Synthesis of monofluorinated analogues of lysophosphatidic acid

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with the nuclear hormone receptor PPARgamma. Synthesis and biological activities of fluorinated analogues of LPA are still relatively unknown. In an effort to identify receptor-selective LPA analogues and to document in detail the structure-activity relationships of fluorinated LPA isosteres, we describe a series of monofluorinated LPA analogues in which either the sn-1 or the sn-2 hydroxy group was replaced by fluorine, or the bridging oxygen in the monophosphate was replaced by an alpha-monofluoromethylene (-CHF-) moiety. The sn-1 or sn-2 monofluorinated LPA analogues were enantiospecifically prepared from chiral protected glycerol synthons, and the alpha-monofluoromethylene-substituted LPA analogues were prepared from a racemic epoxide with use of a hydrolytic kinetic resolution. The sn-2 and sn-1 fluoro LPA analogues were unable to undergo acyl migration, effectively "freezing" them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively. The alpha-monofluoromethylene LPA analogues were unique new nonhydrolyzable ligands with surprising enantiospecific and receptor-specific biological readouts, with one compound showing a 1000-fold higher activity than native LPA for one receptor subtype.