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Efficient Super-Reducing Organic Photoredox Catalysis with Proton-Coupled Electron Transfer Mitigated Back Electron Transfer

A. K. Bains,^† A. Sau,^† B. S. Portela, K. Kajal, A. R. Green, A. M. Wolff, L. F. Patin, R. S. Paton, N. H. Damrauer* & G. M. Miyake*

Science 2025, 388, 1294–1300 (DOI: 10.1126/science.adw1648)

Despite its transformative impact, visible-light photoredox catalysis remains constrained by the thermodynamic limits of photon energy and inefficiencies arising from unproductive back electron transfer. In this work, the authors introduce an organic photoredox catalyst system that overcomes these obstacles to partially reduce a broad scope of challenging arene substrates. This advancement is accomplished by coupling the energy of two photons into a single chemical reduction, whereas inefficiencies from back electron transfer are mitigated through a distinct proton-coupled electron transfer mechanism embedded in the catalyst design.

Accessing Sulfonamides via Formal SO₂ Insertion into C–N Bonds

M. Kim, C. E. Obertone, C. B. Kelly,* C. A. Reiher,* C. Grosanu, J. C. Robertson & M. D. Levin*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01848-2)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-vj26z) 🔓

The authors report SO₂ insertion into the C–N bond of primary amines, enabling the direct synthesis of primary sulfonamides without pre-activation and effectively inverting the nitrogen’s properties (acidity, hydrogen bonding etc.). The key to this was the implementation of a dual-function anomeric amide that served to cleave the initial C–N bond and deliver a nitrogen atom to the product after SO₂ incorporation. The process tolerates a wide array of functionalities, can be run in an automated fashion, and was used to conduct a high-throughput library diversification campaign. The synthesis and modification of active pharmaceutical ingredients, and a net CO-to-SO₂ isosteric replacement approach was also demonstrated.

On-DNA C–H Functionalization of Electron-Rich Arenes for DNA-Encoded Libraries

E. de Pedro Beato, L. Torkowski, P. Hartmann, L. Vogelsang, K.-J. Dietz & T. Ritter*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01844-6) 🔓

The authors present the C–H functionalization of electron-rich arenes on DNA by utilising a key selenoxide reagent to achieve the regio- and chemoselective formation of arylselenonium salts in aqueous media. The introduction of arylselenonium salts offers a versatile linchpin on DNA conjugates, which gives access to a multitude of analogues through subsequent reactions, including transition-metal-mediated and photochemical transformations for the formation of C–C, C–I and C–S bonds.

Synthesis of Diverse Terpenoid Frameworks via Enzyme-Enabled Abiotic Scaffold Hop

H. Deng, J. Yang, F. Li,* J. Li* & H. Renata*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01852-6)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-4kpr3-v2) 🔓

The authors report a versatile synthetic strategy to access a range of terpenoids from the sesquiterpene lactone sclareolide by viewing a biocatalytically installed alcohol as an exploitable motif rather than a structural endpoint, resulting in substantial divergence from the original drimane ring system of sclareolide. Using this approach, the syntheses of four terpenoid natural products, namely, merosterolic acid B, cochlioquinone B, (+)-daucene and dolasta-1(15),8-diene, were achieved.

C–H Functionalization via Single Atom Metathesis of C–H and C–X Bonds

T. C. Jankins, B. Berger, F. A. Aouane, S. Barbeira-Arán, C. Didier, B. Hürlimann, C. Zimmer & B. Morandi*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04754)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-fgc4s) 🔓

The authors report a C–H/C–X metathesis reaction through a radical swapping protocol wherein hydrogen and halogen are traded between molecules via reversible hydrogen atom transfer and halogen atom transfer that allows for mild C–H halogenation. The reversibility of this process allows for the selective dehalogenation of polyhalogenated products to form monohalogenated products.

Monocyclic Azetidines via a Visible-Light-Mediated Aza Paternò-Büchi Reaction of Ketone-Derived Sulfonylimines

C. H. Ng,^† E. R. Wearing,^† D. E. Blackmun,^† G. G. Terrones, J. Toigo, K.-M. Tong, K. C. Harper, J. C. Donovan, M. A. Gonley, E. A. Voight, B. D. Bergstrom, M. O. Wolf,* H. J. Kulik* & C. S. Schindler*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04692)

The authors report a visible-light-mediated aza Paternò-Büchi reaction of acyclic ketone-derived sulfonylimines, which are previously unexplored substrates in this transformation, with activated alkenes (i.e., styrenes and dienes) to form 2,2-disubstituted monocyclic azetidines that can be further modified to reveal free N–H azetidines.

