UEDIN-DSZ-BIO · Synthesis and Biological Target Identification of the Potent Tubulin Inhibitor Disorazole C1 and Novel Heterocyclic Analogues

Synthesis and Biological Target Identification of the Potent Tubulin Inhibitor Disorazole C1 and Novel Heterocyclic Analogues

The disorazoles are a group of marine-derived natural products which display promising anticancer activity against a variety of transformed cell lines, including multidrug resistant cells. The key family member, disorazole C1, has been shown to act as a highly potent inhibitor of microtubule stabilisation. Although there has been one total synthesis and several approaches published towards disorazole C1, these have been lengthy and poor-yielding. Consequently, much remains to be learnt about the mode of action of these natural products, including how and where they bind to tubulin. Our synthetic approach is ideally placed to explore how changes in the oxazole portion, which is one of the key structural features of disorazole C1, affects the natural product structure and function. The oxazole region of disorazole C1 has been shown to control much of its reactivity, but as yet has not been explored in structure-activity relationship studies. The synthetic strategy for the construction of the 30-membered di-lactone disorazole C1 includes an Evans-Tishchenko reaction followed by an alkyne cross metathesis (ACM) / ring-closing alkyne metathesis (RCAM) sequence. In this project, a new synthetic route to the C(1)-C(9) oxazole fragment of disorazole C1 has been developed. We chose to pursue a route with a starting material from the chiral pool, offering the advantage that it would allow for rapid exchange of the oxazole portion of the natural product for other heterocycles. Thus, a commercially available mannitol derivative was converted into a key primary tosylate intermediate, which would allow for straightforward heterocycle introduction by SN2 reactions. Next, we focused on making the natural product itself and careful optimisation of key reactions resulted in a successful synthetic pathway to the oxazole acid 1 (Scheme 1). Key reactions include a highly (E)-selective palladium catalysed hydrostannylation, a Negishi coupling and stepwise construction of the oxazole from serine. The synthetic sequence is 13 steps long, with an overall yield of 5.4% and an average yield per step of 80%. Another achievement was the coupling of 1 to the C(10)-C(19) fragment of disorazole C1. This gave access to the advanced bis-alkyne 2 (Scheme 1) and its rather complex NMR assignment was conducted by the Fellow. This is the starting material for the crucial ACM/RCAM steps and therefore meant a significant boost for this ambitious project. Efforts to achieve the ACM/RCAM sequence using a commercially available catalyst were also made during the last month of the project. However, it quickly became clear that this ambitious reaction sequence would require careful optimisation and due to the time constraints this task was handed over to another member of the Hulme group. Fortunately, significant progress has been made recently and efforts to complete the total synthesis are currently ongoing.

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