Stereoselective synthesis of (2S,3S,4Z)-4-fluoro-1,3-dihydroxy-2-(octadecanoylamino)octadec-4-ene, [(Z)-4-fluoroceramide], and its phase behavior at the air/water interface.

Sphingolipids belong to the most important constituents of the membranes of eukaryotic cells. As intermediates in sphingolipid metabolism, sphingosine and its N-octadecanoyl-derivative, ceramide, exhibit a variety of biological functions. These compounds play a crucial role in many essential biological processes such as cell growth, cell differentiation, cell recognition and apoptosis. More specifically, sphingolipids are crucial e.g. for the function of the skin because they contribute to the formation of the water permeability barrier consisting of a highly organized multilaminar lipid matrix of free fatty acids, cholesterol and ceramides containing additional hydroxyl groups in the sphingosin part and longer fatty acid amide functions. In a short synthetic route (2S,3S)-4-fluorosphingosine and 4-fluoroceramide, the fluorinated analogues of the natural products, D-erythro-sphingosine and ceramide, have been prepared. The key step of the synthetic sequence is an asymmetric aldol reaction of (Z)-2-fluorohexadec-2-enal, prepared in three steps from tetradecanal, with an enantiopure N-protected iminoglycinate. Deprotection of the imino function and reduction of the ester group led to the 4-fluorosphingosine, which on acetylation with stearoyl chloride gave 4-fluoroceramide. After careful HPLC purification of the latter compound its phase behavior was investigated by Langmuir film balance technique and compared to that of natural ceramide. While the isotherms are quite similar in shape, they differ significantly in the starting point of increasing film pressure (56 or 67 A(2)/molecule) and in the film collapse pressure (38 or 56 mN/m) for ceramide and 4-fluoroceramide, respectively. Moreover, the hysteresis curves are very different. While consecutive isothermic compression - expansion cycles are reversible for the 4-fluoro derivative, substantial substance loss into the subphase or irreversible formation of multi-layers was observed for natural ceramide. Asymmetric aldol reaction proved to be successful for the preparation of enantiopure 4-fluoroceramide. Surface/pressure isotherms and hysteresis curves of ceramide and its 4-fluoro derivative showed that the presence of fluorine leads to stronger intermolecular interactions between the hydrophobic chains of neighboring molecules, and therefore to increasing stability of the monolayer of 4-fluoroceramide at the air water interface.