Studies On The Total Synthesis Of Marine Natural Product Puupehenone

The search of new medicines from marine natural products becomes a high prioritywith the search of these medicines from land sources becoming harder and harder.Biological diversity and chemical diversity are being found in marine thanks to itsspecial and diverse environmental conditions. As the bioactive compounds are usuallyscarce in marine life, the total synthesis of them would reduce the dependence on therelated marine sources.Puupehenone, an important bioactive marine natural product, displays a wide varietyof biological activities such as antitumor, antimalarial, antifungal and anti-HIVproperties. Accordingly, this thesis is centered on the synthetic studies of bioactivepuupehenone. The bioassay of the synthesized puupehenone intermediate has beenperformed, and the corresponding structure-activity relationships have beensubsequently studied.We planed to synthesize marine natural product puupehenone from the startingmaterials of (+)-sclareolide and protacatechualdehyde. Two synthetic routes aredesigned as follows:In the first route, two key moieties were connected before the configurationconversion of the chiral C-8position. On one hand, the key borono-sclareolideintermediate is synthesized from (+)-sclareolide via the DIBAL-mediated controlledreduction of the ester moiety of (+)-sclareolide to the hemiacetal, the photo-activatediodination reaction of the hemiacetal to the iodoformate ester, the elimination ofhydrogen iodide, the hydrolysis of the new-formed ester functionality, and the boronesterification. On the other hand, the key aromatic bromide intermediate was preparedfrom protacatechualdehyde by the Bn-protection of the phenolic hydroxyl group, theBaeyer-Villiger oxidation of the aldehyde to the ester, the hydrolysis of the ester to thephenol, the TBS-protection of the new-formed phenolic hydroxyl group, and aromaticbromination. The Suzuki-Miyaura cross-coupling reaction of the borono-sclareolideintermediate with the aromatic bromide intermediate afforded the tertiary alcoholintermediate, which in turn would be converted to the puupehenone-type marine naturalproducts via the remove of TBS protection, the key intramolecular Mitsunobu reactionand subsequent known transformations. Now, the key intramolecular Mitsunobureaction is still in progress and one (+)-yahazunol analogue has been synthesized. Thebioassay of this puupehenone intermediate has been performed, which was found topossesses little inhibitions for HL-60, MCF-7, and Hep G2.In the second route, the configuration the chiral C-8was conversed before theconnection of the sclareolide part and the aromatic ring part.(+)-Sclareolide wasconverted into the iodoformate ester intermediate through the configuration conversionof the chiral C-8of (+)-sclareolide, the DIBAL-mediated controlled reduction of the ester to the hemiacetal, and the photo-activated iodination reaction of the hemiacetal.The coupling reaction of this iodoformate ester intermediate with the aromatic bromideintermediate mentioned previously afforded the cyclic precursor of natural product.