Strategic Atom Replacement

Strategic Atom Replacement Enables Regiocontrol in Pyrazole Alkylation

A. Fanourakis, Y. Ali, L. Chen, P. Q. Kelly, A. J. Bracken, C. B. Kelly* & M. D. Levin*

Nature 2025 (DOI: 10.1038/s41586-025-08951-x)

The authors describe a “Strategic Atom Replacement” where N-alkyl pyrazoles are synthesised from isothiazoles. The net forward transformation is a “swap” of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole. Linking the two azoles is an orphaned heterocycle class, 1,2,3-Thiadiazine-S-Oxides, whose synthetic potential has yet to be tapped. By proceeding via these unusual heterocycles, the typical nitrogen-selectivity and therefore isomer separation challenges associated with established pyrazole preparations are circumvented.

Photoinduced Copper-Catalysed Deracemization of Alkyl Halides

F. Zhong,^† R. Li,^† B. K. Mai, P. Liu* & G. C. Fu*

Nature 2025, 640, 107–113 (DOI: 10.1038/s41586-025-08784-8)

Deracemization is an emerging strategy for generating enantioenriched compounds; however, substantial challenges for this potentially powerful approach have not yet been addressed, including the exploitation of C–X (rather than only C–H and C–C) bond cleavage to achieve deracemization, as well as the development of processes that provide broad classes of enantioenriched compounds, and tetrasubstituted stereocentres. Here, the authors describe a straightforward method that addresses these challenges, using a chiral copper catalyst, generated in situ from commercially available components, to achieve the photoinduced deracemization of tertiary (and secondary) alkyl halides through C–X bond cleavage.

Oxa-π, σ-Methane Rearrangement Approach for Epoxide Synthesis

Q.-Z. Wang,^† Y. Zheng,^† W.-T. Wu & H.-M. Huang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01400)

The authors describe an unprecedented photochemical rearrangement for synthesizing a diverse collection of epoxides enabled by energy transfer catalysis under visible light conditions. This process enables the easy preparation of α-amino-substituted epoxide derivatives with broad substrate scope and functional group tolerance under mild reaction conditions. The rearrangement has been applied to complex architectures and the epoxides were easily transformed into amino alcohol derivatives.

Palladium-Catalyzed Transfer Iodination from Aryl Iodides to Nonactivated C(sp³)–H Bonds

E. Le Saux & B. Morandi*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02553)

The authors report a new strategy for the catalytic iodination of nonactivated C(sp³)–H bonds. The method merges the concepts of shuttle and light-enabled palladium catalysis to employ aryl iodides as both hydrogen atom transfer reagents and iodine donors. A non-canonical Pd⁰/Pd^I catalytic cycle is harnessed to transfer iodine from a C(sp²) to a C(sp³)–H bond under mild conditions, which tolerate sensitive functional groups.

Phenothiazine Sulfoxides as Active Photocatalysts for the Synthesis of γ-Lactones

N. Hölter,^† N. H. Rendel,^† L. Spierling, A. Kwiatkowski, R. Kleinmans, C. G. Daniliuc, O. S. Wenger* & F. Glorius*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01988) 🔓

The authors describe the discovery and application of N-phenylphenothiazine sulfoxide as a photocatalyst for the reductive activation of cyclic malonyl peroxides, giving access to complex γ-lactones from simple olefins. Detailed mechanistic studies were carried out and the synthetic utility of the protocol was demonstrated through facile access to complex spirocyclic γ-lactones, which are widely recognized for their biological importance.

Ligand Enabled Iridium-Catalyzed Enantioselective Hydroalkenylation of α-Olefins and Styrenes with Acrylamides

K. Wang, K.-Y. Tian, X.-N. Wang, J.-H. Chen, C. Fan & Q.-L. Zhou*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c18412)

Using a new type of chiral spiro diphosphite ligand, an iridium-catalyzed enantioselective hydroalkenylation of α-olefins and styrenes with acrylamides has been developed. A variety of aliphatic and aromatic alkenes were successfully coupled with acrylamides to produce γ-substituted chiral acrylamides. The reaction exhibits excellent branched selectivity, high enantioselectivity and a broad substrate scope with good functional group tolerance.

Catalytic Enantioselective Smiles Rearrangement Enabled by the Directed Evolution of P450 Radical Aryl Migratases

W. Fu, K. Murcek, J. Chen, A. Liu, Y. Zhao, P. Liu* & Y. Yang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c01179)

Through the directed evolution of P450 radical aryl migratases (P450_Smiles) the authors describe the first example of a catalytic enantioselective Smiles rearrangement. A range of racemic N-arylsulfonyl-α-chloroamides were transformed in an enantioconvergent manner, affording acyclic amide products possessing an all-carbon quaternary stereocenter with excellent chemo- and enantioselectivity. Importantly, the evolved P450 variants were capable of overriding the innate cyclization activity of the N-alkyl amidyl radical intermediate, allowing for chemoselective formation of acyclic products.

Chiral Lewis Acid-Catalyzed Intramolecular [2+2] Photocycloaddition: Enantioselective Synthesis of Azaarene-Functionalized Azabicyclo[2.1.1]hexanes and Bicyclo[1.1.1]pentanes

D. Tian,^† Y. Pan,^† X. Zhao, Y. Yin & Z. Jiang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03542)

The authors present an asymmetric intramolecular [2+2] photocycloaddition enabled by a dual catalyst system involving DPZ as a photosensitizer and chiral Sc(III) complex, leading to azaarene-functionalized 2-azabicyclo[2.2.1]hexanes (aza-BCHs), which can undergo nitrogen-deletion skeletal editing to yield 2-substituted bicyclo[1.1.1]pentanes (BCPs). The products were achieved in high enantioselectivity, a broad substrate scope was observed and all-carbon quaternary stereocenters can be formed.

