New approaches to synthesis of stereospecific sphingomyelin

Enormous progress in the asymmetric synthesis of stereochemically and chemically pure D-erythro-sphingosine and ceramides led to the development of a practical, efficient, easily scaleable process to provide industrial quantities of chiral sphingosine and ceramides. This established a new platform of chiral starting materials which facilitate the synthesis of complex sphingolipids. Utilizing stereochemically homogeneous, fully synthetic ceramides, two efficient synthetic methods were developed for the preparation of ultra pure stereochemically homogeneous sphingomyelins. The first method adapted highly efficient phosphoramidite technology from oligonucleotide chemistry. This method allows selective insertion of a phosphocholine moiety into 3-O-protected ceramide through phosphitylation, followed by choline attachment, phosphite oxidation and deprotection. This route provides stereochemically homogeneous sphingomyelin in 35-79% yield. The second route is based on the reaction of selectively protected ceramides with cyclic chlorophosphate followed by treatment with trimethylamine to give the desired sphingomyelins in 50% yield. Multigram quantities of 14C-labeled N-palmitoyl-D-erythro-sphingomyelin were produced with specific activity > 1000 dpm/nmol.