Synthesis and growth inhibitory activity of chiral 5-hydroxy-2-N-acyl-(3E)-sphingenines:: Ceramides with an unusual sphingoid backbone

The unusual sphingoid base 5-hydroxy-3-sphingenine was identified in the hydrolysate of brain sphingolipids more than 40 years ago. We present here the first synthesis of the 5R and 5S diastereoisomers of the N-acyl derivatives of 5-hydroxy-3-sphingenine, 2 and 3, respectively, which represent regioisomers of (2S,3R)-ceramide (1). The key steps include the synthesis of alpha,beta-unsaturated ketone intermediates 4 and 5 from N-Cbz- and N-Boc-L-serine and diastereoselective reduction of the enones. The configuration at the new carbinol center was deduced by proton NMR analysis of (R)- and (S)-Mosher [methoxy(trifluoromethyl)phenylacetate] ester derivatives. Ceramide analogues 2 and 3 showed a markedly higher antiproliferative activity than 1 on MCF-7 cells.