Novel Strategies for the Syntheses of Sphingosine Kinase Inhibitors, b-Fluoroamines and Enantioenriched Allenes

Identifier:  TDX:2888

Handle: https://hdl.handle.net/20.500.11797/TDX2888

Authors:  Corro Morón, Macarena

Abstract:
Sphingolipids play a central role in numerous biological and physiological processes and they are converted into each other through the action of enzymes. Ceramide, sphingosine and sphingosine-1-phosphate have been found to be involved in cancer processes and the balance that controls their syntheses determines the cell fate. Whereas ceramide and sphingosine are associated with apoptosis, sphingosine-1-phosphate is related to cell proliferation. In this context, many research groups are investigating the synthesis of inhibitors for sphingosine kinase, enzyme which promotes the synthesis of sphingosine-1-phosphate. In chapter 3, we describe the synthesis of new sphingosine kinase inhibitors and also show the inhibitory potency of all of them. Besides, docking studies to predict interaction between our compounds and the enzyme are also presented. In Chapter 4, we develop a new strategy in the synthesis of β-fluoroamines starting from carbamates. Presumably, the reaction proceeds via aziridination and ring-opening processes in which we have found an unexpected diastereoselectivity. Fluoroamines present syn configuration instead trans expected. Although several tests have been performed to explain the observed selectivity, further studies should be done before confirming or discarding the suggested mechanisms. In Chapter 5, we work in a novel enantioselective synthesis of allenes mediated by copper. It was found that enantioselectivity could be increased by the presence of phosphites to give anti-elimination. The use of bulkier phosphites led to syn-elimination. This process is influenced by steric and electronic properties of substrates and present moderate tolerance towards different groups.