Novel optimized process for large scale preparation of D-erythro-sphingosine 1-phosphate

ORGN 507

Zdzislaw M. Szulc, Yusuf A. Hannun, and Alicja Bielawska. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425
In recent years, there have been significant efforts directed towards the development of methods for the efficient synthesis of naturally occurring phospholipids and their analogs. We have developed a novel and practical three-component phosphorylation system (TCPS) for the efficient and regioselective introduction of a phosphoryl-group into the sphingolipid system. This method utilizes trimethyl phosphite as a phosphorylation reagent, 1,2-dibromotetrachloroethane as an oxidizer, and an aqueous solution of NaOH as a base. Using N-Boc-protected D-erythro-sphingosine as a model substrate, and performing the TCPS protocol under two-phase-catalyzed conditions, the corresponding 1-O-phosphate dimethyl ester was obtained in 92% yield. The prepared ester was easily transformed to D-erythro-sphingosine 1-phosphate (SPP) using TMSCl/NaI in acetonitrile. The invented optimized process delivered high purity SPP (>95%) with 70% overall yield,when scaled-up from 1- to 50-mmol.