Qing-An Chen

Terpenoids represent one of the most structurally diverse and biologically relevant families of natural products, yet the development of controllable biomimetic synthetic strategies using bulk feedstocks remains a critical challenge. Isoprene, an abundant and atom‐economical building block, holds great promise for terpenoid synthesis, but its four electronically and sterically similar olefinic carbons generally lead to poor regioselectivity and uncontrollable chemoselectivity in catalytic transformations. In this study, we reported a nickel‐catalyzed chemodivergent telomerization and hydrofunctionalization reaction for constructing terpenoids, wherein precise ligand control enables selective reactivity tuning. Leveraging the in situ formation of benzyl group from hydrazone‐mediated carbonyl umpolung reaction, telomerization is promoted by triarylphosphine ligand featuring both large steric hindrance and electron‐donating characteristics, while hydrofunctionalization benefits from the combination of less bulky, electron‐withdrawing triarylphosphine ligand and BEt ₃ . Mechanistic studies and density functional theory calculations validate the chemoselectivity governed by ligand sterics and electronics, as well as the role of BEt ₃ in enhancing regioselectivity. Moreover, this protocol created a series of value‐added terpenoids, all of which are amenable to further structural derivatizations. This mild, operationally simple catalytic manifold enables facile access to unnatural terpenoids and broadens the accessible chemical space of terpene frameworks.

Terpenoids represent one of the most structurally diverse and biologically relevant families of natural products, yet the development of controllable biomimetic synthetic strategies using bulk feedstocks remains a critical challenge. Isoprene, an abundant and atom‐economical building block, holds great promise for terpenoid synthesis, but its four electronically and sterically similar olefinic carbons generally lead to poor regioselectivity and uncontrollable chemoselectivity in catalytic transformations. In this study, we reported a nickel‐catalyzed chemodivergent telomerization and hydrofunctionalization reaction for constructing terpenoids, wherein precise ligand control enables selective reactivity tuning. Leveraging the in situ formation of benzyl group from hydrazone‐mediated carbonyl umpolung reaction, telomerization is promoted by triarylphosphine ligand featuring both large steric hindrance and electron‐donating characteristics, while hydrofunctionalization benefits from the combination of less bulky, electron‐withdrawing triarylphosphine ligand and BEt ₃ . Mechanistic studies and density functional theory calculations validate the chemoselectivity governed by ligand sterics and electronics, as well as the role of BEt ₃ in enhancing regioselectivity. Moreover, this protocol created a series of value‐added terpenoids, all of which are amenable to further structural derivatizations. This mild, operationally simple catalytic manifold enables facile access to unnatural terpenoids and broadens the accessible chemical space of terpene frameworks.

Visible light-induced dearomative cycloaddition has emerged as a powerful strategy for constructing complex polycyclic frameworks from simple aromatic precursors. Angularly fused polycyclic systems, which exhibit distinctive structural rigidity and tunable physicochemical properties, represent privileged scaffolds in bioactive natural products and pharmaceuticals. Herein, we report a robust photocatalytic protocol for the direct assembly of angularly fused tetracyclic scaffolds through intermolecular dearomatization of benzothiophene/indole derivatives with N-aryl cyclopropylamines. This transformation is achieved via a mechanistically intriguing cascade involving photocatalytic dearomative [3 + 2] cycloaddition and subsequent cyclization. This work demonstrates the synthetic feasibility of photocatalytic intermolecular dearomative [3 + 2] processes, providing direct access to structurally distinct angularly fused tetracyclic cores.

Ring-expansion editing offers a transformative strategy that could reshape the landscape of ring scaffold construction in synthetic chemistry. The introduction of three-dimensionality ring into flat aromatic systems could afford important semisaturated fused heterocycles, yet efficient method to access sulfur-containing semisaturated fused pyridines (SSFPs) remains scarce. Herein, we report a pyridyl radical-driven catalytic strategy for the direct two-carbon ring expansion of readily available cyclic thioethers, providing efficient access to synthetically challenging SSFPs. This transformation is enabled by synergistic dual photoredox cycles that orchestrate a cascade of radical cross-coupling, C(sp³)-S bond cleavage, and intramolecular cyclization between commercial bromopyridines and cyclic sulfides. The protocol demonstrates broad functional-group tolerance and substrate generality. Gram-scale synthesis and extensive downstream derivatizations, including late-stage semisaturation of pharmaceutical cores, highlight its synthetic utility. Mechanistic studies support a stepwise radical process involving discrete pyridyl and carbon-centered radical intermediates. This method offers a step-economical and modular alternative to conventional de novo synthesis for the rapid construction of complex, drug-like heterocyclic architectures.

Allenes, as versatile intermediates with unique cumulative double bond systems, have been widely used in cycloaddition reactions for constructing various cyclic skeletons, yet the selective synthesis of cyclobutenes via double allenes [2 + 2] annulation still remains a long‐standing challenge. Herein, we report a phosphine‐catalyzed unsymmetric [2 + 2] annulation of allenyl phosphonates for the efficient construction of highly substituted cyclobutenes. The reaction exhibits broad substrate scope, delivering the target cyclobutenes in moderate to good yields with exceptional Z / E selectivities and diastereoselectivities. Mechanistic studies reveal that the reaction proceeds via phosphine‐induced zwitterion formation and deprotonation of allene. The Lewis acid enables precise control of diastereoselectivity, while silane effectively suppresses allene isomerization to conjugated dienes and prevents catalyst deactivation, thus ensuring reaction efficiency. Furthermore, the synthesized cyclobutene derivatives demonstrate good structural modifiability through diverse transformations. This work enriches the field of phosphine‐catalyzed allene chemistry, fills a gap in allene‐based [2 + 2] cyclization modes, expands the methodological toolbox for cyclobutene synthesis, and provides a versatile platform for accessing complex cyclobutene‐containing molecules.

