Highly Stereoselective Total Synthesis of (+)‐9‐<i>epi</i>‐Dictyostatin and (–)‐12,13‐Bis‐<i>epi</i>‐dictyostatin

Abstract

Abstract The total syntheses of (+)‐9‐ epi ‐dictyostatin ( 1a ) and (–)‐12,13‐bis‐ epi ‐dictyostatin ( 1b ), diastereomers of the antimitotic marine sponge‐derived macrolide (–)‐dictyostatin ( 1 ), were achieved by creating 11 stereogenic centers and 4stereogenic double bonds with a high level of stereocontrol. The yield for the 29‐step longest linear sequence from Roche ester was 1.53 and 1.52 %, respectively. The final key steps to these unnatural products were the addition of vinylzincates C10‐C26 to aldehyde C1–C9 (leading surprisingly to complete stereoselectivity for the 9 R ‐configuration in 28a and for the 9 S ‐configuration in 12,13‐bis‐epimeric 28b ), followed by Yamaguchi macrolactonization and global deprotection. (–)‐12,13‐Bis‐ epi ‐dictyostatin ( 1b ) displayed a dramatic decrease of cytotoxicity and of the affinity toward the paclitaxel binding site of microtubules.