First isolated in 1948 from the Trichothecium roseum fungus, trichothecenes are a diverse class of sesquiterpene natural products with the structures of over 250 congeners established to date. Their general structure consists of the tricyclic “trichothecene” core, marked by the C12,13 exocyclic epoxide and C9,10 olefin, with further structural complexity generated through esterification of macrolide chains to afford macrocyclic trichothecenes including verrucarin A. Owing to their complex structures and potent anticancer activity, trichothecenes have captured the attention of numerous academic groups since the 1970s, resulting in total syntheses of both non-macrocyclic and macrocyclic trichothecenes. The macrocyclic compounds exhibit increased potency, with recent biological studies suggesting involvement of novel molecular targets. The dissertation research described herein is focused on efforts toward the total synthesis of (–)-verrucarol, the flagship trichothecene natural product, and related trichothecene congeners.
(–)-Verrucarol was the subject of six total syntheses throughout the 1980s, serving as an entry point for macrocyclic trichothecenes including verrucarin A. Compelled by the recent literature on insight into their therapeutic activity, we have established a concise route to the trichothecene core of verrucarol in eight steps. The construction of the tricyclic system is enabled by a novel samarium (II) iodide (SmI2)-mediated radical cyclization to an enol sulfonate to generate a complex oxabicyclo[3.2.1]octanone ring system. Significant synthetic efforts focused on a key late-stage olefin isomerization, which was ultimately accomplished through Mukaiyama-hydration and elimination.
Furthermore, while significant synthetic efforts have gone into constructing the tricyclic trichothecene core, only a single successful, albeit lengthy, enantioselective synthesis of (–)-verrucarol has been reported. To evaluate the full therapeutic potential of trichothecenes, a concise asymmetric synthesis to access the prerequisite tricyclic core is needed. Herein, we report a Cr (III)-salen complex-mediated Diels-Alder cycloaddition of 4-pyrones and the simple diene, isoprene, for rapid access of an enantioenriched precursor for the trichothecene core. Future efforts and synthetic strategies to generate macrocyclic analogues for structure-activity-relationship studies are provided, as focused synthetic efforts to evaluate their clinical potential are sorely needed. / 2025-09-20T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46987 |
| Date | 20 September 2023 |
| Creators | Powers, Madison Henry |
| Contributors | Porco, Jr., John A. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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