Drug discovery process usually optimizes pharmacological properties of a starting candidate, tuning its chemical structure through modification of the carbon/functional group array. As natural products constitute a valuable template to find biological active molecules, strategies that enable the synthesis of not only the natural entities but related compounds from a common precursor are strongly desirable. Herein we present the progress in the synthesis of sphingosine (cellular proliferation agent) and its analogues such as safingol (an inhibitor of sphingosine kinase) using a diastereoselective Heck-Matsuda arylation of a pyroglutamic acid-derived enecarbamate which afforded a versatile building block, the trans-5-aryl-2-hydroxymethyl-3-pyrroline. This intermediate provided a ent-safingol precursor using a directed-substrate epoxidation, benzylic C-N hydrogenolysis that opens the pyrrolidine ring, followed by an aromatic oxidative degradation and carboxylic acid reduction. In order to complete the safingol synthesis the chain elongation with an alkylcuprate remains to be done.

General strategy for sphingosine congeners synthesis via Heck-Matsuda reaction

243rd National Meeting (2012)

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