One-Step-Three-Ring Propellanation Reaction of Yne-Vinylcyclobutanones Catalyzed by Nickel: Reaction Development, Mechanism, and Formal Synthesis of Modhephene

The [3.3.3]propellane scaffold, present in various natural products, is a three-dimensional structure of interest in synthetic chemistry. Traditionally, these compounds are synthesized through a ring-by-ring strategy that is tedious (long steps of synthesis) and challenging (building two adjacent bridgehead quaternary centers of the target motifs is a formidable task). Herein, we report a nickel-catalyzed one-step, three-ring propellanation reaction that constructs the [3.3.3] propellane core from linear yne-vinylcyclobutanones. This method employs Ni(COD)₂ and P(Ad)₃ as the catalytic system and exhibits a broad substrate scope. The utility of this reaction has been further demonstrated through the formal synthesis of modhephene, a natural product featuring a [3.3.3] propellane skeleton. This propellanation reaction can be envisioned as biscarbene insertion of alkyne into the C-C bond in cyclobutanone and the C-H of the vinyl group in the substrates, but it actually takes place through oxidative cyclometalation of the alkyne and carbonyl group, Cope rearrangement, β-hydrogen elimination, trienolate cyclization, and reductive elimination, supported by DFT calculations and a deuterium labeling experiment. The detailed ligand exchange reaction (reaction initiation process) from Ni(COD)₂ to the Ni complex coordinated by the phosphine ligand and substrate, has also been studied computationally. How the tether group in the substrates affects the propellanation reaction and the side rearrangement reaction of vinylcyclobutanones to cyclohexenones has been analyzed, finding that electron-withdrawing tethers such as NTs and O favor the propellanation reaction, while the electron-neutral tether such as CH₂ and NBn tether, which is less electron-withdrawing compared to NTs, reduce this preference.