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

Abstract

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(sp(3))-C(sp(3)) 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(sp(2))-C(sp(3)) 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.

Rhodium(I)‐Catalyzed Bridged [5+2] Cycloaddition of cis‐Allene‐vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton

“…[17] In 2008, we reported the intramolecular [5+ +2] cycloaddition of cisene-vinylcyclopropanes (cis-ene-VCPs) to afford cis-fused bicyclicp roducts (Scheme 1a). [17] In 2008, we reported the intramolecular [5+ +2] cycloaddition of cisene-vinylcyclopropanes (cis-ene-VCPs) to afford cis-fused bicyclicp roducts (Scheme 1a).…”

“…We also synthesized the substrates 1p-r and examined how the variations on the VCP moiety of the substrates affected the reaction outcomes (entries [16][17][18]. No reaction occurred when substrate 1r with substitution at the cyclopropane moiety was used, which could be attributed to the steric hindrance of the substrate.S ubstrates 1p-q with substitution in the alkene moiety showed low reactivities so the catalyst loading was increased to 10 mol %a nd the temperature was raised to 100 8 8C.…”

Mechanism, reactivity, and regioselectivity in rhodium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes: a DFT Investigation

“…Since the discovery of the Wilkinson complex [RhCl(PPh 3 ) 3 ] which was proved to be the harbinger of the development of modern organorhodium chemistry, the new field of homogeneous catalysis was opened. Particularly in the preparation of enantiomerically enriched compounds, numerous rhodium-catalyzed reactions have been developed, such as asymmetric hydrogenation3, isomerization of olefins4, hydroacylation5, cycloaddition6 and C–H insertion7, etc. Over the past decade, several metal-catalyzed asymmetric ring cleaving reactions have been developed that generate ring-opened products in high yield and enantiomeric excess.…”

“Cut and Sew” Transformations via Transition-Metal-Catalyzed Carbon–Carbon Bond Activation

“…36 Typically, VCPs are classified based on their substitution positions. Terms such as 1-ene-/2-yne/β-yne-VCPs are often seen from literatures (Scheme 19).…”