An efficient approach to angular tricyclic molecular architecture via Nazarov-like cyclization and double ring-expansion cascade

Polycarbocyclic scaffolds bearing quaternary carbon centers are prevalent in bioactive natural products and functional molecules but are challenging to construct due to rigid, congested structures. Angular tricycles (e.g., triquinanes) occur in terpenes, alkaloids, and lactones with diverse biological activities, yet efficient synthetic access is limited, often requiring lengthy, multi-step routes. Building on prior efforts combining semipinacol rearrangements with other cascade processes, the authors hypothesized that 1,3-dicycloalkylidenyl ketones could undergo a Lewis-acid-promoted Nazarov-like cyclization followed by two consecutive ring expansions to rapidly forge angular tricyclic architectures. This approach leverages strain release from vicinal quaternary centers and two cyclobutanes generated during the Nazarov step. The study aims to develop a general, selective, and mild method, elucidate substituent effects and mechanism, and demonstrate utility through total synthesis of (±)-waihoensene.

Previous work has combined Nazarov cyclization with rearrangements to access complex carbocycles. A stoichiometric SnCl4-mediated Nazarov cyclization/rearrangement furnished fused [5-5] bicycles but only in a single example and as a mixture of three isomers (71% total yield). Polarized dienone substrates (push–pull systems with EDGs and EWGs) often facilitate Nazarov reactions and have dominated earlier studies. Frontier and others developed Nazarov/Wagner–Meerwein cascades to monocycles and spirocycles, often under conditions favoring polarized substrates. The authors’ group previously merged Nazarov cyclization with semipinacol-type ring expansion to make chiral spiro-bicycles with quaternary centers. However, concise access to angular tricycles remained unmet, motivating exploration of a Nazarov-like cyclization of 1,3-dicyclobutylidene ketones terminated by two ring expansions to deliver angular triquinanes.

Reaction development started with 1,3-dicyclobutylidene ketones as substrates, examining Lewis acids and solvents at room temperature. Two test substrates were used: symmetric 2a (1,3-dimethyl) and polarized 2w (1-methyl, 3-carbonate). Optimal conditions identified were 0.1 equiv In(SbF6)3 in CHCl3 at room temperature, providing fast reactions and high yields. For 2a, 0.05–0.1 equiv In(SbF6)3 in CHCl3 completed within 1 h or 0.5 h (93–95% yield). For 2w, 0.1–0.2 equiv In(SbF6)3 in CHCl3 provided product in up to 81% yield albeit slower (12 h). Alternative Lewis acids (BF3·Et2O, Cu(OTf)2, TiCl4) and solvents (DCM, toluene, Et2O) were benchmarked. Substrate scope studies varied substitution on the 4π system (R1, R2) and on the cyclobutyl rings (R3, R4). Electronic effects, bonding mode, and sterics on R1/R2 were correlated to reactivity and regioselectivity of the two ring expansions. Additional scope explored fused and extended-ring substrates, E/Z mixtures, and larger ring analogs, documenting diastereoselectivity and reaction times/temperatures. Mechanistic studies employed DFT (computed in CHCl3) on representative substrates 2a and 2w. Energy profiles, activation barriers, and intrinsic reaction coordinate (IRC) analyses were used to identify the rate-determining step and rationalize substituent effects and the order of ring expansions. General procedure: In a glovebox, InCl3 and AgSbF6 were combined, CHCl3 added, then substrate (2 or 4) was introduced. The mixture was stirred at the indicated temperature/time. Workup involved filtration through silica, concentration, and purification by flash chromatography. NMR, IR, HRMS, and X-ray crystallography supported structure assignments.

