Synthesis of a TNF inhibitor, flurbiprofen and an i-Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents.

The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH3 and TMSCCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner.