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

The 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 S N 1 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 S N 2 mechanism and/or (ii) a benzenecoordinated transition state in an S N 1-like mechanism.