Optimization of Sphingosine Synthesis by Tkaczuk--Thornton Method

Josef Jampílek¹ (jamp@faf.cuni.cz), Martin Doležal¹ (dolezalm@faf.cuni.cz), Hans Peter Deigner² (hans-peter.deigner@ix.urz.uni-heidelberg.de)

¹Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic,
²Institute for Pharmaceutical Chemistry, University of Heidelberg, D-69120 Heidelberg, Germany

Summary

The 4-(methoxycarbonyl)-2-phenyl-4,5-dihydrooxazole formed from (S)-serine provides the basis for a useful synthesis of various types of sphingolipids, sphingomyelins and their unnatural analogues or isosteres. This paper deals with optimization (increase of yields) of synthesis (4S,1'R)-4-(1'-hydroxy-2'-(E)-hexadecenyl)-2-phenyl-4,5-dihydrooxazole, respectively (2S,3R)-sphingosine from (S)-serine via oxazolin methyl ester by Tkaczuk—Thornton method. Two stereoisomers (4S,1'R and 4S,1'S), respectively (2S,3R and 2S,3S) are obtained after the final step of the synthetic pathway, but 4S,1'R epimer of sphingosine oxazoline respectively, subsequently convertion to 2S,3R sphingosine has biological activities (inhibition of the protein kinase C) only. A modification of the mobile phase for separating 4S,1'R and 4S,1'S forms is suggested in this paper.