It's Time for a Radical Rethink

Stereoretentive Radical Cross-Coupling

J. Sun,^† J. He,^† L. Massaro,^† D. A. Cagan, J. Tsien, Y. Wang, F. C. Attard, J. E. Smith, J. S. Lee, Y. Kawamata & P. S. Baran*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-h9snj) 🔓

Enantiospecific cross-couplings involving free radicals are unknown and generally believed to be impossible due to near-instantaneous racemization (picosecond timescale). As a result, controlling the stereochemical outcome of these reactions can only be achieved on a case-by-case basis using bespoke chiral ligands or in a diastereoselective fashion guided by nearby stereocenters. Here, the authors show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to enable the enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands.

Excited-State Configuration of Nitroarenes Enables Oxidative Cleavage of Aromatics over Alkenes

W. J. Olivier,^† P. Błyszczyk,^† E. M. Arpa, K. Hitoshio, M. Gomez-Mendoza, V. de la Peña O’Shea, I. Marchand, T. Poisson, A. Ruffoni* & D. Leonori*

Science 2025, 387, 1167–1174 (DOI: 10.1126/science.ads3955)

The authors demonstrate that the oxidative cleavage of aromatics over alkenes can be achieved by using photoexcited nitroarenes. Crucial to the success of this chemoselective process is the use of a nitroarene that is preferentially excitable to a triplet π,π* state over the n,π* state. This switch in excited-state configuration provides an otherwise inaccessible manifold, in which oxidative cleavage is diverted toward aromatics in the presence of alkenes.

Aryl Halide Cross-Coupling via Formate-Mediated Transfer Hydrogenation

Y. Cho,^† Y.-H. Chang,^† K. P. Quirion,^† Z. H. Strong,^† Z. J. Dubey, N. Nguyen, S. Lee, N. S. Taylor, J. M. Hoover,* N. A. White,* P. Liu* & M. J. Krische*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01729-0)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-fmc1n) 🔓

By exploiting the distinct reactivity of Pd^I species, an efficient catalytic system for the reductive cross-coupling of activated aryl bromides with aryl iodides via formate-mediated hydrogen transfer is described. The process displays orthogonality with respect to Suzuki and Buchwald–Hartwig couplings as pinacol boronic esters and anilines are tolerated, and owing to the intervention of chelated intermediates, challenging 2-pyridyl systems are also tolerated.

The Combination of Synthesis and Ultra-High-Resolution NMR Spectroscopy Reveals the Correct Structure of Caylobolide A

M. R. P. George, M. Deering, D. Fiorito, K. Solomon, K. Tidgewell, A. Noble, C. P. Butts* & V. K. Aggarwal*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00762-2) 🔓

Polyketide-derived natural products bearing repeat 1,5-polyols are commonly encountered but their structures are difficult to determine due to spectral overlap and chemical shift degeneracy. Caylobolide A is a representative member of this class of natural products, bearing a 36-membered lactone, with six 1,5-diol units and two 1,3-diol units. Its partial structure had been proposed, but only 4 of the 12 stereogenic centres had been assigned. Here, the authors report a blueprint for the structure determination of this class of natural products, comprising the use of ultra-high-resolution NMR spectroscopy, Mosher’s ester analysis and an efficient mixed isomer synthesis to unveil the correct structure of caylobolide A. With this approach, the partial stereochemistry proposed and the position of the triol unit within the carbon chain has been reassigned, culminating in the total synthesis of caylobolide A in 17 steps.

Synthesis of (+)-Saxitoxin Facilitated by a Chiral Auxiliary for Photocycloadditions Involving Alkenylboronate Esters

Y. Jiao, J. Liu, W. Mao, R. Fang, T. Xia, Q. Lang & T. Luo*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00666)

The authors report a concise and asymmetric total synthesis featuring an intramolecular [2+2] photocycloaddition of an alkenylboronate ester equipped with a new chiral auxiliary. This auxiliary, compatible with UV light and easily exchangeable on Bpin derivatives, enabled high stereocontrol through hydrogen-bond-mediated transition-state stabilization.

Enantioselective Total Synthesis of Fortalpinoid Q via a TEMPO⁺BF4^–-Mediated Dehydrative Nazarov Cyclization

H.-K. Mao, Q. Wang & Jing Xu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c00319)

The authors report a 15-step, enantioselective, total synthesis of the Cephalotaxus diterpenoid fortalpinoid Q. Highlights of the approach include: (1) a Jacobsen’s catalytic enantioselective Claisen rearrangement that enabled the single-step formation of two vicinal stereogenic centers, (2) a mild, oxoammonium salt (TEMPO⁺BF4^–)-promoted dehydrative Nazarov cyclization that forged the cyclopentadiene moiety, and (3) a facile aldol-lactonization cascade that resolved the last obstacle in the synthesis.

Size-Programmable Matteson-Type Annulation: Construction of Spirocycles from Simple Cyclic Ketones

W. Jo, J. K. Scholz, H. Lyu, S. H. Cho & G. Dong*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202503269) 🔓

The authors report an iterative boron-homologation approach to construct various carbocycles from a single precursor. Using an electron-withdrawing group as a handle to enable intramolecular Matteson-type couplings, carbocycles of different ring sizes with multiple stereocenters can be prepared stereoselectively. In addition, the method can be extended to the preparation of diverse, hard-to-make spirocycles and an iterative approach to synthesize double spirocycles is also demonstrated.

