Accelerating Medicinal Chemistry

Accelerating Medicinal Chemistry: A C(sp³)-Rich Fragment Toolbox for Redox-Neutral Cross-Coupling

J. Tsien,^† Á. Péter,^† X. Zeng, S. Wang, B. Jiang, M. A. Emmanuel, M. S. Oderinde, P. N. Bolduc, M. C. Nicastri, S. Dey, M. R. Collins, J. W. Lee, M. Bravo, M. D. Palkowitz, J. X. Qiao, Y. Kawamata & P. S. Baran*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-2k4tc) 🔓

The authors disclose a toolbox of 15 sulfonyl hydrazide reagents to facilitate redox-neutral, nickel-catalyzed radical cross-coupling of 14 distinct small fragments onto (hetero)arenes under mild conditions. These crystalline, bench-stable reagents are straightforward to synthesize and require no additional oxidants, reductants or precious metals. Demonstrated across a diverse set of >60 (hetero)aryl halides, the method exhibits exceptional substrate scope and functional group tolerance, accommodating complex, medicinally relevant scaffolds. Comparative studies with existing techniques include a 51% yield for trideuteromethylation of a MET kinase inhibitor precursor (vs. a precedented 14% via Kumada coupling) and a one-step cyclobutylation of an NLRP3 inhibitor intermediate in 41% yield (vs. a known <5% over a four-step sequence).

Enantioselective Type II Intramolecular [5+2] Cycloadditions of Oxidopyrylium Ylides using Chiral-Phosphoric-Acid Catalysis

L. Yang, K. L. Chan, K. K. Cheung, P. Chiu, Z. Lin* & J. Sun*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00803-w)

The authors report the enantioselective type II intramolecular [5+2] cycloaddition of oxidopyrylium ylides enabled by a non-covalent activation strategy using chiral phosphoric acid catalysis. Multiple stereogenic centres can be constructed in one step with high efficiency, excellent enantioselectivity and diastereoselectivity under mild conditions.

Organocatalytic Regio- and Stereoselective Cyclopropanation of Olefins

C. Zhu,^† S. Das,^† A. Guin, C. K. De* & B. List*

Nat. Catal. 2025 (DOI: 10.1038/s41929-025-01340-7) 🔓

The authors report a metal-free, highly enantioselective cyclopropanation of olefins with diazoalkanes utilising asymmetric counteranion-directed photoredox organocatalysis. Specifically, an ion pair was identified featuring a thioxanthylium photoredox cation and a chiral imidodiphosphorimidate counteranion that catalyses the highly enantioselective cyclopropanation of styrenes and aliphatic dienes with diazo compounds.

Total Synthesis of (−)-Illisimonin A Enabled by Pattern Recognition and Olefin Transposition

B. Xu, Z. Zhang & M. Dai*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05409) 🔓

The authors report an asymmetric total synthesis of (−)-illisimonin A, a sesquiterpene natural product with neurotrophic activity, which possesses a unique cage-like 5/5/5/5/5 pentacyclic scaffold containing a trans-pentalene and a norbornane. The synthesis exploits a pattern recognition strategy to identify a 5,6-fused bicyclic intermediate derived from (S)-carvone as the starting point and leverages five sequential olefin transposition reactions to decorate the bicyclic carbocycle. Other key steps include a tandem Mukaiyama hydration-translactonization to form the γ-butyrolactone and an intramolecular aldol cyclization to close the cage and deliver (−)-illisimonin A in 16 steps.

Dehomologative C–C Borylation of Aldehydes and Alcohols via a Rh-Catalyzed Dehydroformylation–Borylation Relay

K. Das, N. Kuźnik & P. Dydio*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c02181) 🔓

The dehomologative conversion of linear or α-methyl aldehydes to vinyl boronic esters is achieved via a one-pot sequence of rhodium-catalyzed transfer dehydroformylation and transfer borylation of the resulting alkenes. Similarly, allylic or aliphatic alcohols are converted to vinyl boronic esters through a sequence involving, respectively, rhodium-catalyzed isomerization or transfer dehydrogenation to aldehyde intermediates, followed by dehydroformylation–borylation. The vinyl boronic ester products can be further hydrogenated to alkyl boronic esters using the same rhodium precatalyst, enabling all five catalytic steps with a single catalyst system.

