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

Abstract

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 alpha,gamma dialkyl gamma-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 EC(50) values of 12 mu M for mPPAR alpha, 9 mu M for mPPAR delta and > 100 mu M for mPPAR gamma. (c) 2010 Elsevier Ltd. All rights reserved.