Boron at the Helm: Steering Molecules into New Shapes

It’s good to be back! In this issue we’re covering any standout papers that have been published since we’ve been away—from Monday 22^nd September to Sunday 12^th October—apologies for any papers that couldn’t be included due to email size requirements. We return to business as usual next week!

Core Diversification Using 1,2-Oxaborines as a Versatile Molecular Platform

Y. Ge, Q. Zhu, Y. Zhu & G. Dong*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01971-0)

The authors report a new strategy to access diverse core structures from a common intermediate using 1,2-oxaborines as a versatile molecular platform. A soft enolization/6π-electrocyclization strategy was developed to synthesize 1,2-oxaborines from enones or enals. Taking advantage of their multifaceted reactivities, 1,2-oxaborines can undergo further C−H functionalization and be transformed into a diverse range of arenes, heteroarenes and non-aromatic heterocycles. Finally, late-stage preparations of a suite of analogues that contain Lipitor substituents but with different aromatic cores are demonstrated using the diversification strategy.

Enantioconvergent Radical Addition of Racemic Alkyl Halides to Access Vicinal Stereocentres

X. Wu,^† T. Xia,^† J. Bai,^† Y. Shi,^† C. Fang, J. Hu, W. Wu, C. Zhang, Q. Wang, G. Huang,* J. Qu & Y. Chen*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01967-w)

The authors report a cobalt-catalysed enantioconvergent reductive addition of racemic alkyl halides with imines, allowing for the efficient construction of various contiguous stereogenic centres, including tertiary-tertiary, tertiary-quaternary and quaternary-quaternary stereocentres with high enantio- and diastereoselectivities. The mild reaction conditions circumvent the use of organometallic reagents, ensuring broad functional group compatibility and enabling the formation of valuable chiral motifs such as amino acids, organophosphorus compounds, amino alcohols and γ-lactams.

Heteroaromatic Swapping in Aromatic Ketones

H. Nakahara, R. Shirai, Y. Nishimoto, D. Yokogawa & J. Yamaguchi*

Nat. Commun. 2025, 16, 8998 (DOI: 10.1038/s41467-025-64041-6) 🔓

The modification of aromatic rings to heteroaromatic rings is widely employed in medicinal chemistry to modulate lipophilicity and improve metabolic stability; however, achieving a one-step, generalizable transformation of aromatic rings into diverse heteroaromatic rings—termed “heteroaromatic swapping”—remains challenging. Here, the authors present an efficient strategy for heteroaromatic swapping via a Claisen/retro-Claisen mechanism, utilizing heteroaryl esters and aromatic ketones. This approach enables the selective exchange of aromatic rings with heteroaromatic rings across a broad substrate range, achieving high-yield conversions of bioactive aromatic ketones into their heteroaromatic counterparts.

Deoxygenative C(sp³)–N(sp³) Cross-Coupling Enabled by Nickel Metallaphotoredox Catalysis

R. Chen,^† T. Kim,^† N. B. Bissonnette,^† R. T. Martin, J. R. Martinelli, A. Cabré & D. W. C. MacMillan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10915)

The authors describe a deoxygenative C–N cross-coupling between alcohols and N-hydroxylamine esters to form tertiary amines. Oxidation of the tertiary amine products is kinetically suppressed under optimized conditions, while a sterically demanding ancillary ligand promotes reductive elimination. This methodology displays broad substrate scope, accommodating diverse functional groups, heterocycles, and pharmaceutical derivatives.

Ligand-Controlled Alkylation–Heck–C(sp³)–H Annulation Cascade for a Divergent Synthesis of Cyclobutane- and Cyclopropane-Containing Heterocycles

W.-X. Wei,^† Y. Kuang^† & M. Tomanik*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c11047) 🔓

The authors report a two-component C(sp³)–H annulation cascade reaction that effectively unites ortho-bromophenols or ortho-bromoanilines with allylic alkyl bromides and provides direct access to two different heterocyclic scaffolds via precise ligand-controlled reactivity. The newly developed transformation proceeds via an initial alkylation followed by a regioselective Heck carbopalladation and is terminated by a regiodivergent C(sp³)–H annulation of a γ-methylene or a δ-methyl C–H bond. This cascade transformation possesses a broad substrate scope, showcased by the preparation of >60 heterocyclic products with excellent regiocontrol.

