Switching Selectivity

Catalyst-Controlled Regiodivergent Oxidation of Unsymmetrical Diols

S. B. Zacate, J. Rein, S. D. Rozema, R. A. Annor, S. J. Miller & S. Lin*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00330)

The authors use aminoxyl-peptide conjugates to catalyze the regiodivergent oxidation of unsymmetrical diols. Through structural tuning of both the aminoxyl catalytic core and the chiral peptide backbone, catalyst control was achieved that either reinforces or overrides the intrinsic steric bias, leading to oxidation of either the less hindered or the more hindered alcohol in high selectivity.

Enantioselective Photocatalytic Synthesis of Bicyclo[2.1.1]hexanes as ortho-Disubstituted Benzene Bioisosteres with Improved Biological Activity

P. Garrido-García, I. Quirós, P. Milán-Rois, S. Ortega-Gutiérrez, M. Martín-Fontecha, L. A. Campos, Á. Somoza, I. Fernández, T. Rigotti* & M. Tortosa*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01746-7)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-f5ll4) 🔓

The authors have developed a Lewis-acid-catalysed [2+2] photocycloaddition to obtain enantioenriched 1,5-disubstituted bicyclo[2.1.1]hexanes, providing an efficient approach for their incorporation into a variety of drug analogues. Retention of the biological activity of the bicyclo[2.1.1]hexane-containing analogues in the specific proteins targeted by the original drugs has confirmed the suitability of this moiety to serve as a bioisostere of ortho-substituted phenyl rings.

Light-Activated Hypervalent Iodine Agents Enable Diverse Aliphatic C–H Functionalization

Z. Lu, J. Putziger & S. Lin*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01749-4)

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

The authors report a hypervalent iodine reagent that releases a potent hydrogen atom abstractor for C–H activation under mild photochemical conditions. Using this reagent, a selective (N-phenyltetrazole)thiolation of aliphatic C–H bonds was developed for a broad scope of substrates. The synthetic utility of the thiolated products is showcased through various derivatizations. Simply by altering the radical trapping agent, the method can directly transform C–H bonds into diverse functionalities, including C–S, C–Cl, C–Br, C–I, C–O, C–N, C–C and C=C bonds.

Direct Stereoselective C(sp³)–H Alkylation of Saturated Heterocycles Using Olefins

Z. Zhou,^† Y. Ke,^† R. Miao, F. Hu, X. Wang, Y. Ping,* S. Xu & W. Kong*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01747-6)

The authors describe a nickel-catalysed enantioselective C(sp³)–H alkylation of saturated heterocycles using olefins, providing an efficient strategy for the stereoselective construction of C(sp³)–C(sp³) bonds. Using readily available olefins and saturated nitrogen or oxygen heterocycles as prochiral nucleophiles, the coupling reactions proceed under mild conditions and exhibit broad scope and high functional group tolerance. Application of this approach to the late-stage modification of natural products and drugs, as well as to the enantioselective synthesis of a range of chiral building blocks and natural products, is demonstrated.

meta-Nitration of Pyridines and Quinolines through Oxazino Azines

K. Balanna & A. Studer*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16051)

Due to the inherent electronic properties of pyridines, achieving direct selective meta–C–H nitration under mild conditions has been a long-standing challenge. To address this, the authors introduce a practical protocol for the highly regioselective meta-nitration of pyridines using a dearomatization-rearomatization strategy. This mild, open-air, one-pot, scalable, and catalyst-free process is employed for the late-stage meta-nitration of pyridine containing drugs, drug precursors, and ligands. Consecutive C3 and C5 difunctionalization of pyridines is also achieved with complete regiocontrol relying on sequential addition.

Nickel-Catalyzed Asymmetric Homobenzylic Hydroamidation of Aryl Alkenes to Access Chiral β-Arylamides

X. Lyu, E. Jeon, C. Seo, D. Kim & S. Chang*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00867)

The authors introduce a Ni-catalyzed asymmetric homobenzylic hydroamidation reaction that addresses the dual challenges of achieving regio- and enantioselectivity in the synthesis of β-(hetero)arylethylamides. The reaction exhibits high functional group tolerance and utilizes readily available starting materials of vinylarenes to react with dioxazolones as a robust amidating source. Notably, this approach was successfully applied to the synthesis of pharmaceutical compounds and natural products, such as Clobenzorex, Direx, Selegiline, Sacubitril, and Cipargamin.

