Enantioselective Synthesis of cis-Decalins by Merging the Birch Reduction and Inverse-Electron-Demand Diels-Alder Reaction

Herein, we show that the combination of the Birch reduction of readily available anisole derivatives and the catalytic asymmetric inverse-electron-demand Diels-Alder reaction of 2-pyrones can serve as a powerful platform for the diverse synthesis of synthetically important cis-decalin scaffolds. Enabled by a well-modified chiral bis(oxazoline) ligand/Cu-II complex, a wide range of polysubstituted cis-decalin scaffolds with up to six contiguous stereocenters were generated efficiently. The synthetic potential of this method is demonstrated by the concise synthesis of the sesquiterpene (+)-occidentalol and a key intermediate for seven triterpenes. Mechanistic studies suggest the 1,3-cyclohexadienes formed in situ are the key intermediates, and efficient kinetic resolution occurs when C2- and/or C3-substituted 1,4-cyclohexadienes are utilized as substrates. DFT calculations elucidated that the Diels-Alder reaction proceeds in a stepwise fashion and revealed the origins of the stereoselectivities.

Automated summary

Here, we demonstrate that the combination of Birch reduction and catalytic asymmetric Diels-Alder reaction is a powerful approach for the synthesis of diverse cis-decalin scaffolds. By utilizing a modified chiral bis(oxazoline) ligand/Cu-II complex, we efficiently generated a wide range of polysubstituted cis-decalin scaffolds. Mechanistic studies revealed the role of 1,3-cyclohexadienes as key intermediates and the origins of stereoselectivities in the Diels-Alder reaction.