Here, we report the efficient synthesis of four stereoisomers of sphingosine and derivatization of unique chiral ceramides through a combinatorial chemistry by solid‐phase activated resin ester.

Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.

The configuration of C4 and C5 in azides 4 defines the stereochemistry of the incipient sphingosine chain, liberated from 4 by the oxidative cleavage of the C1−C6 olefin.

The four stereoisomers of sphingosine and sphinganine can be produced in protected form by a short, convergent, biomimetic synthesis from serine. Yields are good (26−38% overall from commercially available serine derivatives), and the stereoselectivities are excellent (>92% de, >95% ee).

Practical syntheses of all four stereomers of sphingosine from serine have been achieved through highly diastereoselective reduction of the N-trityl protected α′-amino enone derivative 5 with NaBH 4 and reduction of the free α′-amino enone derivative 7 with Zn(BH 4) 2.