Enantioselective Synthesis of (−)-Exiguolide by Iterative Stereoselective Dioxinone-Directed Prins Cyclizations


  • Financial support for this work was provided by the NCI (RO1 CA126827 and SPORE in Prostate Cancer P50 CA090386), the American Cancer Society (Research Scholar Award to K.A.S.) and Amgen. We are grateful to Boehringer-Ingelheim for the New Investigator Award in Organic Chemistry supporting T.P.Z. R.L.F. thanks the NIH for a predoctoral fellowship (F31CA138097). E.A.C. and R.L.F. thank the Malkin Scholars Program for additional support (Robert H. Lurie Comprehensive Cancer Center at Northwestern University). We would like to thank Dr. Andrew Mazar, Keith Macrenaris, Rich Ahn, and Elden Swindell (NU) for providing the cancer cell lines and cell culture technical support.


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Three become one: The title compound can be prepared in 26 steps by employing a unified Prins cyclization strategy to construct both tetrahydropyran rings (see scheme). The route combines two similar dioxinone fragments and one aldehyde component to generate the core structure. (−)-Exiguolide selectively inhibits the growth of A549 cancer cells at low concentrations; the triene side chain and the Z-enoate geometry are both necessary for this cytotoxicity.