Stereoselective Intramolecular Rhodium(I)-Catalyzed [(3+2+2)] Cycloaddition Reactions of Alkylidenecyclopropanes (ACPs) for the Concise Synthesis of Bridged Tricyclic Products

Abstract

Transition metal-catalyzed higher-order [m+n+o] cycloadditions are an important class of reactions for constructing elaborate carbocycles and heterocycles in a highly convergent manner. In particular, cycloadditions with alkylidenecyclopropanes (ACPs) as three-carbon synthons offer a versatile strategy for the chemo-, regio-, and stereoselective construction of complex cyclic scaffolds. While the diastereoselective synthesis of fused bicyclic and tricyclic systems has been explored, the stereoselective assembly of the more challenging bridged tricyclic skeletons—present in bioactive sesquiterpenes—remains underdeveloped. Chapter 1 introduces transition metal-catalyzed higher-order [m+n+o] cycloaddition reactions, followed by a focused review of stereoselective metal-catalyzed intramolecular [(m+2+2)] cycloadditions for the direct synthesis of polycyclic products containing five- to eight-membered rings. The review is divided into intramolecular [(2+2+2)], [(3+2+2)], and [(4+2+2)] cycloaddition, highlighting seminal examples in which all the 𝜋-components are tethered. This organization emphasizes current developments and limitations, thereby setting the stage for the studies presented in Chapters 2-4. Chapter 2 highlights the development of a diastereoselective, intramolecular, rhodium-catalyzed [(3+2+2)] cycloaddition involving ACPs tethered to skipped dienes, enabling the formation of bridged tricyclic products bearing up to three new quaternary stereocenters in a single step. Furthermore, a concise, stereoselective total synthesis of the sesquiterpene (+)-zizaene, which employs this cycloaddition as a key step, underscores the advancement and synthetic utility of this methodology. Chapter 3 presents the development of a more challenging enantioselective variant of the [(3+2+2)] cycloaddition reaction. Following a review of the historical development of transition metal-catalyzed enantioselective cycloaddition of ACPs and the emergence of asymmetric chiral counteranion-directed catalysis (ACDC) strategies, our work—enantioselective intramolecular rhodium-catalyzed [(3+2+2)] cycloaddition of ACPs leveraging a novel ACDC approach—is discussed. This strategy enables asymmetric induction via the ion-pairing chiral counterion of the catalyst, offering a compelling alternative to conventional chiral ligand control. Chapter 4 concludes the achievements and outlines future directions for advancing synthesis, including diastereodivergent approaches enabled by counterion control as well as the broader potential of the ACDC strategy to facilitate other enantioselective, metal-catalyzed cycloadditions of ACPs. These proposed developments aim to expand the synthetic toolbox for constructing complex polycyclic systems.