Allenes, as versatile intermediates with unique cumulative double bond systems, have been widely used in cycloaddition reactions for constructing various cyclic skeletons, yet the selective synthesis of cyclobutenes via double allenes [2 + 2] annulation still remains a long‐standing challenge. Herein, we report a phosphine‐catalyzed unsymmetric [2 + 2] annulation of allenyl phosphonates for the efficient construction of highly substituted cyclobutenes. The reaction exhibits broad substrate scope, delivering the target cyclobutenes in moderate to good yields with exceptional Z / E selectivities and diastereoselectivities. Mechanistic studies reveal that the reaction proceeds via phosphine‐induced zwitterion formation and deprotonation of allene. The Lewis acid enables precise control of diastereoselectivity, while silane effectively suppresses allene isomerization to conjugated dienes and prevents catalyst deactivation, thus ensuring reaction efficiency. Furthermore, the synthesized cyclobutene derivatives demonstrate good structural modifiability through diverse transformations. This work enriches the field of phosphine‐catalyzed allene chemistry, fills a gap in allene‐based [2 + 2] cyclization modes, expands the methodological toolbox for cyclobutene synthesis, and provides a versatile platform for accessing complex cyclobutene‐containing molecules.

Transition metal‐catalyzed nucleophilic telomerization of isoprene is an efficient strategy for the construction of monoterpene skeletons, yet its development has been impeded by inherent challenges of chemo‐ and regioselectivity control, especially in reactions with carbon nucleophiles. Herein, we developed a versatile palladium catalysis for the regiodivergent telomerization of isoprene with oxindoles through synergistic control of ligands, solvents, and additives. In the presence of aprotic solvent NMP, we revealed the electron‐rich and less bulky tri(2‐furyl)phosphine (TFP) ligand can facilitate the exclusive formation of tail‐to‐tail geranyl oxindoles, meanwhile the reactivity was severely improved by adding base as additive. On the other hand, a newly designed hemilabile phosphine ligand enables selective access to tail‐to‐head isomer, where the MeOH worked as an irreplaceable solvent choice. Mechanistic experiments and density functional theory (DFT) calculations were conducted, which indicate that protolysis of the η ¹ ,η ³ ‐diallyl–Pd(II) complex is speculated to be the rate‐determining step. Apart from oxindoles, this regiodivergent protocol could also be applied to the nucleophilic telomerization of isoprene with a broad scope of amines. Furthermore, the synthetic utility of current synthetic strategy was illustrated by late‐stage alkene isomerization, as well as various derivatizations that effectively expand the structural diversity of monoterpenoids and complement alkaloid frameworks.

Transition metal‐catalyzed nucleophilic telomerization of isoprene is an efficient strategy for the construction of monoterpene skeletons, yet its development has been impeded by inherent challenges of chemo‐ and regioselectivity control, especially in reactions with carbon nucleophiles. Herein, we developed a versatile palladium catalysis for the regiodivergent telomerization of isoprene with oxindoles through synergistic control of ligands, solvents, and additives. In the presence of aprotic solvent NMP, we revealed the electron‐rich and less bulky tri(2‐furyl)phosphine (TFP) ligand can facilitate the exclusive formation of tail‐to‐tail geranyl oxindoles, meanwhile the reactivity was severely improved by adding base as additive. On the other hand, a newly designed hemilabile phosphine ligand enables selective access to tail‐to‐head isomer, where the MeOH worked as an irreplaceable solvent choice. Mechanistic experiments and density functional theory (DFT) calculations were conducted, which indicate that protolysis of the η ¹ ,η ³ ‐diallyl–Pd(II) complex is speculated to be the rate‐determining step. Apart from oxindoles, this regiodivergent protocol could also be applied to the nucleophilic telomerization of isoprene with a broad scope of amines. Furthermore, the synthetic utility of current synthetic strategy was illustrated by late‐stage alkene isomerization, as well as various derivatizations that effectively expand the structural diversity of monoterpenoids and complement alkaloid frameworks.

Pyranocoumarins are widely distributed in natural products and exhibit intriguing biological activities, making their efficient synthesis highly desirable. Herein, we developed an efficient method for synthesizing two new types dimethylallyl-decorated pyranocoumarins in efficiency through catalytic formal [3 + 3] annulation of 4-hydroxycoumarins with valylene. Under acid catalysis, exclusive 1,3-alkenoxylation afforded natural product-like angular pyranocoumarins, while Rh catalysis switched regioselectivity to 3,1-alkenoxylation. The protocol features high atom-economy, readily available substrates, and excellent regio- and chemo-selectivity. Mechanistic studies indicated the reaction proceeds via regioselective hydroalkoxylation to form diene or allene intermediates, followed by intramolecular cyclization. This work not only represents a good paradigm in addressing selectivity challenges in reactions involving substrates with multireactive-site but also offers a robust platform for rapid construction of skeletal variants beyond naturally occurring structures.