Vinylcyclopropanes as Three-Carbon Synthons in Rhodium-Catalyzed Cycloadditions: Reaction Development, Mechanistic Studies, New Inspirations, and Synthetic Applications

ConspectusCyclic structures are common in natural products and pharmaceuticals, but pose major synthetic challenges. Transition metal-catalyzed cycloadditions provide a direct and efficient route to complex ring systems in a single step. The demand for new transition metal-catalyzed cycloadditions remains high, as these methods enable access to diverse ring systems with unique substituents and stereochemistries that are often unattainable through existing cycloaddition techniques. Vinylcyclopropanes (VCPs) are widely recognized as versatile five-carbon (C₅) synthons in various transition metal-catalyzed cycloadditions, including [5 + 1], [5 + 2], and [5 + 2 + 1] reactions. In these reactions, VCP uses its vinyl group to facilitate C-C bond cleavage in the strained cyclopropane, aided by transition metals. In contrast, isolated cyclopropanes typically lack this reactivity. Building on these advantages, we discovered that by altering the connectivity between VCPs and other synthons, such as alkenes, alkynes, allenes, or dienes, VCPs can act as novel three-carbon (C₃) synthons, enabling previously unknown cycloadditions. This account outlines these discoveries.By connecting two-carbon (C₂) synthons to VCPs at positions 1, 2, or α, we created various substrates, including 2-<i>trans</i>-ene/allene-VCPs, 1-ene/yne/allene-VCPs, and α-ene-VCPs. These substrates undergo [3 + 2] cycloadditions to construct fused bicyclic structures. Notably, 1-ene/yne/allene-VCPs enable the construction of 5/5 fused rings with bridgehead quaternary centers, representing a remarkable synthetic advancement. This reaction has also been extended to its asymmetric variant, marking the first asymmetric [3 + 2] reaction of its kind. Furthermore, 1-ene/yne-VCPs have been adapted for [3 + 2 + 1] cycloadditions, allowing the synthesis of 5/6 and 6/6 fused ring systems with bridged quaternary centers. The utility of this method is demonstrated through its application in the synthesis of several natural products. The success of the [3 + 2 + 1] cycloaddition further inspired the development of a novel [4 + 2] reaction using yne-vinylcyclobutanones (yne-VCBOs). While VCBO has traditionally been used as a six-carbon (C₆) synthon, we discovered that it functions as a four-carbon (C₄) synthon when alkynes are connected at the 1-position of VCBOs. This [4 + 2] reaction cocatalyzed by Rh and Zn yields 5/6 or 6/6 fused rings with bridgehead quaternary centers, which is the same motif formed via the [3 + 2 + 1] reaction of 1-yne-VCPs and CO.The synthesis of seven-membered rings remains a challenging endeavor. By connecting a diene to the 1-position of VCPs, we developed a Rh-catalyzed [4 + 3] cycloaddition, yielding 5/7 fused ring structures. Additionally, introducing CO into the reaction enabled a [4 + 3]/[4 + 1] cycloaddition, generating 5/7/5 triangular ring scaffolds. Both [4 + 3] and [4 + 3]/[4 + 1] reactions feature an unprecedented <i>endo</i>-oxidative cyclometalation mode, which could be utilized in future cycloaddition design. Further developments may include expanding reaction scopes, applying these methods to natural product synthesis and medicinal chemistry, realizing asymmetric variants, understanding reaction mechanisms, and inventing new synthons and cycloaddition reactions.