Synthesis of Pladienolide B and Its 7-Epimer with Insights into the Role of the Allylic Acetate

Diastereomeric macrolactones 41 and 48, which are epimeric at C-7, were both prepared by a synthesis based on our previously developed route to the macrolactone core of pladienolide B. Both compounds contain all the functionality of the macrolactone core plus the vinyl iodide unit in the side chain. The key step to construct the seco acid for the macrolactonization was a Horner-Wadsworth-Emmons (HWE) reaction to produce acyclic enone 17. The required keto phosphonate for the HWE reaction was originally obtained from (R)-(-)-linalool. The derived macrolactone underwent a reduction of the enone function to give 7-epi-alcohol 20, and its acetylation, either under Mitsunobu or classical acylation conditions, produced allylic acetate 40. This represents a rare case in which a Mitsunobu reaction occurred with retention of configuration. The complete side chain that contains all the functionality was attached by a Stille cross-coupling reaction to lead to 7-epi-pladienolide B (42). To obtain pladienolide B (1), the reduction of acyclic enone 17 under chelation-controlled conditions [Zn(BH4)(2), Et2O] gave allylic alcohol 43 with the correct configuration at C-7 with regard to the natural product. Conversion of this allylic alcohol to seco acid 46 followed by a Shiina macrolactonization afforded vinyl iodide 48. Its Stille coupling with vinylstannane 39 provided pladienolide B (1). Preliminary testing for cytotoxicity against the L929 cell line showed 7-epi-pladienolide B (42) to be completely inactive, which is in contrast to pladienolide B (1) that displayed an IC50 (half maximal inhibitory concentration) value of 7.5 nM. These results point to the importance of the correct configuration of the OAc functional group at C-7 of pladienolide B.