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978-3-8439-1632-5, Reihe Organische Chemie
Higher Marine Phenylpropanoids: Synthesis and Biology of Maculalactones and Ophiodilactones
338 Seiten, Dissertation Universität Basel (2014), Softcover, A5
Phenylpropanoids 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, isolated from the marine cyanobacterium Kyrtuthrix maculans, as well as the structurally related ophiodilactones, isolated from Ophiocoma scolopendrina, showed interesting biological activities as against different cancer cells.
All three literature known syntheses of maculalactone A possess yields below 10%. By a newly developed route over a rare, intramolecular butenolide synthesis, we obtained maculalactone A in an overall yield of 45%.
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, all 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, 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. Nevertheless, the synthesis of the ophiodilactone A carbon skeleton was achieved in five steps.