Photochemical Transposition

1,2-Acyl Transposition through Photochemical Skeletal Rearrangement of 2,3-Dihydrobenzofurans

R. T. Steele,^† M. Fujiu^† & R. Sarpong*

Science 2025, 388, 631–638 (DOI: 10.1126/science.adv9915)

The authors report a formal 1,2-acyl transposition through the photochemical exchange of the C₂–C₃ positions of C₂-acylated dihydrobenzofurans. This strategy relies on an unusual photochemical isomerization of the dihydrobenzofuran core to a highly electrophilic spiro-cyclopropane intermediate that is then intercepted by a halide nucleophile. A variety of aryl ketones are transposed using 370-nanometer centered irradiation. Additionally, carboxylic acids, esters, and amides can be transposed using 310-nanometer centered irradiation.

Iron-Mediated Nitrate Reduction at Ambient Temperature for Deaminative Sulfonylation and Fluorination of Anilines

T. Schulte,^† D. Behera,^† D. Carboni, A. Höppner, F. Waldbach, J. Mateos, A. Altun, M. Leutzsch, M. L. Krebs & T. Ritter*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17981) 🔓

Preparation of arylsulfonic acids can be achieved under mild conditions from aryldiazonium salts, although conventional methods often require isolation or accumulation of these potentially hazardous intermediates. Here, the authors report that iron nitrate reduction at 25 °C enables the in situ generation of diazonium salts, which allows for direct deaminative chlorosulfonylation and fluorination from anilines via aryldiazonium salts as fleeting intermediates. Other sulfonic acid derivatives, such as sulfonamides, sulfonyl fluorides, and sulfonic acids, are readily accessible from this method.

10-Step, Gram-Scale Total Synthesis of (−)-Bipinnatin J

A. J. Rodriguez,^† M. S. Pokle,^† G. L. Barnes & P. S. Baran*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04761)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-6d1f5) 🔓

A concise, scalable total synthesis of (−)-bipinnatin J is disclosed. Commencing from inexpensive starting materials, this marine diterpenoid was fashioned through a convergent synthesis enabled by Ni-electrocatalytic decarboxylative cross-coupling taking advantage of succinate as an ethylene 2-carbon bridge, a unique halogen dance-Zweifel sequence to access a trisubstituted furan, a Ni-mediated 1,6-conjugate addition, and an asymmetric proton transfer.

From Reagent to Catalyst: Dispersion-Driven Design of a General Asymmetric Transfer Hydrogenation Catalyst

W. Leinung,^† B. Mitschke,^† M. Leutzsch, V. N. Wakchaure, R. Maji & B. List*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00641) 🔓

The authors report a broadly applicable second-generation catalyst system for the transfer hydrogenation of α,β-unsaturated aldehydes via asymmetric counteranion-directed catalysis (ACDC) by introducing dispersion energy donors into the catalyst instead of the Hantzsch ester reagent, as was reported previously.

A Unified Approach to Chiral α-Aryl Ketones and Aldehydes via Ni-Catalyzed Asymmetric Reductive Cross-Coupling

C. Qiu,^† L. Liu,^† K. Zhang, S. Du, Y. Chen, X. Wang* & H. Gong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03418)

The authors disclose a highly enantioselective protocol for the preparation of protected tertiary α-aryl ketones and aldehydes, enabled by chiral Ni/Biox-catalyzed reductive coupling of readily accessible α-iodo-acetals and -ketals with (hetero)aryl halides. The method is applicable across a range of (hetero)cyclic and acyclic carbonyl scaffolds, and avoids the post-reaction epimerization issues often encountered with unprotected tertiary α-aryl carbonyls.

Asymmetric Vicinal and Remote Hydroamination of Olefins by Employing a Heck-Reaction-Derived Hydride Source

R. Mi, X. Yao, Y. Xu, S. Hu, G. Huang & X. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03076)

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

The hydroamination of unactivated olefins is described by coupling a Heck reaction with a hydroamination reaction between an aryl boronic acid, olefin and a dioxazolone. The system features a broad scope, mild conditions, excellent enantioselectivity, and depending on the length of the olefin’s alkyl group, α- or β-amino amides were obtained in excellent regio- and enantioselectivity via direct or remote (migratory) hydroamination, respectively.

