Synthesis of fused tricyclic systems by thermal Cope rearrangement of furan-substituted vinyl cyclopropanes

Abstract

A novel method for the stereoselective construction of hexahydroazuleno[4,5-b]furans from simple precursors has been developed. The route involves the use of our recently developed Brønsted acid catalysed cyclisation reaction of acyclic ynenones to prepare fused 1-furanyl-2-alkenylcyclopropanes that undergo highly stereoselective thermal Cope rearrangement to produce fused tricyclic products. Substrates possessing an E-alkene undergo smooth Cope rearrangement at 40 °C, whereas the corresponding Z-isomers do not react at this temperature. Computational studies have been performed to explain the difference in behaviour of the E- and Z-isomers in the Cope rearrangement reaction. The hexahydroazuleno[4,5-b]furans produced by Cope rearrangement have potential as advanced intermediates for the synthesis of members of the guaianolide family of natural products.

Recent Advancement of the Cope Rearrangement in Organic Synthesis

“…As aplicações recentes que ilustram rearranjos de Cope também foram descritos por outros pesquisadores. [93][94][95][96][97][98][99][100] Esquema 30. Proposta mecanistica para obtenção de de hapalindole e fischerindole Esquema 31.…”

Function‐Oriented and Modular (+/−)‐cis‐Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF‐κB Inhibitors

“…[30][31][32][33][34][35][36] As such, the (pseudo)guaianolide family and their analogues have been implicated as leads in drug development. While the majority of medicinal chemistry and drug discoverye fforts re- lated to (pseudo)guaianolides involves isolation and/or semisynthesis, [37] there are numerous total syntheses(pseudoguaianolides [12][13][14][15] and guaianolides [38][39][40][41][42][43][44][45] )m ethods/approaches, [36,[46][47][48][49][50][51] and de novo analogue syntheses. [52,53] For drug discovery purposes, it would be ideal to have am odularr oute to pseudoguaianolide-analogues that retains the structural complexityo f the natural product family,c an tempert he reactivity of the Michael acceptors, [36] and allows for significant diversification aroundt he scaffold.…”