Practical multigram-scale synthesis of 4,6- and 4,8-sphingadienes, chemopreventive sphingoid bases

Sphingadienes are chemopreventive agents that act by blocking signaling pathways that are activated in cancer. A practical synthesis of 4,6- and 4,8-sphingadienes on a scale of gram quantities is reported here in order to allow evaluation of the biological properties of these sphingolipids. The key steps in the preparation of 4,6-sphingadiene (1a) are an intramolecular cyclization of N-Boc derivative 5a to oxazolidinone derivative 6a, followed by conversion to carbamate intermediate 7a and base-mediated hydrolysis to afford the product without further purification. 4,8-Sphingadiene (1b) was prepared in a similar fashion; the requisite trans-γ,δ-unsaturated aldehyde 15 was prepared by an ester enolate Ireland-Claisen rearrangement.

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► Efficient chemical synthesis of 4,6-sphingadiene and 4,8-sphingadiene on a multiple gram scale.
► Avoided allylic rearrangements and elimination reactions in the preparation of 4,6-sphingadiene.
► Facile detection and removal of the undesired threo diastereomer by formation of a carbamate intermediate.