Scalable Synthesis of 17S-FD-895 Expands the Structural Understanding of Splice Modulatory Activity

Highlights

• Process scaled synthesis of a complex polyketide

• Complete control of regioselective bond assembly

• Installation of 11 stereocenters with high enantioselectivity

• Synthetic access to single stereoisomeric and single-atom isotopically labeled analogs

Summary

While splice modulators have entered clinical trials, limited clinical efficacy in splicing factor mutation-driven malignancies, such as acute myeloid leukemia, has remained a challenge. There is a pressing unmet medical need for developing potent small molecule splice modulators for the treatment of a broad array of malignancies characterized by splicing deregulation. However, the inability to practically access gram-scale lead molecules with viable pharmacological properties continues to hinder their application. Here, we report a scalable approach to prepare 17S-FD-895, a potent in vivo active splice modulator. The strategy described herein not only provides material to enable clinical translation but also furthers lead validation by expanding the structure-activity relationships that guide splice modulation.