Unlocking Chromium Decarboxylative Ligand-to-Metal Charge Transfer: Efficient and Redox-Neutral Allylation of Aldehydes Using Carboxylic Acids

S. Wu,^† Z. Jiao,^† A. T. Sung, A. B. Faulhaber, N. D. Schley & A. W. Schuppe*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04691) 🔓

The authors report the light-induced decarboxylative ligand-to-metal charge transfer of Cr(III) carboxylate complexes and demonstrate its applicability toward stereoselective Nozaki-Hiyama-Kishi allylation reactions. The critical design element of the reaction was identifying a bipyridyl ligand scaffold that enabled a single Cr catalyst to facilitate both photolytic dissociation and aldehyde addition.

Quaternary Carbon as a Locus for Skeletal Disconnection. Total Synthesis of (±)-Tubingensin A Featuring Assembly of the Backbone Stereotriad Using a Halo-Prins/Halo-Nazarov Cascade

A. Milosavljevic, G. Alachouzos & A. J. Frontier*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06475) 🔓

The first successful fragment coupling/cationic cascade approach for the synthesis of a complex indoloditerpenoid, tubingensin A, is described. The synthesis is the first example of a novel disconnection strategy targeting a central quaternary carbon locus. A halo-Prins/halo-Nazarov cationic cascade sequence enabled the rapid preparation of a complex intermediate as a single diastereomer, containing the vicinal quaternary centers found in the backbone stereotriad.

Stereocontrolled First Generation Synthesis of RIPK1 Inhibitor GDC-8264

A. Y. Hong,* N. Wong, S. M. Kelly, L. E. Sirois, S. Schwegler, X. Linghu, C. Molinaro, C. G. Sowell & F. Gosselin

Org. Process Res. Dev. 2025, ASAP (DOI: 10.1021/acs.oprd.5c00125)

The authors report an efficient, stereocontrolled and chromatography-free first-generation manufacturing process for GDC-8264, a RIPK1 inhibitor. The 12-step process successfully produced >3.5 kg of GDC-8264 in 19% overall yield with 99.2 A % HPLC purity, >99% e.e. and >99.9:0.1 d.r. to support early stage clinical studies.

Difluoroenol Phosphinates as Difluoroenolate Surrogates: Synthesis and Applications in Defluorination and Deoxygenative Coupling

M. B. Kurosawa,^† S. Shimoyama,^† H. Tanaka & J. Yamaguchi*

Chem. Sci. 2025, Accepted (DOI: 10.1039/D5SC03915K) 🔓

The authors report defluorinative and deoxygenative functionalization reactions of trifluoromethyl ketones mediated by the phospha-Brook rearrangement. Trifluoromethyl ketones react with phosphine oxides to undergo a phospha-Brook rearrangement followed by β-fluoride elimination, providing difluoromethyl ketones in good yields. By tuning the reaction conditions, the selective synthesis of monofluoromethyl and methyl ketones was also achieved, alongside a range of deoxygenative transformations from key intermediates, such as difluoroenol phosphinates.

Migrative Reductive Amination of Ketones Enabled by Multitasking Reagents

A. Khegay & D. G. Hall*

J. Org. Chem. 2025, ASAP (DOI: 10.1021/acs.joc.5c01094)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-ln5f6) 🔓

The authors report a migrative reductive amination of ketones by orchestrating three distinct reactions in a single flask, without solvent changes, using two inexpensive and non-toxic reagents: a Zn(II) salt and a hydrosilane. The method was demonstrated across a wide scope of acyclic and cyclic ketones with both aliphatic and aromatic groups, including bioactive molecules and macrocyclic natural products.

Remarkable Regeneration

🧬 Remarkable regeneration. Certain species, such as flatworms, lizards, zebrafish, and axolotls exhibit extraordinary regenerative abilities, with the latter even capable of regrowing entire limbs. Researchers are now hoping to harness these insights to investigate the regenerative potential of human cells.

Zebrafish, for example, can recover from spinal cord injury-induced paralysis within just eight weeks due to a population of cells that bear similarities to human fetal astrocytes. However, due the considerable evolutionary gap between zebrafish and humans, translating these findings could be a challenge. By contrast, lizards (such as the green anole lizard picture above) are more closely related, sharing several of the same genes with the added bonus of being able to regenerate their tail following injury.

Another intriguing species is the marine bristle worm, which has a nervous system not too dissimilar to the vertebrate central nervous system. Remarkably, when its trunk is severed, nearby cells at the wound site transform into stem cells and begin to rebuild the body. This cellular reprogramming could provide a powerful model for spinal cord repair and regenerative medicine in humans.