Higher marine phenylpropanoids : synthesis and biology of maculalactones and ophiodilactones

Bader, Samuel Leonhard. Higher marine phenylpropanoids : synthesis and biology of maculalactones and ophiodilactones. 2015, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_11220

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Phenylpropanoids, consisting of the characteristic C6C3 subunits, are one of the most prevalent secondary metabolites in nature. While terrestrial plants produce a wide variety of these natural products, few examples from marine prokaryotes are known. In this thesis, we will discuss our investigations on the synthesis and biology of two marine natural product families. The maculalactones were isolated from the marine cyanobacterium Kyrtuthrix maculans. While maculalactone A was found to be a potential antifouling agent, maculalactone E exhibits interesting activities against human tumor cell lines. The structurally related ophiodilactones, isolated from Ophiocoma scolopendrina, showed comparable cytotoxicities against leukemia cells.
All three literature known syntheses of maculalactone A possess yields below 10%. In our optimization, we investigated shortcuts of the known routes and a butenolide formation by metathesis. Finally, we obtained maculalactone A in an overall yield of 45% utilizing a rare, intramolecular butenolide synthesis.
In our concept for the antifouling protection of metal surfaces, we envisioned connecting maculalactone A through a linker to a catechol anchor. An appropriate derivative of the natural product for this purpose was identified in a small SAR study. We then labeled the active maculalactone A analogue with a rhodamine B fluorophore. In vivo experiments in Artemia salina demonstrated a selective accumulation of this molecular probe along the intestine.
Unfortunately, our efforts towards the total synthesis of ophiodilactone A and B over two independent strategies were unsuccessful. In a linear strategy, a bisallylic precursor was desymmetrized via a Sharpless epoxidation. After Payne rearrangement and nucleophilic epoxide opening, we successfully elongated the linear chain. However, the steric repulsion of the benzyl- and protecting groups prevented further conversion. In an alternative, protecting group-free approach, maculalactone A was added to cinnamaldehyde in a diastereo- and enantioselective vinylogous Michael addition by phase transfer catalysis. Despite attempts with various reagents, the subsequent oxidation of the butenolide double bond was not achieved. In addition, different strategies to work around the insufficient reactivity of the olefin were investigated.
In conclusion, we developed an efficient synthesis of maculalactone A and used this material for our biological investigations. Furthermore, we achieved the synthesis of the ophiodilactone A carbon skeleton in five steps.
Advisors:Gademann, Karl
Committee Members:Pfaltz, Andreas
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Organische Chemie (Gademann)
UniBasel Contributors:Gademann, Karl and Pfaltz, Andreas
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:11220
Thesis status:Complete
Number of Pages:321 S.
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:52
Deposited On:08 Jun 2015 15:07

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