Synthesis of a TNF inhibitor, flurbiprofen and an -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)CHCHOTBDPS with 3--CH-4-MeOCHMgBr, 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))CHCHOTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH and TMSCCCH(OH)--Pr with 3-F-4-PhCHMgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its -Pr analogue, respectively.

α- and γ-Regiocontrol and Enantiospecificity in the Copper-Catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents.

The regioselectivity (r.s.) and enantiospecificity (e.