Ir-Catalyzed Stereoselective Total Synthesis of (+)-Rubriflordilactone A

J.-J. Liu,^† Z.-B. Ni,^† L. Li, K. Wei & Y.-R. Yang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05000)

A stereocontrolled asymmetric total synthesis of the Schisandra nortriterpenoid (+)-rubriflordilactone A employing Krische’s Ir-catalyzed 2-(alkoxycarbonyl)allylation for late-stage γ-butenolide formation is described. Additional noteworthy aspects include the integration of Carreira’s Ir/amine dual-catalyzed allylation, a Catellani reaction, and Morken’s Pt-catalyzed diboration/oxidation.

Double Deoxygenative Coupling of Carboxylic Acids and Alcohols

V. Ciccone,^† R. E. McNamee,^† E. Lin, C. N. P. Kullmer & D. W. C. MacMillan*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-mz8hz) 🔓

The authors report a photoredox-catalyzed, double deoxygenative fragment coupling of alcohols and carboxylic acids that provides rapid access to sp³-rich ketone scaffolds. New avenues for “C1 logic” is also highlighted through a bis-radical SOMO stitching approach that delivers ketone products from two alcohol substrates.

Dibromocarbene Addition to Bicyclo[1.1.0]butanes: A Facile Route to Substituted Bicyclo[1.1.1]pentanes

F. C. Attard,^† A. Slobodianyk,^† R. Bychek, Y. Panasiuk, P. Neigenfind, L. Massaro, M. G. Gardiner, V. V. Levterov, P. S. Baran,* P. K. Mykhailiuk* & L. R. Malins*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2024-rr5p5-v2) 🔓

The synthesis of 2,2-dibromo-bicyclo[1.1.1]pentanes (Br₂-BCPs) is described, presenting a class of novel substituted BCPs and circumventing the need for [1.1.1]propellane-based precursors. Scalable access to these compounds is demonstrated in a simple and inexpensive process, and their applicability to medicinal chemistry campaigns is highlighted through the synthesis of valuable building blocks—including highly sought-after bridge arylated BCP derivatives, which have been prepared via a novel electrocatalytic cross-coupling procedure.

Data Science-Guided Development of Deoxyfluorination Reagents with Enhanced Reactivity, Practicality, and Safety

M. E. Ruos, N. P. Romer,^‡ J. A. Deichert,^‡ L. M. Alabanza, S. S. Gandhi, G. Z. Brown, R. C. Walroth, K. Cruz, F. Gosselin, A. Y. Hong,* M. S. Sigman* & A. G. Doyle*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-l4zvs) 🔓

The authors report the discovery and development of several new (hetero)aryl sulfonyl fluoride reagents that have enhanced deoxyfluorination reactivity, improved physical properties, and excellent safety profiles compared to PyFluor, PBSF and DAST. To select structurally diverse reagents, a virtual library of (hetero)aryl sulfonyl fluorides was computed and training set design principles were leveraged to survey structure-activity relationships in a model deoxyfluorination reaction. Predictive models were developed to optimize sulfonyl fluoride reagents for the deoxyfluorination of a key intermediate used in the synthesis of RIPK1 inhibitor GDC-8264. The top-performing reagents demonstrated broad applicability across diverse alcohol substrate classes, including complex natural products and active pharmaceutical ingredients.

Asymmetric Total Synthesis of (–)-Crotonine G and (–)-Crotonolide D

H. Yu, Y. Hatano, P.–J. Chen, S. C. Virgil & B. M. Stoltz*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-zh07z) 🔓

The first enantioselective total syntheses of crotonine G and crotonolide D are disclosed. The synthetic approach employs a SmI₂ mediated ketyl radical cyclization to form the highly congested quaternary carbon at the center of these complex molecules. Following the furan introduction, the core structure of the natural product is constructed via oxidative olefin cleavage to install the unusual C-19 and C-20 oxidation. Finally, palladium catalyzed carbonylation, furan oxidation and acid mediated condensation/epimerization completes the synthesis.

Regiodivergent α- and β-Functionalization of Saturated N-Heterocycles by Photocatalytic Oxidation

J. W. Rackl,^† A. F. Müller,^† A. Profyllidou & H. Wennemers*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-14hmc) 🔓

The authors present a photocatalytic, regiodivergent method for the functionalization of saturated N-heterocycles at either the α- or the β-position. A tert-butyl carbamate (Boc)-stabilized iminium ion serves as the key intermediate en route to either α-hydroxylation or β-elimination, depending on the choice of base. The operationally simple procedures use a readily available flavin-based catalyst, aqueous media and do not require metals. Combined with facile downstream derivatization, the regiodivergent reaction gives rapid access to a large set of functionalized piperidines.

