Leiodermatium, a deep-water marine sponge, was collected by Fenical and co-workers off the coast of Palau as reported in 2006. Leiodelide A, a 19-membered ring macrolide which showed increased cytotoxicity when screened against HL-60 leukemia and OVAR-3 ovarian cancer cell lines, was isolated from the sponge. The synthesis of the related macrolide leiodelide B was reported by Fürstner and co-workers in 2011, but the synthetic sample did not match the spectral data of the known compound. Leiodelide A is an attractive target for natural product synthesis, due to its biological activity and undetermined structure.
A highly convergent synthetic route to leiodelide A has been developed. The molecule is broke into three portions, the side chain, the northern hemisphere, and the southern hemisphere of the macrolactone. The high convergence of the synthesis will allow for rapid access to a number of possible isomers if the proposed structure proves to be incorrect, while aiding in the synthesis of numerous analogs for structure activity relationship (SAR) studies.
Two versions of the side chain were produced to allow for greater screening of conditions for the olefination step. The side chain producing the greatest selectivity for the desired E-geometry will be used to connect the side chain to the macrolactone in the penultimate step. The northern hemisphere was synthesized from D-xylose producing both C13 epimers. Having both possible epimers at the unassigned center of leiodelide A will allow for determination of the absolute configuration of leiodelide A.
The southern hemisphere of leiodelide A was produced in three steps from known starting materials. Both stereocenters in the southern hemisphere are set in a single step via an Evans aldol reaction, while the α,β-unsaturated ester is installed via a Horner-Wadsworth-Emmons olefination.
The southern and northern hemispheres have been coupled to the oxazole portion of the molecule. The coupling strategy utilized methodology developed by our laboratory to allow for palladium-mediated couplings to form 2,4- and 2,5-disubstituted oxazoles. Unfortunately the macrolactone could not be closed using Mitsunobu macrolactonization conditions, but an alternate route has been devised in order to complete the total synthesis of leiodelide A.
A palladium-catalyzed oxidation of alkyl enol ethers to α,β-unsaturated aldehydes was developed. The reaction utilizes palladium loadings far lower than those used in traditional Saegusa oxidations of silyl enol ethers. Despite a number of published modifications of the Saegusa oxidation allowing for lower loadings of palladium, a full equivalent of palladium is still often used in the synthesis of natural products. The conditions tolerate a vast array of functional groups and are applicable to the synthesis of di-, tri-, and tetrasubstituted olefins. Thus, the substrate scope of the reaction was increased relative to previous methods.
An intramolecular version of the palladium-catalyzed oxidation of alkyl enol ethers was discovered which produces furans and dihydrofurans. The 4-hydroxy alkyl enol ether starting materials can be easily obtained from the addition of allyl alkyl ethers to aldehydes or ketones. The developed methodology provides rapid access to easily modified furan and dihydrofurans, which are found in a large number of biologically active compounds.
|Commitee:||Bong, Dennis, Forsyth, Craig|
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Chemistry, Organic chemistry|
|Keywords:||Enal, Enol ether, Leiodelide, Leiodolide, Oxazole, Saegusa|
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