Hetero[3.1.1]propellanes

Hetero[3.1.1]propellanes

R. I. Revie, A. Dasgupta, Y. Biddick, K. E. Christensen, R. C. Smith & E. A. Anderson*

Nat. Chem. 2026 (DOI: 10.1038/s41557-026-02072-2) 🔓

The authors report the unified synthesis of a family of heterocyclic [3.1.1]propellanes featuring oxygen, nitrogen and sulfur heteroatoms in the three-carbon bridge. The developed approaches are distinct from the established routes to carbocyclic propellanes, and utilize a common precursor that is conveniently assembled on a multigram scale via rhodium-catalysed cyclopropanation. These hetero[3.1.1]propellanes undergo a range of radical ring-opening reactions, affording bridged heterocycles that are of high utility in drug-discovery programmes.

Organocatalyst-Controlled Stereoselective Head-to-Tail Macrocyclizations

J. W. Rackl, L. B. Boll & H. Wennemers*

Science 2026, 391, 931–936 (DOI: 10.1126/science.aec8992)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-m78z8) 🔓

The authors report a catalyst-controlled, stereoselective head-to-tail macrocyclization using a bifunctional peptide catalyst that templates the terminal functional groups of a linear precursor, favoring intra- over intermolecular reaction and enabling exquisite control over the stereochemistry of emerging stereogenic centers. Diverse 12- to 18-membered macrocyclic lactones and lactams were obtained from achiral precursors, and the organocatalyst also dictated the stereochemical outcome in the cyclization of chiral substrates. The method’s utility was demonstrated by synthesis of the core of the natural product robotnikinin.

Markovnikov Hydroamination of Terminal Alkenes via Phosphine Redox Catalysis

F. Fan, K. F. Sedillo, A. J. Maertens & A. G. Doyle*

Nature 2026 (DOI: 10.1038/s41586-026-10263-7)

Main-group catalysts that mimic transition metal reactivity can expand substrate tolerance and enable transformations not currently possible with metal catalysis. The discovery that P^III and P^V phosphorus intermediates can undergo transition metal-like two-electron chemistry raises the question whether radical P^IV intermediates can mimic other elementary steps in organometallic chemistry. Here, the authors describe a phosphine-photoredox catalyst system that promotes intermolecular Markovnikov hydroamination of unactivated terminal alkenes with numerous classes of N–H azoles, a reaction that is not possible with late transition metal catalysis.

Desymmetrization of meso-Pyrrolidines via Oxoammonium-Catalyzed Enantioselective Hydride Transfer

J. Rein,^† B. Górski,^† A. M. Keskin, M. Hoang Le & S. Lin*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c20639) 🔓

The authors report the oxidative desymmetrization of urea-protected pyrrolidines via site-selective hydride transfer from enantiotopic C–H bonds. The optimal oxoammonium–peptide conjugate catalyst provided >90% e.e. across all tested pyrrolidines, providing products that can readily undergo subsequent N-deprotection and other derivatization reactions to form medicinally relevant compounds.

Peptidic Catalysts Conformationally Tuned for Fluoride Binding and Delivery

G. Poškaitė, T. Schlatzer, Z. Chen, M. V. Popescu, R. S. Paton & V. Gouverneur*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c01667) 🔓

Knowledge on how fluoride interacts with peptides is currently limited to in silico studies. Here, the authors report an experimental investigation on the ability of peptidic scaffolds to bind fluoride using TBAF·3H₂O or CsF. For CsF, in-depth NMR and GOAT-DFT studies shed light on peptides acting as chelators to both fluoride and cesium ions. This finding led to the development of the first peptide-catalyzed fluorination reactions.

Divergent Asymmetric Synthesis of Four Pentacyclic Homoproaporphine Alkaloids via C–H Elaboration

L. Pu, Z. Wang, J. Xia, Z. Chen, M. Xiao, L. Zhu & J. Huang*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c00213)

Pentacyclic homoproaporphine alkaloids contain a [6/6/6/6/6]-spiro-bridged framework and multiple stereocenters, presenting several synthetic challenges. Here, the authors report a divergent synthesis of four pentacyclic homoproaporphine alkaloids, (−)-robustamine, (−)-robustamine cis-N-oxide, (+)-regelinine, and (+)-regeline, through sequential C–H elaboration that proceeds via a two-stage cyclization–functionalization strategy.

