Total Synthesis of 6‑Deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 Cancer Cell Line

A total
synthesis of the natural product 6-deoxypladienolide D
(1) has been achieved. Two noteworthy attributes of the
synthesis are (1) a late-stage allylic oxidation which proceeds with
full chemo-, regio-, and diastereoselectivity and (2) the development
of a scalable and cost-effective synthetic route to support drug discovery
efforts. 6-Deoxypladienolide D (1) demonstrates potent
growth inhibition in a mutant SF3B1 cancer cell line, high binding
affinity to the SF3b complex, and inhibition of pre-mRNA splicing.