Synthesis of the polycyclic Natural Product Lingzhiol
Final Report Abstract
In medicine, natural substances are of great importance as medicinal substances and remedies in the form of extracts. In 2013, the isolation of the polycyclic meroterpenoid lingzhiol from the medicinal mushroom Ganoderma lucidum was described. Lingzhiol was also said to have kidney-protective properties. This triggered enormous interest in organic chemistry, as syntheses of lingzhiol were in demand with regard to structure-activity relationships. In the meantime, ten total syntheses of lingzhiol have been described in the literature. Our group achieved two fundamentally different syntheses for racemic lingzhiol. Firstly, a substituted cyclopentane derivative with an exo-cyclic double bond was converted to a substrate for an intramolecular Friedel-Crafts alkylation via allylic hydroxylation and epoxidation of the double bond. In the presence of Lewis acid, the tetracyclic ring system of lingzhiol was obtained. From there, the natural product was obtained in four steps. In a second strategy, a tetralone derivative was used as the starting point. After an alkynyl residue and a spiroepoxide had been introduced, reductive conditions led to a radical cyclization to form the cyclopentane ring of lingzhiol. Six further steps also yielded the natural product lingzhiol. Other strategies were also investigated, but ultimately did not lead to the desired result. For example, a goldcatalyzed Conia-ene reaction to a substituted cyclopentane with an exo-cyclic double bond was successful. However, the allylic oxidation resulted in a product mixture. The synthesis of a tricyclic precursor to a lingzhiol analog failed due to the synthesis of the substrates for the planned intramolecular Pauson-Khand reaction. With the inclusion of an intramolecular pinacol coupling, a bicyclo[3.3.0] ring system was formed, as found in simpler meroterpenoids. However, the final cyclization to form the lingzhiol ring system could not be realized. Overall, good contributions were made to the chemistry of lingzhiols.
Publications
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Total Synthesis of Lingzhiol and its Analogues through the Wittig Reaction of an Oxocyclopentane Carboxylate. Asian Journal of Organic Chemistry, 6(1), 108-117.
Rengarasu, Rathikrishnan & Maier, Martin E.
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A Radical-Based Synthesis of Lingzhiol. The Journal of Organic Chemistry, 82(18), 9844-9850.
Mehl, Lea-Marina & Maier, Martin E.
