Polycarbocycles and quaternary carbon centers are crucial structural motifs in a vast array of organic molecules, significantly impacting their chemical, biological, pharmacological, and physical properties. However, synthesizing these structures presents considerable challenges due to their rigid and sterically crowded nature. Angular tricyclic molecules, incorporating both polycycles and quaternary carbon centers, represent a particularly challenging yet important class of compounds, encompassing numerous natural products (terpenes, alkaloids, lactones) and synthetic compounds with diverse biological activities. Examples include molecules with anti-inflammatory, antimicrobial, anticancer, and antioxidant properties. Despite the first angular tricyclic molecule being discovered in the early 1970s, efficient and practical synthetic methods for accessing this framework remain scarce. Existing approaches often involve complex, multi-step transformations, limiting their widespread applicability. This research aims to develop a novel, efficient, and modular method for the synthesis of angular tricyclic architectures, focusing on a tandem Nazarov cyclization/double ring expansion strategy. The success of this approach hinges on overcoming the challenges posed by the high steric strain inherent in the proposed intermediates. The authors hypothesize that a Nazarov cyclization of a 1,3-dicyclobutylidene ketone precursor, followed by a double ring expansion, could lead to the desired angular tricyclic framework. This strategy exploits the release of strain from the crowded vicinal quaternary centers and congested cyclobutane rings to drive the cascade reaction. The readily accessible 1,3-dialkylidenyl ketone precursors make this approach particularly attractive, provided the initial Nazarov cyclization, known to be challenging with such sterically hindered substrates, can be effectively achieved.

The authors review existing methods for the synthesis of angular tricyclic compounds, highlighting the limitations of current approaches. They discuss previous work combining Nazarov cyclization with semipinacol-type ring expansions, which resulted in the synthesis of chiral spiro-bicyclic systems. They also mention a stoichiometric SnCl₄-mediated Nazarov cyclization/rearrangement, yielding a mixture of three fused [5-5] bicycle isomers. Previous studies on Nazarov cyclization often focused on substrates with electron-withdrawing and electron-donating groups (push-pull systems). However, the authors point out that effectively constructing the desired angular tricycles using these strategies remained elusive. This lack of a robust and efficient synthetic method motivates the development of the novel cascade reaction proposed in this study.

The researchers began by optimizing the reaction conditions for their proposed cascade reaction. They investigated various Lewis acids, including Cu(OTf)₂, BF₃·Et₂O, and In(SbF₆)₃, in different solvents such as DCM, toluene, Et₂O, and CHCl₃. They used two model substrates: a symmetric 1,3-dimethyl-substituted ketone (2a) and an unsymmetrical ketone (2w) with electron-donating (methyl) and electron-withdrawing (carbonate) groups. The optimal conditions were found to be 0.1 equiv of In(SbF₆)₃ in CHCl₃ at room temperature. Under these conditions, the symmetric substrate 2a gave the desired product 1a in high yield (95%), while the unsymmetrical substrate 2w reacted more slowly, providing the product 1w in 81% yield. The reaction time varied considerably depending on substrate substitution. The study then explored the effect of R¹ and R² substitution at the 4π-system. Electron-donating groups (EDGs) at these positions significantly favored the reaction, while electron-withdrawing groups (EWGs) or protons greatly reduced yields or prevented the reaction entirely. The regioselectivity, or the order of the two ring expansions, was found to be influenced by the electronic and steric properties of the R¹ and R² substituents. EDGs favored initial ring expansion at their respective sites. The influence of R³ and R⁴ substituents on the cyclobutane rings was also investigated, showing that a wide range of substituents was tolerated. Although some substrates gave diastereomeric mixtures, the diastereoselectivity could be improved by modifying the reaction conditions. The methodology was finally applied to the total synthesis of (±)-waihoensene, a complex tetracyclic natural product, which was achieved in 18 steps. The synthesis involved several key steps, including decarboxylation, vinylogous aldol addition, Dess-Martin oxidation, and selective methylation.

The study successfully established a new, efficient method for constructing angular tricyclic frameworks through a tandem Nazarov-like cyclization and double ring-expansion cascade. The reaction demonstrates high selectivity, utilizes mild conditions, and boasts a wide substrate scope. The key findings are: 1. **Electron-donating groups (EDGs) at the 4π-system are crucial for the reaction success:** Substrates with EDGs at R¹ and R² positions consistently yielded higher yields compared to substrates with EWGs or protons. The EDGs stabilize the carbocation intermediates, facilitating the reaction. EWGs or protons significantly hindered the reaction or completely prevented it. 2. **Regioselectivity is controlled by electronic properties and steric effects:** The electron-donating ability of R¹ and R² directs the initial ring expansion. Substituents with n-π or p-π interactions (e.g., aryl or carbonyl groups) favored the second ring expansion due to the preservation of the conjugated system. 3. **Stereoselectivity is governed by steric effects and migration ability:** The steric interactions between R³ and R⁴ substituents on the cyclobutane rings, along with the migratory aptitude of the migrating atoms, determine the stereochemical outcome. Diastereomeric mixtures were observed in some cases, but improved diastereoselectivity was achievable through adjusted reaction conditions. 4. **Broad substrate scope:** The reaction tolerated various substituents at the cyclobutane rings (R³ and R⁴), including alkyl groups, silyl groups, and fused rings, leading to diverse angular tricyclic products. The methodology also allowed for the construction of complex tetracycles and larger 6- and 7-membered tricycles. 5. **Successful total synthesis of (±)-waihoensene:** The developed methodology was successfully applied to the efficient 18-step total synthesis of the complex natural product (±)-waihoensene, showcasing the synthetic utility of the novel cascade reaction. 6. **DFT calculations support the proposed mechanism:** Density functional theory (DFT) calculations revealed that the initial Nazarov cyclization is likely the rate-determining step. The calculations also elucidated the reaction pathways for different substrates, providing insights into the observed reactivity and selectivity.

This research provides a significant advancement in the synthesis of angular tricyclic molecules. The developed cascade reaction offers a superior alternative to previously reported multi-step methods, providing high efficiency and selectivity under mild conditions. The broad substrate scope enables the synthesis of a wide array of functionalized angular tricycles, including biologically active compounds and potential drug candidates. The insights gained from the DFT calculations significantly enhance our understanding of the reaction mechanism, and pave the way for further optimization and the development of related cascade reactions. The successful total synthesis of (±)-waihoensene underscores the synthetic utility of this methodology. This work opens up new avenues for the preparation of complex polycyclic molecules with potential applications in various fields, from medicinal chemistry to materials science.

This study presents a novel and highly efficient approach to constructing angular tricyclic molecular architectures via a Nazarov-like cyclization and double ring-expansion cascade. The reaction features high selectivity, mild conditions, a broad substrate scope, and facile operation, making it a valuable tool for organic synthesis. The successful application of this methodology in the total synthesis of (±)-waihoensene highlights its potential in accessing complex natural products and other biologically relevant molecules. Future work will explore the application of this strategy to the synthesis of even more complex polycyclic systems and the further optimization of reaction parameters.

While the developed methodology demonstrated high efficiency and selectivity for a wide range of substrates, some limitations were noted. Certain substrates, particularly those with electron-withdrawing groups or protons at the 4π-system, showed low yields or failed to react. In some cases, diastereomeric mixtures were obtained. Although the diastereoselectivity could be improved by adjusting the reaction conditions, further optimization might be necessary for some specific applications. The study primarily focused on the synthesis of angular tricycles; further investigation is needed to determine the applicability of this methodology to the synthesis of other types of polycyclic structures.