Highly Stereoselective Total Synthesis of (+)-9-epi-Dictyostatin and (–)-12,13-bis-epi-Dictyostatin Eur. J

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 9R-configuration in 28a and for the 9S-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