Regiodivergent Alkylation of Pyridines: Alkyllithium Clusters Direct Chemical Reactivity

W. Jo,^† C. Thangsrikeattigun,^† C. Ryu, S. Han, C. Oh, M.-H. Baik* & S. H. Cho*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17198)

The authors report a regiodivergent alkylation of electronically unbiased pyridines using 1,1-diborylalkanes as the sole alkylating agent. The key to controlling regioselectivity lies in the choice of alkyllithium activator: methyllithium directs alkylation predominantly to the C4 position, while sec-butyllithium promotes C2-alkylation. Mechanistic studies reveal that the structural dynamics of alkyllithium clusters dictate the regioselectivity, with tetrameric clusters favoring C4-alkylation and dimeric clusters preferring C2-alkylation.

Nickel-Catalyzed Branched Hydroalkylation of Alkenes with Diazo Compounds

N. Kvasovs,^† V. Iziumchenko,^† A. J. Sterling & V. Gevorgyan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17586)

A nickel-catalyzed, branched-selective hydroalkylation of alkenes using diazo compounds has been developed. This protocol enables the functionalization of both activated and unactivated alkenes, in directed and non-directed manners. Mono-, di-, and trisubstituted alkenes can be effectively transformed and highly diastereoselective hydroalkylations have also been demonstrated.

Generation of Stereocenters via Single-Carbon-Atom Doping Using N-Isocyanides

H. Fujimoto,* T. Nishioka, K. Imachi, S. Ogawa, R. Nishimura & M. Tobisu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00882)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-666ll) 🔓

Atomic carbon remains a challenging species for organic synthesis despite its potential to form four covalent bonds in a single step. Single-carbon-atom doping (SCAD) offers a powerful approach to enhancing molecular complexity in one process without atom loss. However, synthetically viable SCAD reactions capable of generating stereocenters have not been realized. Here, the authors report an SCAD reaction that creates stereocenters by unlocking the reactivity of (N-isocyanoimino)phosphorane as an atomic carbon equivalent. This reagent facilitates the single-step conversion of various acyl chlorides into homologated α-chloro cyclic ketones, proceeding via the formation of four different bonds: one C–Cl, one C–H, and two C–C bonds at the incorporated carbon atom.

Enantioselective Total Syntheses of (+)-Kobusine, (+)-Spirasine IX and the Purported Structure of (+)-Orgetine: Strategic Use of C–H Bonds

M. Deng, F. Wu, T. Liu, Z. Jiang & T. Luo*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00650)

Enantioselective total syntheses of (+)-kobusine, (+)-spirasine IX and the proposed structure of (+)-orgetine were achieved. A unique approach was developed to construct a cage-like hexacyclic ring system that underwent a HAT-initiated radical rearrangement to forge the hetisine-type scaffold. Subsequent late-stage redox manipulations, including an intramolecular hydride shift, were deployed to provide different C20-diterpenoid alkaloids.

An Approach to Alkyl Azetidines for Medicinal Chemistry

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

ChemRxiv 2025 (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 mg-, g-, and even multigram quantities.

Protecting-Group-Free Synthesis of Lycojapomine Alkaloids Enabled by Radical Dearomatization of a Pyrrole

B. M. Gross & B. M. Stoltz*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-d3n5f) 🔓

Alkaloids represent one of the most important classes of natural products and are defined by carrying one or more basic nitrogen atoms. Their preparation in the laboratory remains tedious however, broadly hampered by nitrogen’s nucleophilic nature and susceptibility to oxidation. To address this, a number of protecting groups have been developed to temper this reactivity, which often leads to an increased step-count and synthetic inefficiency, disrupting further investigation of biological properties. Here, the authors address this problem by achieving the synthesis of a class of complex Lycojapomine alkaloids, utilizing a photo-induced radical dearomatization of a pyrrole derivative and a subsequent ionic functionalization cascade.

