A stereo-controlled synthesis of 2,4-dimethyl-4-hydroxy-16-phenylhexadecanoic acid 1,4-lactone and its PPAR activities.

A novel class of natural PPAR agonists, 2,4-dimethyl-4-hydroxy-16-phenylhexadecanoic acid 1,4-lactone (1), were discovered in marine natural product libraries. The synthesis of 1 was accomplished starting from vinylmethyl ketone. Ring formation of the α,γ dialkyl γ-lactone was achieved via the stereo-controlled reaction of a ketyl radical anion with a chiral methacrylate. In the PPAR agonistic assay, the most potent of the four stereoisomers had EC50 values of 12μM for mPPARα, 9μM for mPPARδ and >100μM for mPPARγ.