Cross-metathesis optimization as a key step for the synthesis of sphingosine analogues

Identifier:  TFG:1341

Handle: https://hdl.handle.net/20.500.11797/TFG1341

Authors:  Bernús Pérez, Miguel

Abstract:
Cross-metathesis optimization as a key step for the synthesis of sphingosine analogues The dynamic balance between ceramide (Cer), sphingosine and sphingosine-1-phosphate (S1P) has demonstrated to play an important role in cancer cells fate. When the equilibrium between these three molecules shifts towards the formation of S1P by activation of Sphingosine Kinase 1/2 enzyme (SphK1/2), proliferation and drug resistance is observed on tumour tissues. On the contrary, a shift towards the formation of Cer implies apoptotic processes and, thus, beneficial progress for the patient. In this scenario, the use of inhibitors of SphK 1/2 comes as a promising strategy for the chemotherapeutic treatment of cancer. Within all the inhibitors sphingosine analogues appear to be one of the most important. The aim of the present work is the synthesis of racemic sphingosine with intramolecular aziridination and cross metathesis as key steps. Moreover, this work is specially focused on the optimization of the cross-metathesis reaction for the introduction of a lipidic chain (1- pentadecene). In the optimization of the cross metathesis reaction, the first parameters submitted to study were the type of catalyst, the addition mode and the reaction time. In this optimization, a 60% yield was obtained as best result with Grubbs Catalyst 2nd generation, batch addition and 72 hours reaction time. Further investigation on the solvents lead to a 71% yield using dichloromethane. During the research in the cross metathesis step, a secondary product was observed in all the trials and its formation and prevention was rationalized in order to future improvements on the yield. Finally, once the cross metathesis has been optimized it is expected that the conditions found will help to introduce new lipidic chains in order to achieve new sphingosine kinase inhibitors.