Total synthesis of endiandric acid J and beilcyclone A from cyclooctatetraene

Abstract

The endiandric acids are classic targets in natural product synthesis. The spectacular 8π/6π-electrocylisation/intramolecular Diels–Alder (8π/6π/IMDA) reaction cascade at the heart of their biosynthesis has inspired practitioners and students of pericyclic chemistry for nearly forty years. All previous synthetic approaches have sought to prepare a linear tetraene and thereby initiate the cascade. In this communication we demonstrate the use of cyclooctatetraene to rapidly intercept the 8π/6π/IMDA cascade at the cyclooctatriene stage. Endiandric acid J and beilcyclone A are prepared for the first time in six and five steps, respectively. The strategy features a tactical overall anti-vicinal difunctionalisation of cyclooctatetraene through S_N2′ alkylation of cyclooctatetraene oxide followed by an intriguing tandem Claisen rearrangement/6π-electrocyclisation from the corresponding vinyl ether. This rapidly constructs an advanced bicyclo[4.2.0]octadiene aldehyde intermediate. Olefinations and intramolecular Diels–Alder cycloadditions complete the syntheses. This establishes a short and efficient new path to the endiandric acid natural products. DFT modelling predicts thermal racemisation of bicyclo[4.2.0]octadiene intermediates, dashing hopes of enantioselective synthesis.