The neoclerodane furanoditerpenoid family of natural products is a compelling target for a divergent total synthesis due to the complexity around their spirolactone-containing decalin core, the similarities between their functional groups, and biological activities that indicate a potential for future medicinal application. While being a relatively small molecule, the most structurally complex compound of the family, teucrin A, contains six stereocenters, five of which are contiguous. Our divergent synthesis route involves the stereo-controlled formation of a common decalin intermediate in four concise steps and 32% overall yield from commercially available starting materials. Additionally, desmethyl montanin A - an analog of montanin A missing its methyl group - can be produced from this key intermediate in one step and 95% yield, for a total of 30% yield over five steps. The dual-key step of this route consists of a Lewis acid-catalyzed Diels-Alder cycloaddition which stereo-selectively forms the spirolactone, followed by a gold-catalysed 6-exo-dig cyclization of the Diels-Alder adduct to complete the decalin core. The complementarity of these two steps is the focus of the synthesis, with the remaining steps for the formation of select neoclerodane natural products consisting of simpler classical chemistry, highlighting the potential for the creation of a large "unnatural" product library for applications such as drug candidate screening. Progress has additionally been made toward teucrin A, setting a cornerstone for future advancements to be made on this project. This concise synthesis advocates for the Barriault group's Diels-Alder/gold cyclization method of forming complex structural cores and will be applied to the total syntheses of other natural products in the future.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/44031 |
| Date | 07 September 2022 |
| Creators | Borba, Victor |
| Contributors | Barriault, Louis |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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