Total Synthesis of the Glycoside Antibiotic Paulomycin A

J. Chen, Y. Ai, H. Wang, Y. Xu, Z. Li, J. Li, N. Huang & C. Li*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c00331)

Paulomycin A is a structurally distinctive glycoside antibiotic that displays potent activity against Gram-positive pathogens, yet its intrinsic chemical instability and high structural complexity have long prevented both drug development and synthetic exploration. Here, the authors describe the first total synthesis of paulomycin A, accomplished through a sequence of highly selective transformations tailored to its unusual reactivity profile.

Catalytic Methods for the Transfer of Nonstabilized Carbenes

E. S. Arnold, I. K. Eckart-Frank & S. M. Wilkerson-Hill*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c08715) 🔓

Despite the utility of metal–carbene alkene couplings, the use of nonstabilized carbene intermediates (i.e., alkyl-substituted carbenes) in cyclopropanation and C–H insertion reactions remains challenging, even though alkyl cyclopropanes are prevalent in natural products and pharmaceuticals. This perspective summarizes catalytic strategies developed to enable the transfer of nonstabilized carbene groups to alkenes and other trapping partners.

Positional Alkene Photo-Isomerization

L. Blank & R. Gilmour*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.6c00322)

Despite advances in stereoselective and regioselective alkene synthesis, strategies to interconvert readily available isomers into less accessible congeners remain limited. The selective relocation of a pre-existing alkene is especially challenging due to small thermochemical differences between isomeric products. Recent light-driven strategies, however, demonstrate that positional alkene isomerization can be achieved with high selectivity, often against thermodynamic bias. This Perspective highlights representative advances in nonground-state approaches to precision alkene transposition.

Visible-Light-Induced Photoactive Bifunctional Nickel Catalyst Enabled C(sp² )–C(sp² ) Cross-Electrophile Coupling

S. Ghosh, C. Nandi, S. Laru & D. Maiti*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000360/v1) 🔓

The authors report a general photoinduced nickel-catalyzed platform for modular C(sp² )–C(sp² ) cross-electrophile coupling under mild conditions. Visible-light excitation of a Ni(II)–ligand complex and a trialkyl amine generates an α-aminoalkyl radical that mediates selective halogen-atom transfer between electrophiles, guided by bond dissociation enthalpies, enabling cross-selective (hetero)aryl–(hetero)aryl coupling. Donor–acceptor bipyridine ligands enable tuning of (hetero)aryl radical formation and oxidative addition, while the Ni(II) complex functions both as the photoactive species and the coupling catalyst.

An Automated Platform for Tailored Late-Stage Halogenation of Pharmaceuticals

C. R. John, E. Tan, C. S. Begg, A. J. P. White, P. J. J. A. Buijnsters, J. Alcázar, A. M. Ganose, R. L. Greenaway* & J. A. Bull*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15000393/v1) 🔓

The authors report an automated, machine-learning aided, high-throughput workflow to investigate how varying acidity affects the C(sp² )–H chlorination, bromination, and iodination of 32 complex pharmaceutical substrates. Different compounds are shown to require significantly different acidities and yields are improved by optimisation of TFA equivalents. 56 halogenated analogues of 22 pharmaceuticals were prepared using conditions determined by the high-throughput workflow with significant benefit to yield. xTB atomic descriptors were used to predict regiochemical outcomes in a computationally inexpensive way.

Why (and how) Curling Stones Curl

🥌 Why (and how) Curling Stones Curl. If you’re missing the Winter Olympics like I am, here’s an interesting physics problem. For a sport played in Scotland since at least 1511, we still don’t fully understand the science behind it.

Those 19 kg curling stones—most of which begin life on Ailsa Craig, a tiny granite island just off Scotland’s west coast where I’m from—curl in the same direction as their rotation. Yet, for a simple rotating object sliding across a flat surface, the opposite happens. Feel free to try it yourself: spin a bowl clockwise while pushing it forward across a table and it will tend to drift left (I accept no responsibility for broken crockery…). In curling, however, a clockwise spin produces a rightward arc, the opposite of what basic sliding mechanics would predict.

The leading explanation is a “pivot–slide” mechanism, in which the roughened running band of the stone intermittently grips the pebbled ice, briefly pivoting before slipping free. As the stone slows, these stick–slip events become more pronounced and thousands of microscopic pivots accumulate into the smooth macroscopic curl.