Unleashing the Power of Potassium 2-Ethylhexanoate as a Mild and Soluble Base for Pd-catalyzed C-N Cross-Coupling

W. D. Lambert,^† S. Felten,^† N. Hadler, N. I. Rinehart, R. Swiatowiec, G. E. Storer, J. Henle, M. Servos, C. Yang, A. V. Bay, P. N. Eyimegwu, S. Shekhar* & J. Hartwig*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-59c10) 🔓

The authors report the discovery of a combination of a phosphorinane ligand and a soluble carboxylate base, potassium 2-ethylhexanoate (K-2-EH) that facilitate the Pd-catalyzed C–N coupling of base-sensitive reactants. To explore the enhanced substrate scope of this reaction, a scope evaluation was performed using representative reactants selected from the chemical literature using chemical descriptors and clustering to ensure their chemical diversity. These results show that this phosphorinane ligand and K-2-EH couple primary aliphatic amines, amides, sulfonamides, and heteroaromatic nucleophiles, as well as acidic secondary nitrogen nucleophiles with a range of electrophiles. The stabilities of several coupling products in the presence of a range of previously reported bases show that other soluble bases decompose those products under standard reaction conditions, while K-2-EH did not.

A Database of Steric and Electronic Properties of Heteroaryl Substituents

T. M. Alturaifi, G. E. Scofield, S. Wang & P. Liu*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-8nrh7) 🔓

The authors introduce HArD, a HeteroAryl Descriptors database, comprising DFT-computed steric and electronic descriptors of 31,500 heteroaryl substituents. The database features heteroaryl substituents comprising 5- and 6-membered rings as well as 5,6- and 6,6-fused ring systems. Different regioisomers and additional substituents on the heteroaromatic ring were included to describe the diverse chemical space of heteroaryl substituents. The database includes 65 descriptors such as buried volume and Sterimol parameters to describe steric effects, atomic charges and HOMO/LUMO coefficients and energies to describe electronic effects, and Harmonic Oscillator Model of Aromaticity (HOMA) values describing aromaticity. In addition, Hammett-type heteroaryl substituent constants (σ_Het) were developed based on computed heteroaryl carboxylic acid pK_a values, which aim to extend the broadly used Hammett constants (σ_p and σ_m) from substituted phenyl groups to substituted heteroaryl groups.

Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle

G. P. Howell, L. R. Agnew, C. Bauer, F. J. Bell, A. D. Campbell, K. Dai, D. Dave, S. R. Ellis, M. J. Foulkes, M. A. Y. Gall, K. Garrec, H. Ge, B. R. Hayter, M. F. Jones, G. Karageorgis, M. Littleson, T. W. Lloyd-Hughes, H. C. McNicholl, D. T. Mooney, B. J. Moore, R. H. Munday, E. Noone, D. Perkins, L. Powell, O. D. Putra, S. Tomasi, M. Turner, H. Wang, H. Zhao & O. T. Ring*

Org. Process Res. Dev. 2025, ASAP (DOI: 10.1021/acs.oprd.4c00524)

The authors describe the total synthesis of AZD5991 from a process development perspective through the complete redesign of the synthetic strategy from the ground up. AZD5991 is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of AZD5991 was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. Here, the authors report the exploration of asymmetric approaches toward the atropisomeric core alongside new routes toward each of the four heterocyclic building blocks. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.

Life on Earth

🌊 Life on Earth. We might be carbon-based life but phosphorus, the 6^th most abundant element in our body, is no less important. It’s a critical component of DNA & RNA, it helps fuel our cells in the form of adenosine triphosphate (ATP) and as phospholipids it forms an integral part of our cell membranes. However, despite this, it’s not actually all that abundant in aqueous environments—the sort of place where early life likely began. Now, new research has suggested that volcanic activity near “soda lakes” may have leached phosphorus from nearby volcanic rocks into the warm waters, allowing it to accumulate over time and potentially kick-starting life. These soda lakes are rich in carbonate salts, making them highly alkaline in nature with a pH between 9–12. In normal bodies of water, phosphorus (in the form of phosphate) is typically bound up by calcium ions as apatite minerals but in soda lakes, the calcium binds to the excess carbonate, preventing the removal of phosphate from the water. Analysis of small and large soda lakes has confirmed this, with elevated levels of phosphate detected in both cases.

NB: As for where all that phosphorus came from in the first place, phosphorus is believed to form during the supernova explosions of massive stars. Interestingly enough and in a similar vein to the above, researchers from the University of Hawaiʻi at Mānoa have proposed that alkyl phosphonic acids brought to Earth by a meteor could have been the early source of phosphorus required for life on Earth.