Pd-Catalyzed Photoinduced Interceptive Decarboxylative Allylation

F.-L. Haut, F. S. Meger, T. G. Santiago, P. Fraňová, D. Kocsi, J. V. Estornell, M. Martínez-Belmonte, J. Benet-Buchholz & R. Martin*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03044) 🔓

The authors describe a photoinduced Pd-catalyzed interceptive decarboxylative allylation of allyl esters, which provides a new gateway to enable atom pair swaps or a series of contractions and elongations, offering unconventional disconnections and a modular yet broadly applicable tool for accessing sp³ architectures in drug discovery.

A Catalytic Asymmetric Intramolecular [4+1]-Cycloaddition for the Total Synthesis of Terpene Alkaloid Natural Products

W. Xiu, C. D. Huffman, W. A. Swann, C. W. Li & C. Uyeda*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04607)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-mh3h8) 🔓

The authors report a nickel-catalyzed asymmetric intramolecular [4+1]-cycloaddition of a vinylidene and a 1,3-diene to form a [4.3.0]-azabicyclic product, which features sterically differentiated tri- and tetrasubstituted alkenes that can be selectively functionalized to achieve divergent syntheses of 7-epi-incarvilline, hydroxyincarvilline, isoincarvilline, incarvilline, tecomanine, 5-hydroxyskytanthine and tecostanine.

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*

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c00468) 🔓

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 (HAT) catalysis, the efficient alkylation of pharmaceutically relevant compounds was achieved without the need for pre-functionalized reagents.

Asymmetric Aziridination of Allylic Carbamates using Ion-Paired Rhodium Complexes and Extrapolation to C–H Amination of Phenethyl Carbamates

A. R. Lit,^† S. Takano,^† C. Zachau, I. Băltărețu & R. J. Phipps*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202507532) 🔓

The authors report that carbamate-functionalized allylic alcohols undergo highly enantioselective aziridination using achiral dimeric Rh(II,II) complexes that are ion-paired with cinchona alkaloid-derived chiral cations. Furthermore, the carbamate group was also found to be effective for directing a highly enantioselective benzylic C–H amination when appended to phenethyl alcohols.

Total Synthesis and Structural Revision of (–)-Sodagnitin E

P. Schoch & T. Gaich*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202506247)

The authors report the total synthesis of malabaricane triterpene sodagnitin E, marking the first synthesis of any malabaricane natural product to date. The enantioselective synthesis of two key fragments, followed by their coupling via a Mukaiyama aldol reaction delivered the triterpene framework. Thorough analysis of the synthetic material led to the elucidation of a previously unassigned stereocenter (C17) as well as the reassignment of the configuration at C27, which enabled the structural revision of the relative configuration at the central lactol moiety.

Monofluoromethyl Radical Mediated Halogen-Atom Transfer

N. Ramkumar,^† A. P. Raiskuma,^† L. Baumane, S. Belyakov, K. Traskovskis & J. Veliks*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-39rgs) 🔓

The authors present a novel halogen-atom transfer (XAT) method that eliminates the need for photocatalysts by utilizing the direct excitation of a monofluoroacetoxy ligand-containing hypervalent iodine(III) reagent, which allows nucleophilic monofluoromethyl radicals to efficiently form carbon radicals from activated alkyl halides. These radicals can subsequently functionalize unactivated alkenes through atom transfer radical addition (ATRA).

β-Arylation of Indanone Derivatives via α-Carbamoylation/Elimination of Isocyanate Sequence

M. Morimoto, R. Shimazumi, V. K. Rawat, H. Fujimoto & M. Tobisu*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-x06bc) 🔓

The authors report a practical and operationally simple protocol for the β-arylation of cyclic carbonyl compounds, which enables the rapid, stereoselective construction of multi-substituted carbonyl compounds.