Base-Catalyzed Remote Hydrogermylation of Olefins

E. Ahrweiler,^† A. Selmani^† & F. Schoenebeck*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202503573)

This work reports the first remote hydrogermylation of alkenes, achieved through a rare base-catalyzed approach, completely free of added transition metal catalysts. The methodology is operationally simple, versatile and capable of achieving up to 8-carbon chain walks, overcoming the previous two-carbon limit of base-mediated processes.

Indirect Anti-Markovnikov Hydrofunctionalization of Terminal Alkenes via an Alkenyl Thianthrenium Intermediate

B. Sóvári, P. Angyal, I. J. Babcsányi, A. M. Kotschy, Á. Dudás, G. Turczel, S. Varga* & T. Soós*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202424422) 🔓

A two-stage dication pool strategy using alkenyl thianthrenium intermediates has been developed for anti-Markovnikov hydrofunctionalization. This approach addresses a significant limitation of previous anti-Markovnikov hydrofunctionalizations, namely, the restricted generality of nucleophiles. Extension of this approach to challenging transformations, including anti-Wacker-type oxidation, hydro-acetylenation, hydrogenation, and deuterium labeling, has also been demonstrated.

Concise Total Synthesis of the Cage-Like Sesquiterpenoid (+)-Daphnepapytone A

E. C. Gonzalez, I. de la Torre Roehl & B. M. Stoltz*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-z55dj) 🔓

The authors report the total synthesis of (+)-daphnepapytone A, an unprecedented member of the guaiane-derived sesquiterpenoids, and several related guaiane-derived natural products including diarthroncha C, daphnenicillata W, and oleodaphnone. The first-generation strategy was thwarted by an unsuccessful late-stage biomimetic [2+2] cycloaddition, however the second-generation de novo approach provided expedient access to the tetracyclic core of daphnepapytone A through an intramolecular allenyl thermal [2+2] cycloaddition and a cage-like Pauson–Khand reaction with a labile cyclobutane.

Bio-Inspired Two-Phase Total Synthesis of Daphnepapytone A

J. Pereira, N. Casaretto, G. Frison & B. Nay*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-0gds5) 🔓

The authors (also) report the total synthesis of daphnepapytone A through a bio-inspired, two-phase sequence of skeleton construction and late-stage oxidation. Oleodaphnone (shown above) was identified as a key intermediate for this strategy and was engaged in a biomimetic [2+2]-photocycloaddition leading to the bridged cyclobutane of the title compound. This paper also describes the total synthesis of three guaiane natural products (oleodaphnone, diarthroncha C, daphnenicillata W) with one being structurally revised.

Late-Stage Heteroarene Alkylation via Minisci Reaction with Gaseous Alkanes Enabled by Hydrogen Atom Transfer in Flow

P. C. Tiwari, A. Pulcinella, E. Hodžić & T. Noël*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-wr8br) 🔓

The authors present a photocatalytic platform that facilitates the alkylation of heteroarenes using abundant gaseous C1-C4 hydrocarbons under continuous-flow conditions. Through hydrogen atom transfer catalysis, an efficient alkylation of pharmaceutically relevant compounds was achieved without the need for prefunctionalized reagents.

Arene and Heteroarene Functionalization Enabled by Organic Photoredox Catalysis

Z. Zhu, X. Wu, Z. Li & D. A. Nicewicz*

Acc. Chem. Res. 2025, ASAP (DOI: 10.1021/acs.accounts.4c00837)

This Account details the dichotomy of reactivity accessed via arene cation radicals: C–H functionalization by nucleophiles under aerobic conditions or cation radical accelerated nucleophilic aromatic substitution (CRA-S_NAr) in anaerobic settings. Building on the success of these arene functionalizations, the authors also discuss their applications to positron emission tomography (PET) radiotracer development.

The Future of Healthcare

💰️ The future of healthcare. The US National Institutes of Health (NIH) dominates global health research, outspending the next biggest funder—London-based charity, Wellcome Trust—more than 25 times on grant investment, all while boasting an annual budget of roughly $47 billion. Those massive expenses pay off though, a recent study found that NIH-funded research contributed to 354 of 356 drugs that were approved by the US Food and Drug Administration between 2010–2019.

In the past decade alone the NIH has also been acknowledged as a funder on over 1.3 million biomedical-research publications. One of which, here, was featured not long ago in Peripheral → Core Heteroatom Transpositions and stood out because it detailed a small molecule that induced complete regression of tumours in multiple mouse models of breast cancer with a single dose!

Now, cuts by the Trump administration have raised concerns about the agency’s future and how that will impact biomedical research and drug discovery as a whole—Derek Lowe has written about this issue extensively in the past few months. Not unrelated is the same administration’s decision to cancel $400 million in federal grants and contracts to Columbia University and $800 million in grants to Johns Hopkins University, the latter of which has led to the loss of 2000 jobs. Between the funding and job cuts, an exodus of scientists from the US to Europe, Australia and Asia seems more and more likely.

💻️ Drug discovery in flow. Be sure to catch the German Chemical Society’s next Medicinal Chemistry webinar this Wednesday (19^th March) on “Enabling High Throughput Chemistry in Flow to Access Novel Chemical Space for Drug Discovery”.