Nickel-Catalyzed Cross-Dehydrogenative Aldehyde Allylation

A. F. Ibrahim, Y. H. Fujisato, P. M. Zimmerman* & J. Montgomery*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-gbv0j) 🔓

The authors describe the nickel-catalyzed cross-dehydrogenative coupling of aldehydes and alkenes utilizing a combination of zinc powder and di-tert-butyl peroxide to enable the synthesis of β,γ-unsaturated ketones through the catalytic union of acyl and allylic radicals generated from the aldehyde and alkene, respectively.

👉️ For a follow-up publication by Montgomery and co-workers on the “Direct Acylation of Alkyl and Aryl Bromides via Nickel-Catalyzed Aldehyde C–H Functionalization”, see: here.

Photoinduced Cleavage of Alkenyl Fluorides for Nucleophilic Acyl Substitution via in situ-Generated Acyl Fluorides

E. S. Gogarnoiu, M. S. Griffin, A. H. Bansode, J. M. Paolillo, J. M. Bergen & M. Parasram*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-jgr1s) 🔓

The authors describe a facile, one-pot protocol to generate acyl fluorides from alkenyl fluorides, the first example of acyl fluoride generation from alkenyl moieties. The transformation is promoted by the visible-light photoexcitation of 4-nitrophthalonitrile, which serves as a photooxidant under anaerobic conditions to cleave the alkenyl fluoride, producing the desired acyl fluoride intermediate. The synthetic utility of this mild and practical approach is demonstrated in the synthesis of linear peptide fragments.

Bench-Stable Reagents for Modular Access to Persulfuranyl Scaffolds

R. Li, C. Liu, C. Hu, J. Tsien, M. Hayes, S.-J. Chen, Y. Kanda, R. R. Merchant, B. S. Matsuura & T. Qin*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-1p2lw) 🔓

The pentafluorosulfanyl group has long been considered a potential bioisostere for tert-butyl and trifluoromethyl groups, yet limitations in methodologies have constrained its use. To bridge this gap, the authors have developed a general pentafluorosulfanylation platform that employs bench-stable solid reagents to generate SF₅ radicals via a decarboxylation and β-scission sequence. This strategy enables a variety of operationally simple transformations, expanding the accessibility of SF₅-containing molecules. Notably, this reagent design is also adaptable to other persulfuranyl groups, such as trifluoromethyl tetrafluorosulfanyl and aryl tetrafluorosulfanyl groups.

Enzymatic Stereodivergent Synthesis of Azaspiro[2.y]alkanes

J. L. Kennemur,^† Y. Long,^† C. J. Ko, A. Das & F. H. Arnold*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-m7201) 🔓

The authors present a stereodivergent carbene transferase platform for the cyclopropanation of unsaturated exocyclic N-heterocycles to provide structurally-diverse and pharmaceutically-relevant azaspiro[2.y]alkanes in high yield (21 to >99% yield) and excellent diastereo- and enantioselectivity (from 52.5:47.5 to >99.5:0.5 and from 51:49 to >99.5:0.5, respectively). These engineered protoglobin-based enzymes operate on gram scale, with no organic co-solvent, at substrate concentrations up to 150 mM (25 g/L) using lyophilized E. coli lysate as the catalyst.

The Midas Touch

⚗️ The Midas Touch. Physicists have uncovered the secret of alchemy and it turns out all you really need is a Large Hadron Collider and two beams of lead smashing into each other at close to the speed of light—not too far off what the original alchemists had in mind really.

The base metal transmutation, known as chrysopoeia, happened at CERN in Switzerland, where researchers use high-energy collisions of lead ions to mimic the extreme conditions that existed in the fractions of a second after the Big Bang occurred. When these lead ions collide, they can shed three protons and thus, ₈₂Pb becomes ₇₉Au (₈₀Hg and ₈₁Tl are also created).

Interestingly, the team calculated that from 2015–2018 these collisions generated 86 billion gold nuclei, which turns out to be approximately 29 trillionths of a gram (that’s 2.9 × 10^–11 grams or 0.000000000029 grams). Unfortunately, most of that gold would have existed in an unstable isotopic form, lasting for only around 1 microsecond before breaking down into other particles or crashing into the apparatus itself.