Divergent Chiral-Pool Synthesis of the C1–C8 and C9–C13 Fragments of Pladienolide B from L-Malic Acid

Pladienolide B (1), a macrocyclic polyketide isolated from Streptomyces platensis Mer-11107, displays potent antiproliferative and antitumor activities through its interaction with the SF3b subunit of the spliceosome. Herein, we report a divergent, stereoselective synthetic route to access both the C1–C8 and C9–C13 fragments of the core moiety of Pladienolide B (1) starting from a common, inexpensive chiral-pool precursor, L-Malic acid. Key stereocenters and structural motifs were established using Sharpless asymmetric epoxidation, regioselective nucleophilic epoxide opening, Mannich reaction for exo-methylene introduction, and a tandem iodination–zinc elimination cascade. This unified precursor approach offers a streamlined tactical route toward the core macrolide framework.