Asymmetric Total Synthesis of a Bioactive Lignanamide Using a 5‐endo‐tet‐Type Cyclization of Activated Cyclopropylcarbinols and Synthetic Support for the Reaction Mechanism

Abstract

AbstractThe first enantioselective total synthesis of a bioactive lignanamide was achieved with high enantiomeric excess. Key synthetic steps include an organocatalytic enantioselective cyclopropanation and a Lewis‐acid‐mediated chirality‐transferring 5‐endo‐tet‐type cyclization that proceeds with a very high degree of stereoinduction. The proposed mechanism of the key reaction is supported by the experimental results. Based on these experimental results, the 5‐endo‐tet‐type cyclization of a cyclopropylcarbinol proceeds predominantly via an SN1 mechanism with high trans‐selectivity, which arises from the steric hindrance of the neighboring substituent. Minor pathways include the anchimeric participation of (i) the oxygen atom of the benzoyl group in an SN2 mechanism and/or (ii) a benzene‐coordinated transition state in an SN1‐like mechanism.