Ynamide Protonation-Initiated Cis-Selective Polyene Cyclization and Reaction Mechanism

Abstract

The diastereoselectivity of conventional polyene cyclization reactions is highly dependent on the configuration of the internal alkenes, where E-poly enes provide trans-decalins, while Z-polyenes offer cis-decalins. Although polyene cyclization has evolved into a reliable and widely used strategy for the construction of trans-decalin frameworks of terpene and steroid natural products, its application for cis-decalin framework is extremely challenging. This is because it not only requires the difficultly approached Z-polyenes but also has usually been accompanied by the formation of undesired transisomer. We herein report a universal polyene cyclization approach to cis-decalin frameworks by employing ynamide-capped polyenes (YCPs), which erase the traditional strict requirement for alkene stereochemistry since both E- and Z-YCPs give cisdecalin frameworks with excellent diastereoselectivity. A broad range of YCPs are compatible to furnish the cis-decalin frameworks in good to excellent yields without any detectable trans-isomer. Both experimental and density functional theory (DFT) calculation results reveal that the ynamide protonation-initiated polyene cyclization proceeds in a stepwise manner involving an unprecedented double protonation mechanism wherein the steric repulsion between the iminium and the forming decalin framework in the Friedel-Crafts transition state is responsible for the unusual excellent cisdiastereoselectivity. DFT calculations also showed that an excess of TfOH was essential for the formation of cis-decalin because the catalytic amount of TfOH resulted in the pretermination of this cascade process.