Organocatalytic aziridination as a key step for the synthesis of novel sphingosine kinase inhibitors

Identifier:  TFG:1178

Handle: https://hdl.handle.net/20.500.11797/TFG1178

Authors:  Cristòfol Martínez, Àlex

Abstract:
The synthesis of a new sphingosine analogue bearing a tetrafluoroethylene moiety has been explored. The design of this new molecule aims at finding SphK1 inhibitors at the nanomolar concentration and has been based on the presence of a tetrafluoroethylene moiety, which should expect to give a better induced fit of the lipophilic tail into the enzyme site, facilitated by the presence of fluorine atoms. Retrosynthetic analysis of the target molecule revealed a 9 step synthesis from cis-2-butene-1,4-diol, using an enantioselective reaction. Key to the enantioselectivity of the process is the organocatalytic aziridination reaction, catalysed by the Jørgensen-Hayashi catalyst. A further Wittig reaction and aziridine ring opening allowed to obtain the appropriate terminal alkene from which to explore the introduction of the tetrafluorinated fragment. The aforementioned synthetic pathway has been explored up to step 6, affording the desired intermediate in 4% overall yield.