BLT Stages

Abstract Bachelor Project FBT 2018-2019: Towards an efficient synthesis of peloruside analogues

Cancer has a big impact on society, being a prevalent cause of death and disability throughout the world. Although there are already treatment options available for some types of cancer a panacea does not yet exist. Through diligent research we can however discover new treatments, improve the effectiveness of current ones and lower the cost of these medications. Paclitaxel (also known as Taxol®) is a well-known chemotherapeutic agent, often used in clinical settings. It exerts its function by binding to microtubules in the cytoplasm and inhibiting their depolymerization, thereby impeding microtubular functions during the cell division, making it the prime example of the microtubule targeting agents.

Nevertheless the clinical importance of paclitaxel and other taxanes, their efficiency and efficacy is limited by the development of multidrug resistance, a disadvantaged pharmacokinetic profile and toxicity. Combined with a need for novel, improved agents, these shortcomings stimulate research into new microtubule-stabilizing agents.

(+)-Peloruside A and B, two polyketides isolated from the marine sponge Mycale hentscheli, show a cytotoxic activity similar to that of paclitaxel. As a result of improved pharmacokinetics, activity towards resistant tumours and better tolerability, this compound class has garnered a strong interest as a potential second generation of MSAs.

Following their discovery, (+)-peloruside A and analogues have been synthesized via long and elaborate routes. Coupled with their low natural abundance, their chemical complexity hinders their economic viability. Furthermore, all synthesized analogues so far have shown a greatly decreased activity. The Laboratory for Organic and Bio-Organic Synthesis researches improved synthetic routes towards pelorusanes as well as simplified analogues. This bachelor thesis aims to make a contribution towards the development of a synthesis for a peloruside analogue building block via a new synthetic route.

This building block was synthesized in eight steps starting from commercially available starting materials. The use of a organozinc reagent for introducing the allylic alcohol functionality is the key improvement. This approach resulted in an improved synthesis with a total yield of 13% in seven steps.