Sphingoid bases play important roles in membrane structure and in cell regulation as second messengers. In principal, sphingoid bases are acyclic molecules, thus adopting multiple conformations depending on the environment. Interestingly, there are several natural products that can be considered as cyclized derivatives of sphingoid bases. We designed the heterocyclic sphingosine analogues based on the structure of natural products. For the synthesis of the designed analogues, cyclic sulfate sphingosine was employed as a common intermediate. We obtained the desired pyrrolidine and pyrrolidone derivatives, through a Staudinger-type reductive cyclization. Bioisosteric analogues of pachastrissamine were synthesized by sequential intermolecular and intramolecular SN2 displacement reactions of the dianions. The synthesized analogues showed more potent cytotoxicity compared to the parent sphingoid base. We believe that the presented heterocyclic analogues, as well as the synthetic method, could be of value in the development of sphingoid base research.

Design and synthesis of heterocyclic sphingosine analogs

244th National Meeting (2012)

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