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Application of an Oxygen Stitching Strategy in the Syntheses of Complex Terpenoids


In the first chapter of this dissertation, a three-step total synthesis of the antimalarial (+)-cardamom peroxide, an endoperoxide-containing monoterpene dimer, is reported. This concise synthesis utilized (–)-myrtenal as an inexpensive terpene building block, and applied a novel oxygen stitching strategy to install all the oxygen atoms in the natural product from molecular oxygen. This strategy has enabled the preparation of large quantities of (+)-cardamom peroxide, and subsequent studies have determined its absolute configuration, and this molecule’s reactivity in iron(II)-induced reductive cleavage. Additionally, the antimalarial activities of cardamom peroxide against the clinical isolates of Plasmodium falciparum from several Cambodia provinces have been evaluated.

In the second chapter, a double allylation strategy for the construction of the [5,7,5]-fused carbocyclic system found in guaianolide sesquiterpenoids is disclosed. This strategy features a robust intramolecular allylation mediated by tin(II) chloride to assemble the seven-membered core. An efficient and scalable total synthesis of the trans-fused 8,12-guaianolide (+)-mikanokryptin via this strategy is reported in nine to ten steps from the abundant monoterpene (+)-carvone, which constitutes the first example of gram-scale total synthesis of any guaianolide natural product.

Subsequently, the oxygen stitching strategy has been expanded from the synthesis of endoperoxides to the strategic installation of multiple oxygen atoms on complex guaianolides in a stereocontrolled manner. A concise total synthesis of (–)-nortrilobolide and a formal synthesis of the anticancer agent (–)-thapsigargin are achieved by merging the oxygen stitching strategy and double allylation strategy.

Preliminary studies on a modular synthesis of guaianolides from the Apiaceae family of plants are also disclosed via an intramolecular allylation strategy. These studies include concise total syntheses of sinodielide A and grilactone from chiral-pool building block linalool, and studies towards the total syntheses of prutenin, ammolactone A, and montanolide. Notably, this strategy has the potential to access the Apiaceae guaianolides encompassing all the oxidation levels in this family.

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