Leiodelide A was isolated from the deep-water marine sponge Leiodermatium off the coast of Palau by Fenical and co-workers in 2006. Along with leiodelide B they form a new family of biologically active macrolides featuring an oxazole-containing 19-membered macrolide, seven stereocenters and a 10-carbon side chain with an α,α-disubstituted carboxylic acid terminus. Both currently have at least one unassigned stereogenic center. Biologically, leiodelide A exhibits cytotoxic activity against HCT-116 human colon carcinoma, HL-60 leukemia, NCI-H522 nonsmall cell lung cancer and OVCAR-3 ovarian cancer cell lines.
The combined factors of low natural supply, biological activity and unusual structure made it an attractive target for total synthesis. We therefore embarked on a quest to devise a strategy for the total synthesis and structure determination of leiodelide A.
Two different versions of the side chain have been synthesized in very efficient manners which will allow screening of conditions for the olefination reaction to attach the side chain to the macrolide as the penultimate step.
The polyoxygenated northern subunit was derived from D-xylose via opening of a fully protected lactone followed by Wittig olefination. This strategy allowed formation of both C13 epimers which will help in the determination of the absolute configuration of leiodelide A.
The C1-C7 southern subunit was rapidly assembled via an aldol reaction using Davies’ SuperQuat auxiliary followed by Horner-Wadsworth-Emmons olefination in a three-step protecting group free synthesis.
In order to obtain gram quantities of the required oxazole, a detailed mechanistic study of the halogen dance reaction was undertaken, which allowed a dramatic improvement in the yield of this reaction on iodooxazoles.
Finally, the macrolactone was closed using coupling chemistry developed in the Stambuli group. Although only an isomer of the assigned structure was synthesized, the overall strategy should be amenable to the synthesis of the required macrolide.