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

Abstract

The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCCCH(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 PhCCCH(OP(O)(OEt)₂)CH₂CH₂OTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH₃ and TMSCCCH(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.