A Convergent Approach to Phragmalin-Type Limonoids: Total Synthesis of Thaigranatin P

J. Lee, S. C. Davis, A. Sheu, J. W. Gu & T. R. Newhouse*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c13081)

The authors report the total synthesis of erythrocarpines M and L and thaigranatin P, topologically complex phragmalin-type limonoids, the latter exhibiting potent agonism on the human pregnane X receptor (hPXR). A key transformation is a SmI₂-mediated reductive coupling of an aldehyde and an alkene, which constructs the signature tricyclo[3.3.1^2,10.1^1,4]decane framework characteristic of phragmalin natural products. The synthesis features a strategically convergent construction of the phragmalin core structure via a cuprate addition, triflation, and intramolecular Heck reaction sequence.

Pd-Catalyzed O-Arylation of Phenols Mediated by a Weak, Soluble Organic Base: Methodology, Mechanism, and Compatibility with Enabling Technologies

M. I. Ostrowska, J. A. Morris & L. T. Ball*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c13469) 🔓

The authors report the development and mechanistic interrogation of a homogeneous, Pd-catalyzed C–O coupling between phenols and aryl triflates that uses a weak, soluble tertiary amine as base. Mechanistic insight allows qualitative a priori prediction of reaction outcome as a function of substrate electronics, and provides an intuitive guide as to how diaryl ether targets should be disconnected. The methodology exhibits broad substrate scope and its homogeneous nature allows safe execution under microwave heating, with elevated temperatures allowing for short reaction times even in the presence of air.

Direct Deaminative Halogenation at Hindered Tertiary Centers

Z. Cui, P. Ma, Q. Sun, K. Lin, P. Tang, S. Wang & H. Lu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c13592)

The authors report a direct deaminative halogenation of α-tertiary amines using commercially available O-diphenylphosphinyl hydroxylamine. This one-pot transformation enables efficient chlorination, bromination, and iodination of structurally diverse amines while maintaining excellent functional group compatibility. The power of this methodology is showcased by the straightforward preparation of valuable aryl-halide isosteres, including halogenated derivatives of bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, 2-azabicyclo[2.1.1]hexane, and cubane.

Overriding Norrish Type II to Access Cyclopropanols

J. W. Pearson, S. L. Dudra, A. F. Palermo, B. S. Y. Chiu, J. Dang, A. L. Gabbey, B. A. B. Henson, T. R. Hou, N. Nabavi & S. A. L. Rousseaux*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c13001)

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

Since its discovery in 1958, Norrish–Yang photocyclization has become a prominent method to access cyclobutanols under mild photoirradiative conditions. However, access to medicinally relevant 3-membered rings remains limited due to the strong kinetic preference for 1,5-HAT over 1,4-HAT. Here, the authors demonstrate the first photocyclization of β-boryl aryl ketones to cyclopropanols. The strategy relies on solvent-controlled selective population of the π,π* triplet state over the n,π* triplet state, with the former preferentially undergoing 1,4-boryl group transfer over 1,5-HAT.

Bicyclic Isosteres of Pyridine/Piperidine: From Synthesis to Applications

O. Stashkevych, V. Kokhalskyi, Y. Mynak, V. Levterov, O. Shablykin, I. Pishel & P. K. Mykhailiuk*

Angew. Chem. Int. Ed. 2025, Early View (DOI: 10.1002/anie.202517814)

2-Azabicyclo[2.2.2]octanes have been designed, synthesized, and validated biologically as isosteres of piperidine/pyridine. The key reaction step was the cyclization of cyclic alkenyl amines with KOt-Bu/I₂/CO₂ and the method proved to be general and scalable (up to 20 g). Finally, combined with nitrogen deletion, this method also opened a practical way toward the previously hardly accessible 1,2-disubstituted bicyclo[1.1.1]pentanes—saturated analogues of ortho-benzenes.

Enantioselective Synthesis of (+)-Auriculatol A

J. K. Thompson, K. C. Youngblood, Y. H. S. Teh, C. M. Farley, Z. Zhang, S. C. Virgil & S. E. Reisman*

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

A total synthesis of the grayanane diterpenoid (+)-auriculatol A is reported. The synthesis features a convergent coupling strategy that joins two fragments by a vinylogous Mukaiyama aldol-type reaction and then constructs the 7-membered ring by a nickel-catalyzed enolate alkenylation. Key findings include the development of a chemoselective Ni-catalyzed intramolecular 1,2-addition to access the bicyclo[3.2.1]octane fragment and the use of electron-deficient olefin supporting ligands as uniquely effective for the Ni-catalyzed enolate alkenylation.

Cross Carbonyl-Olefin Metathesis (XCOM) of Unactivated Olefins

J. Wu, M. Vargas-Penalver & T. H. Lambert*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-hb5l1) 🔓

A method for the olefination of aryl aldehydes with unactivated alkenes via cross carbonyl-olefin metathesis (XCOM) is described. Reaction of an aldehyde substrate and a cis-1,2-disubstituted or monosubstituted olefin with the HBF₄ salt of 2,3-diazabicyclo[2.2.2]octane results in high-yielding olefination with exclusive trans-stereoselectivity. The reaction is shown to accommodate a range of substitution patterns on the aryl aldehyde and a diverse set of functional groups, including protic functionality that would complicate traditional olefination methods.

Angle-Strained Cycloalkyne-Mediated Carbonyl 1,2-Transposition

K. Ji, Y. Liao, S. Deng & Z. Wu*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-79gqk) 🔓

The authors report a strain-release-driven strategy for the one-step translocation of carbonyl moieties within prevalent cyclic ketones. This method exploits the pronounced reactivity of angle-strained cycloalkynes, generated in situ directly from accessible cyclic ketones, which then undergo regioselective 1,2-addition followed by hydrolysis to yield the desired carbonyl-migrated products.

Amine to Halogen Exchange Enables an Amine-Acid Etherification

A. McGrath,^† S. K. Das,^† E. Shim, A. Outlaw, S. Zhumagazy, H. R. Nodeh, J.-F. Brazeau, Z. Shi, J. D. Venable, C. Gelin, P. M. Zimmerman & T. Cernak*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-twl14) 🔓

The authors report an amine-acid etherification reaction that proceeds via a facile amine-halogen exchange and an ester-selective reduction. The method employs aliphatic amines and carboxylic acids to form C(sp³)–O ether bonds directly, enabling a range of readily available alkyl amines and acids to be transformed into synthetically valuable alkyl ethers that are challenging to access by conventional methods. Additionally, this methodology provides a straightforward approach for accessing medicinally relevant α-deuterated ethers and the deamination strategy can be extended to other nucleophiles, facilitating the synthesis of phenolic ethers and a range of halide products.

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Molecular Architects Win Nobel Prize

🏆️ Molecular Architects Win Nobel Prize. The 2025 Nobel Prize in Chemistry has been awarded to Susumu Kitagawa, Richard Robson, and Omar M. Yaghi for the development of metal–organic frameworks (MOFs)—porous, crystalline materials with enormous internal surface areas. These so-called “molecular hotels” use vast internal cavities to trap, store, and release molecules with exceptional precision. MOFs have been harnessed to capture and store carbon dioxide, remove PFAS from water, and quite literally pluck water out of thin (desert) air.

In the late 1980s, Richard Robson (University of Melbourne) pioneered the concept of constructing predictable three-dimensional coordination networks by linking metal ions with organic molecules. Building on this idea, Susumu Kitagawa (Kyoto University) and Omar M. Yaghi (UC Berkeley) independently developed stable and tunable frameworks in the 1990s. Kitagawa demonstrated that gases could enter and exit these structures without changing shape, and shortly afterwards, Yaghi coined the term “metal–organic framework” and created a MOF with a surface area of around 3000 m²/g—roughly half the area of a football pitch. Subsequent MOFs have since doubled that capacity.

As the Nobel Committee remarked, MOFs represent “a new form of matter”, a fusion of design and function with these three pioneering molecular architects building new worlds at the molecular scale, giving matter new spaces to live.