New Progress in Chemodivergent Synthesis Enabled by a Novel Metallocarbene Generation Platform from ECUST Published in Angew. Chem. Int. Ed.
Recently, the research group led by Professor Jun Zheng from the School of Pharmacy at ECUST, in collaboration with Professor Peng Liu’s group at the University of Pittsburgh, published a paper titled “Catalyst-Controlled Chemodivergent Carbene Transfer Reactions With Bicyclo[1.1.0]butane-Derived Acceptor Metallocarbenes” in Angewandte Chemie International Edition.
This study developed an acceptor-type carbene precursor platform based on bicyclo[1.1.0]butane (BCB) derivatives, enabling a new catalyst-controlled chemodivergent synthesis strategy and paving the way for green, safe, and atom-economical metallocarbene chemistry.
Transition-metal-catalyzed carbene transfer reactions are powerful tools in organic synthesis. However, they traditionally rely on diazo compounds, which are associated with stability and safety concerns.
While alternative precursors have emerged, a general, redox-neutral, and atom-economical platform for metallocarbene generation remains a persistent challenge.
In this study, the research team designed and introduced carboxamide-functionalized BCBs as versatile acceptor-type carbene precursors. These compounds exhibit good stability and are easy to handle. Under catalysis by earth-abundant metals like nickel or copper, they undergo strain-release-driven dual C–C cleavage to regioselectively generate acceptor-type metallocarbenes, thereby providing a novel, diazo-free approach to metallocarbene generation.
The team discovered that by simply switching the catalyst, they could precisely switch the reaction pathway to achieve chemodivergent synthesis: nickel catalysis enables cyclopropanation of alkenes to afford azabicyclo [n.1.0] architectures bearing multiple contiguous stereocenters with excellent diastereocontrol (dr>19:1).
Conversely, copper catalysis promoted efficient and chemoselective formal C(sp²)-H insertion to access allyl oxindoles. Both protocols exhibit 100% atom economy and required no additional oxidants or reductants, aligning with green chemistry principles.
Through isotope labeling, kinetic isotope effect (KIE) studies, quantitative ¹³C NMR analysis, and density functional theory (DFT) calculations, the team revealed the mechanistic divergence between the two systems: Ni-carbene formation proceeded via a stepwise peripheral C–C oxidative addition and retro-[2+2] cycloaddition pathway, while the copper system follows a concerted dual C–C cleavage followed by an electrophilic aromatic substitution pathway.
The synthetic utility of this methodology was highlighted through various transformations, successfully constructing core structures of bioactive molecules such as dihydroquinolin-2-ones, bicifadine, and horsfiline. Furthermore, the allyl and carboxamide groups in the products serve as versatile handles for further functionalization.
In summary, this study not only established a safe, efficient, and atom-economical platform for generating BCB-derived metallocarbenes but also accomplished the first formal insertion of this type of metallocarbene into C(sp²)–H bonds, leveraging catalyst control to precisely toggle reaction pathways. As the application of earth-abundant first-row transition metals (such as Ni and Cu) in carbene chemistry continues to deepen, this strategy is expected to drive the development of sustainable and diverse carbene transfer reactions.
Ph.D. candidate Haosong Ren from the School of Pharmacy, ECUST, and Postdoctoral Fellow Peipei Xie from the University of Pittsburgh are the co-first authors of this paper. Professor Jun Zheng from ECUST and Professor Peng Liu from the University of Pittsburgh are the co-corresponding authors.
This research was supported by the National Youth Talent Program, the National Natural Science Foundation of China, the Shanghai Scientific and Technological Innovation Projects, and the State Key Laboratory of Bioreactor Engineering.