Synthesis of gem­-Difluorocyclobutanes: Organolanthanum Enabled Synthesis and Divergent Catalytic Functionalization of gem-Difluorocyclobutanols

H. Ishikura, J. J. Rojas, C. S. Begg, C. Choi & J. A. Bull*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-dfrd1) 🔓

The authors report the synthesis and divergent functionalization of gem-difluorocyclobutanols to generate a diverse range of 1,1-disubstituted-3,3-difluorocyclobutanes. The use of organolanthanum reagents is crucial to achieve the addition of carbon nucleophiles to commercially available difluorocyclobutanone to avoid undesired elimination of HF by controlling nucleophile basicity. The generated difluorocyclobutanols enable functionalization through carbocation and radical intermediates, providing diverse 1,1-disubstitued difluorocyclobutanes.

Skeletal Editing Strategies Driven by Total Synthesis

S. F. Kim,^† C. Amber,^† G. L. Bartholomew^† & R. Sarpong*

Acc. Chem. Res. 2025, ASAP (DOI: 10.1021/acs.accounts.5c00174)

For the past several years, the Sarpong group has developed several skeletal editing methodologies, including single-atom ring contractions, expansions, and transpositions of both saturated and unsaturated heterocycles. This Account details the evolution of “skeletal editing logic” within the context of their work on natural product total synthesis.

Science 🤝 Diplomacy

✍️ Science 🤝 Diplomacy. Chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, known commercially as Freon-12, were first developed in the 1920s in a major collaboration between Frigidaire, General Motors, and DuPont as a safer, non-toxic alternative to the refrigerants used at the time, which included ammonia, sulfur dioxide, and chloromethane—the latter of which was notorious for leaking out of refrigerators and causing numerous fatalities.

The first CFCs were synthesised in the late 1920s by Thomas Midgley of General Motors who unveiled his discovery to the public by inhaling the gas and using it to blow out a candle, apparently to demonstrate its safety. This, sadly, wasn’t Midgley’s first flamboyant public display of recklessness, earlier in the decade he discovered that adding tetraethyllead to gasoline prevented “knocking” in car engines, which upon widespread adoption caused countless incidences of lead poisoning, hallucinations, insanity, and several deaths. It was around this time that Midgley, who was also privately suffering from lead poisoning at the time, decided to hold a press conference to allay people’s fears of the substance by pouring it all over his hands and inhaling its vapour for 60 seconds… This incident may help explain his frame of mind when developing CFCs.

It didn’t take long for scientists to realise that these gases posed a substantial risk for the ozone layer with chemists Molina and Rowland reporting in 1974 that CFCs can break down at high altitudes under strong UV radiation to release chlorine radicals, which catalyse the destruction of ozone - so much so that one chlorine radical can destroy >100,000 molecules of ozone. Just over 10 years later, in May 1985, scientists reported the first evidence of substantial ozone depletion above Antarctica and only 2 years later, the Montreal Protocol was adopted worldwide to protect the ozone layer by phasing out ozone-depleting substances (ODS) like CFCs. Since then ODS emissions have dropped 99% and by the mid-century, the ozone layer is expected to recover to pre-1980 levels. However, as interest in photocatalysis and the incorporation of fluorine in pharmaceuticals and agrochemicals grows, notorious ODS banned by the Montreal Protocol such as bromodifluoromethane continue to find use in synthetic protocols, generally for difluoromethylation chemistry.

Nature have decided to mark the 40^th anniversary of that May 1985 report with an editorial on how science and international cooperation successfully closed the ozone hole. Hopefully, we can learn from the Montreal Protocol and apply it towards more effective climate action

📰 Science 🤝 Newsletters. There’s a growing interesting in science-focused newsletters to help researchers keep up with the latest developments in their field and that’s why I’m happy to highlight Plenty of Room, a newsletter from Marco Lolaico that delivers weekly insights into the frontiers of AI-driven protein design and DNA nanotechnology!

NB: Environmental historian J. R. McNeill remarked that Midgley "had more impact on the atmosphere than any other single organism in Earth's history" and in 1940, Midgley contracted polio, which left him disabled and to help him get out of bed unassisted, he devised a device—an elaborate system of ropes and pulleys, which in 1944, accidentally strangled him to death after becoming entangled.