unactivated 1,2-Diol Motifs via Light-Induced Spin-Center Shift

J. Ordóñez,^† A. J. B. Rucinski,^† C. Romano & R. Martin*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.4c07260)

The authors report a light-induced strategy that enables catalytic deoxygenation of unactivated aliphatic 1,2-diol derivatives via a spin-center shift (SCS) manifold. Divergent reactivity can be accomplished depending on the nature of the alkyl radical intermediate. Specifically, secondary alcohols result in α-deoxygenated ketones, whereas a tandem C–C bond-formation/SCS can be promoted with primary alcohols in the presence of an appropriate radical acceptor.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Aryl Silicon Nucleophiles in Bismuth Catalysis

T. Faber, S. Engelhardt & J. Cornella*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202424698)

The authors present a catalytic protocol utilizing bismuth for the synthesis of aromatic fluorinated thiosulfones, showcasing a seminal example of aryl silicon nucleophiles in Bi catalysis. This catalytic process is enabled by a series of Bi-based organometallic transformations, including an unprecedented transmetalation of aryl silicates to Bi(III) complexes and the formal migratory insertion of sulfur dioxide (SO₂) into the Bi‒C bond. The protocol is compatible with a wide range of anionic and neutral Ar‒Si compounds, including heterocycles.

Total Synthesis of the Marine Diterpenoids Caucanolide E and F by Alkyne gem-Hydrogenation: Rigorous Reassignment of Two Almost Indistinguishable Diastereomers

R. M. Betancourt, M. Leutzsch & A. Fürstner*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202500124)

As the spectra of the diastereomeric marine seco-cembranoids caucanolide E and F are almost identical, the isolation team had not been able to firmly assign their stereostructure. This has now been solved by a synthetic approach predicated on biogenetic considerations, which suggested that both natural products are 10S configured but differ in the configuration of their C8 stereocenter. Both reference compounds needed for this investigation were accessible from a single precursor via ruthenium catalyzed gem-hydrogenation of an enyne to furnish an alkoxyfuran. The recorded data showed that the assignment proposed in the literature is incorrect and needs to be reversed; this conclusion was independently confirmed by a combined NMR/DFT approach using a CP3 probability analysis.

CHEM
para-Selective C–H Alkylation of Aroyl Chlorides Through Organic Photoredox-Catalyzed Radical tele-Substitution

R. Oya, H. Sato, K. Nagao* & H. Ohmiya*

Chem 2025, Online Now (DOI: 10.1016/j.chempr.2025.102446)

The authors demonstrate the para-selective C(sp²)–H alkylation of aroyl chlorides with alkyltrifluoroborates and trialkylphosphine through an organic photoredox-catalyzed radical tele-substitution. The reaction proceeds through the para-selective addition of alkyl radicals to in situ-generated aroyl trialkylphosphonium intermediates followed by a hydrogen shift. This metal-free site-selective C(sp²)–C(sp³) bond formation allowed for the streamlined synthesis of siponimod and SR-31747.

ORGANIC LETTERS
Stereoselective Synthesis of Benzoylated Gulmirecin A and Disciformycin B

K.-P. Rühmann, K. Ji & D. Trauner*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.4c03727) 🔓

Disciformycins and gulmirecins are potent inhibitors of the bacterial RNA polymerase. They show promising activities against multidrug-resistant pathogens often found in clinical settings, such as methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). The authors modular and scalable synthetic approach started with the desymmetrization of divinyl carbinol and provided benzoylated precursors for both natural product classes. The 12-membered macrocycle was assembled by a stereoselective Nozaki–Hiyama–Takai–Kishi macrocyclization.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Third Case of Resistance to Alzheimer’s Disease Found

🧠 Third case of resistance to Alzheimer’s disease found. In the U.S. alone, Alzheimer’s disease (AD) affects 6.9 million people aged 65 and over (about 1 in 9 within that demographic) and that figure is expected to double by 2060. Now, researchers have identified a man who seemed genetically destined to develop AD (carrier of the PSEN2 mutation typically associated with dominantly inherited AD) reach his mid-70s without any cognitive decline—nearly two decades past his expected age of onset. This is only the third recorded case of such a resistance and raises questions about the specific role of the proteins that drive neurodegeneration. Interestingly, brain scans revealed significant amyloid plaques, a characteristic hallmark of AD, yet no clusters of tau protein, another common biomarker of AD that forms neurofibrillary tangles (thread-like structures that collect inside neurons).

Ultimately, the researchers were able to uncover nine genetic variants that were not present in the patient’s relatives who had the same mutation, all of whom developed dementia in their 50s. This combined with lifestyle, environmental factors and lower brain inflammation than is typical for those with AD may all have played a protective role in staving off the development of the disease for over 18 years. The researchers hope that their findings will contribute to the development of treatments aimed at restricting tau spread to prevent or slow the progression of AD.

💻️ Drugging the undruggable. Be sure to watch the German Chemical Society’s next Medicinal Chemistry webinar on Tuesday 25th February with “Targeting the Oncogenic State of RAS with Tri-Complex Inhibitors”.