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Total Synthesis of Callyspongiolide/Totalsynthese von Callyspongiolid

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Wölfl,  Bernhard
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Wölfl, B. (2019). Total Synthesis of Callyspongiolide/Totalsynthese von Callyspongiolid. PhD Thesis, Technische Universität, Dortmund.


Cite as: http://hdl.handle.net/21.11116/0000-0003-93F4-3
Abstract
The scope and limitations of contemporary molybdenum-based ring-closing alkyne metathesis (RCAM) and relevant downstream chemistry were investigated in the context of a challenging total synthesis campaign of Callyspongiolide. This compound was isolated in 2014 from a marine sponge belonging to the genus Callyspongia and was found to exhibit remarkable in vitro cytotoxicity against human lymphocytes, thus representing a potential lead compound for the development of new anticancer agents. The natural product combines this promising biological activity with a unique molecular framework. In order to verify the originally proposed structure and provide material for further biological testing, a novel synthesis was envisioned. In a first approach towards callyspongiolide, a sequence of late-stage trans-hydrostannation and rotodestannation was utilized as a postmetathetic transformation to obtain the desired acrolactone core. The efforts to establish the highly challenging E-alkene motif in the macrocycle via this formal semi-reduction ultimately failed due to steric hindrance. A second approach based on RCAM of an ynoate derivative was therefore developed. However, this strategy bore considerable risk as only few recorded examples of RCAM on simple ynoates exist. Despite our initial concerns, the planned ynoate metathesis could be carried out in high yield, highlighting the performance of the latest generation of molybdenum-based catalysts. Another key-step of the devised synthesis was the subsequent Z-selective semi-reduction of the resulting ring-internal alkyne. An optimized nickel boridecatalyzed hydrogenation ensured efficient reduction, while tolerating alkene and alkenyl iodide functionalities. Finally, the unique enyne side-chain was installed via Sonogashira reaction, concluding the efficient total synthesis of callyspongiolide in 20 steps in the longest linear sequence and 4 % overall yield. During the course of this project the structure was revised to be the enantiomer of the originally proposed motif. This total synthesis illustrates the first example of a RCAM on a highly complex ynoate.