Rhodium-Catalyzed [5 + 2 + 1] Cycloaddition of Ene–Vinylcyclopropanes and CO: Reaction Design, Development, Application in Natural Product Synthesis, and Inspiration for Developing New Reactions for Synthesis of Eight-Membered Carbocycles

• Published in: Accounts of chemical research Vol. 48; no. 8; pp. 2288 - 2296
• Main Authors: Wang, Yi, Yu, Zhi-Xiang
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 18.08.2015
• Subjects: Alkenes - chemistry; Alkynes - chemistry; Biological Products - chemical synthesis; Biological Products - chemistry; Carbon Monoxide - chemistry; Catalysis; Construction; Cycloaddition; Cycloaddition Reaction; Cyclopropanes - chemistry; Insertion; Inspiration; Natural products; Rhodium - chemistry; Strategy; Synthesis; Synthesis (chemistry)
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/acs.accounts.5b00037

Practical syntheses of natural products and their analogues with eight-membered carbocyclic skeletons are important for medicinal and biological investigations. However, methods and strategies to construct the eight-membered carbocycles are limited. Therefore, developing new methods to synthesize the eight-membered carbocycles is highly desired. In this Account, we describe our development of three rhodium-catalyzed cycloadditions for the construction of the eight-membered carbocycles, which have great potential in addressing the challenges in the synthesis of medium-sized ring systems. The first reaction described in this Account is our computationally designed rhodium-catalyzed two-component [5 + 2 + 1] cycloaddition of ene–vinylcyclopropanes (ene–VCPs) and CO for the diastereoselective construction of bi- and tricyclic cyclooctenones. The design of this reaction is based on the hypothesis that the C­(sp3)–C­(sp3) reductive elimination of the eight-membered rhodacycle intermediate generated from the rhodium-catalyzed cyclopropane cleavage and alkene insertion, giving Wender’s [5 + 2] cycloadduct, is not easy. Under CO atmosphere, CO insertion may occur rapidly, converting the eight-membered rhodacycle into a nine-membered rhodacycle, which then undergoes an easy C­(sp2)–C­(sp3) reductive elimination process and furnishes the [5 + 2 + 1] product. This hypothesis was supported by our preliminary DFT studies and also served as inspiration for the development of two [7 + 1] cycloadditions: the [7 + 1] cycloaddition of buta-1,3-dienylcyclopropanes (BDCPs) and CO for the construction of cyclooctadienones, and the benzo/[7 + 1] cycloaddition of cyclopropyl-benzocyclobutenes (CP-BCBs) and CO to synthesize the benzocyclooctenones. The efficiency of these rhodium-catalyzed cycloadditions can be revealed by the application in natural product synthesis. Two eight-membered ring-containing natural products, (±)-asterisca-3(15),6-diene and (+)-asteriscanolide, have been synthesized using the [5 + 2 + 1] cycloaddition as the key step. In the latter case, excellent asymmetric induction was obtained using a chiral substrate. The efficiency of the [5 + 2 + 1] reaction was further demonstrated by the synthesis of four sesquiterpene natural products, (±)-pentalenene, (+)-hirsutene, (±)-1-desoxyhypnophilin, and (±)-hirsutic acid C, containing linear or branched triquinane skeletons utilizing the tandem or stepwise [5 + 2 + 1] cycloaddition/aldol reaction strategy. With the success of [5 + 2 + 1] cycloaddition in natural product synthesis, application of the [7 + 1] and benzo/[7 + 1] cycloadditions in target- and function-oriented syntheses can be envisioned.