Synthesis of antitumor marine natural products and structure revision of Niphateolide A
Han, T. (2025). Synthesis of antitumor marine natural products and structure revision of Niphateolide A. Université Laval: Quebec. 223 pp.
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Document type: Dissertation
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| Abstract |
This research concerns the synthesis of antitumor marine sponge metabolites and their analogues. In particular, it involves the development of new methodologies and strategies enabling the expedient construction of five-membered heterocycles. Moreover, this work demonstrates the indisputable value of total synthesis for establishing the correct structure of natural products that have been misassigned in the literature. My work began with the first synthesis of the steroidal alkaloid plakinamine G, accomplished in 5 steps from ergosterol. This concise synthesis is protecting-group-free, employing a strategy that makes use of the azido group as a masked amine through a series of particularly harsh transformations involving strong bases and ozone gas. It also expands the serviceability of Li's method for constructing (Z)-γ-alkylidene-γ-lactams in the context of chiral, potentially epimerizable substrates. Also, we developed a new synthetic route to γ-alkylidene-γ-lactams from 2-siloxyfurans and aldehydes via γ-alkylidene-γ-butenolides, illustrated by the synthesis of a pulchellalactam analogue. My next project concerns the total synthesis of the originally assigned structure of the γ-hydroxybutenolide-containing diterpenoid niphateolide A. This synthesis was particularly challenging as it entailed the stereocontrolled assemblage of a (Z)-configured exocyclic olefin onto a sterically hindered site of the cyclopentane core. We were able to overcome this challenge by structural optimization of a key intermediate needed for Wittig olefination and appropriate modification of the synthetic route. Ultimately, the synthesis was achieved in 16 linear steps from (R)-pulegone. However, the originally reported structure of niphateolide A was proven to be incorrect by comparing the NMR data and optical rotation of our synthetic sample with those of the natural product. Upon re-evaluation of the reported NMR data, and biosynthetic considerations, we proposed a revised structure for niphateolide A along with a synthetic plan that is completely different from the one employed earlier. The revised structure of niphateolide A was synthesized in 11 linear steps from commercially available cyclohex-2-en-1-one. Key steps include: (i) an asymmetric Michael addition/C-acylation and (ii) Kumada sp²-sp³ coupling to install the requisite aliphatic chain onto the cyclohexene core. Pleasingly, our revised structure displayed NMR and optical data in full agreement with those reported for niphateolide A. After completion of this synthesis, an article appeared in the literature describing the same "revised" structure for a natural product, named echinohalimane B. The authors also noted that the spectra of echinohalimane B were "confusingly" in perfect agreement with those reported in the literature for niphateolide A. Our work unambiguously establishes the correct structure of niphateolide A which, of course, is identical to that of echinohalimane B. |
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