- Optimal conditions: 0.1 equiv In(SbF6)3 in CHCl3 at room temperature; for 2a, 95% yield in 0.5 h; for 2w, up to 81% yield in 12 h. Even 0.05 equiv catalyst gave 93% yield for 2a in 1 h. - Alternative catalysts/solvents: BF3·Et2O (96% for 2a in 0.25 h); In(SbF6)3 effective in toluene, Et2O, CHCl3; Cu(OTf)2 ineffective for 2w in DCM; TiCl4 gave moderate yield (49% for 2w). - Electronic effects: EDG substitution at R1/R2 on the 4π system accelerates and improves yields (typically 55–96%); EWGs or proton substitution reduce activity and yields (36–88%) or can stop reactivity entirely (e.g., 2s with two H; 2ee with dicarbonate esters, no reaction). Electron-polarized substrate 2w reacted more slowly than unpolarized 2a, opposite to classic 4π Nazarov behavior. - Regioselectivity: The initial ring expansion occurs preferentially adjacent to the stronger electron-donating substituent. Directing ability order: i-Pr > n-Pr = Et > Bn > Allyl > Me = H > Ph > CO2Me. Substituents capable of n–π or p–π conjugation (heteroatoms, aryl, carbonyl) favor the second ring expansion near their location, preserving conjugation with the enone. - Stereoselectivity: High diastereoselectivity in most cases (often dr > 20:1). When para-mono-substituted cases (e.g., 4c–4f) gave mixtures, selectivity could be improved by adjusting conditions (e.g., 3c from 4:1 to 7:1 at −10 °C in DCM/HFIP with NaBArF4). Migration preference: methine migrates before methylene in general. - Scope breadth: Diverse R1/R2 variants delivered angular triquinanes in good yields and variable times (e.g., 1a 95%/0.5 h; 1t 71%/4 h; 1v 51%/48 h; 1ff 36%/12 h; 1gg 88%/12 h). Variations at R3/R4 across 4a–4p provided 3a–3p in 50–90% yields, including tetracycles and larger 6- and 7-membered tricycles. - Mechanism (DFT): The initial Nazarov cyclization is the rate-determining step. Calculated highest barriers (TS5) were ~19.1 kcal/mol (2a) and ~21.9 kcal/mol (2w), consistent with faster reaction of 2a. IRC analysis indicates for 2a a stepwise path via oxyallylic cation 6 and initial ring expansion TS1; for 2w, a more concerted progression to product driven by formation of an extended conjugated system with CO2Me. - Application: A racemic total synthesis of (±)-waihoensene was accomplished in 18 steps from the angular scaffold (via 3c), featuring key transformations including vinylogous aldol addition, photochemical [2+2], SmI2 ring opening, Barton–McCombie deoxygenation, Tamao–Fleming oxidation, and IBX oxidation.

The study validates the central hypothesis that a Lewis-acid-promoted Nazarov-like cyclization of 1,3-dicycloalkylidenyl ketones can be efficiently terminated by two consecutive ring expansions to construct angular tricyclic frameworks in a single operation. The method addresses the longstanding challenge of rapidly assembling congested tricycles with quaternary centers by exploiting strain-release from the initially formed vicinal quaternary centers and cyclobutanes. Systematic exploration of substituent effects established clear electronic control over both reactivity and the order of ring expansions: EDGs accelerate the cascade and direct the first expansion; n–π/p–π substituents promote the second expansion proximal to their position to preserve conjugation. Stereochemical outcomes are largely governed by sterics at the expanding rings and migrating group ability, with generally high diastereoselectivity and tunable selectivity when needed. DFT corroborates that the Nazarov cyclization is rate-determining and explains the unusual observation that unpolarized 2a reacts faster than polarized 2w under these conditions. The successful total synthesis of (±)-waihoensene demonstrates the synthetic utility of the angular scaffolds produced by the cascade, enabling concise access to complex natural product frameworks.

A general, modular cascade comprising a Nazarov-like cyclization followed by two ring expansions provides the most straightforward one-step construction to date of angular tricyclic carbocyclic skeletons bearing quaternary centers. The protocol operates under mild conditions with catalytic Lewis acid, exhibits broad substrate scope and high regio- and stereoselectivity, and tolerates diverse substitution patterns on both the 4π system and cyclobutanes. Electronic effects govern reactivity and ring-expansion order, and DFT identifies the Nazarov step as rate-determining. The method’s value is showcased in an 18-step racemic total synthesis of (±)-waihoensene. Future work will explore more intricate cascade designs to access higher-order polycycles, deepen mechanistic understanding, and expand synthetic applications to additional bioactive and functional molecules.

- Reactivity diminishes with electron-withdrawing or proton substitution on the 4π system; some substrates showed no reaction (e.g., two protons at R1/R2, or dicarbonate esters). - Electron-polarized substrates can react more slowly than unpolarized analogs under these conditions. - Certain substitution patterns led to mixtures of diastereomers, requiring condition optimization (temperature, solvent, additives) to improve selectivity. - Some examples required longer reaction times or elevated temperatures (e.g., up to 48 h or 50 °C), indicating sensitivity to substrate electronics and sterics.