Cross-Electrophile Coupling of Aryl Chlorides with Alkyl Chlorides Using Rotating Magnetic Field and Metal Rods

X. Feng,^† X. Li,^† N. Zhang, L. Zhang, F. Sun, H. Liu, Z. Zhao & X. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00381)

The authors report the development of a novel approach in which electromagnetic induction could participate in the coupling of organochlorides using a rotating magnetic field and metal rods. This strategy was applied to the nickel-catalyzed cross-electrophile coupling of aryl chlorides with alkyl chlorides under mild conditions and with a broader scope than current protocols.

Ni-Catalyzed Cyanation of (Hetero)Aryl Electrophiles Using the Nontoxic Cyanating Reagent K₄[Fe(CN)₆]

N. A. Wilson, W. M. Palmer, M. K. Slimp, E. M. Simmons, M. V. Joannou, J. Albaneze-Walker, J. M. Ganley* & D. E. Frantz*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c00158) 🔓

A Ni-catalyzed cyanation of aryl halides using potassium ferrocyanide (K₄[Fe(CN)₆]) as a nontoxic cyanide source has been developed. The scope of this Ni-catalyzed cyanation reaction was demonstrated on a range of (hetero)aryl bromides, chlorides, and sulfamates using catalyst loadings as low as 2.5 mol%. This methodology was further translated to the decagram synthesis of a pharmaceutical intermediate, usurping the prior Pd-catalyzed process that employed a hazardous cyanide source and solvent pair (Zn(CN)₂, DMAc).

Concise Total Syntheses of Leuconoxine-Type Alkaloids Enabled by Palladium/Norbornene-Catalyzed Pyrrole Difunctionalization

X. Liu, Y. Zhou, Y. Meng, Q. Zhu, R. Li* & G. Dong*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202502736) 🔓

Concise total syntheses of five leuconoxine-type alkaloids: chloromelodinine, leuconodine A, leuconodine F, melodinine E and leucinixine, were achieved using a newly developed palladium/norbornene-catalyzed pyrrole double C–H functionalization reaction and a divergent oxidative dearomatization. No protecting groups were employed and the discovery of an unusual chloro-1,2-migration reaction enabled the first total synthesis of chloromelodinine E.

Indole Photocatalysts and Secondary Amine Ligands Enable Nickel-Photoredox C(sp²)–Heteroatom Couplings

H. P. Chavda, K. J. Liang, T. J. Megna, O. R. Taylor, G. Kim, A. L. López & A. Bahamonde*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-wvhb2) 🔓

The authors introduce a photocatalytic initiation strategy driven by inexpensive indoles and demonstrate the effectiveness of highly tunable secondary amine ligands in facilitating coupling while suppressing side reactions that sequester the Ni catalyst off-cycle. The approach enabled a broad range of amination and etherification reactions with excellent yields and functional group tolerance, providing a scalable platform for C–N and C–O couplings.

Deoxygenative Functionalization of Alcohols and Carbonyl Compounds via Electrochemical Reduction

A. J. Ressler, J. I. Martinez-Alvarado, R. Hariharan, W. Guan & S. Lin*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-0dfb4) 🔓

The authors develop a general activation strategy that employs hydrosilanes as activating reagents for alcohols, carbonyls, and esters to afford a common silyl ether intermediate. Electrochemical reduction of the in situ generated silyl ether results in C–O cleavage to afford a carbanion, which reacts with a number of electrophiles for the construction of C–Si, C–B, C–Ge, and C–Sn bonds.

Alkyl Azetidines via Batch and Flow Photochemistry

O. P. Datsenko, A. Baziievskyi, I. Sadkova, B. Campos, J. T. Brewster II,* J. Kowalski, R. J. Hinklin* & P. K. Mykhailiuk*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c00922)

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

Alkyl azetidines have been prepared by photochemical modifications of azetidine-2-carboxylic acids in batch and in flow. The reaction has been realized in milligram, gram, and even multigram quantities. The obtained azetidines are valuable building blocks for drug discovery.

From Cortisone to Enlicitide: A Journey of Synthetic Chemistry Innovations at Merck

L.-C. Campeau*

J. Org. Chem. 2025, ASAP (DOI: 10.1021/acs.joc.4c02919) 🔓

The pharmaceutical industry first brought mass production and formulation of natural products for medicinal purposes but quickly started tinkering with molecular structure to modify compounds’ properties, eventually designing molecules from scratch. This necessity for invention of new molecules to improve human health and to manufacture them on large scale is an excellent stimulus for synthetic chemistry innovations. In this Perspective, examples from Merck’s chemistry groups are used to highlight the types of innovations that can arise from these endeavors.

Shark Uber

🦈 🐙 Shark Uber. Nature have just released their selection of the best science images in March, featuring a video of a Maori octopus riding atop a short-fin mako shark. The unusual sighting, caught by researchers at the University of Auckland, has yet to be explained—octopuses tend to prefer the sea bed to the surface and would likely not enjoy reaching speeds of up to 50 mph. However, this unlikely pairing could just be the work of a particularly brave marine biologist and their fondness for the low-budget Sci-Fi movie Sharktopus.