2,2,3-TRISUBSTITUTED TETRAHYDROFURANS AND 2H-TETRAHYDROPYRANS BY TANDEM DEMETHOXYCARBONYLATION MICHAEL ADDITION-REACTIONS

A tandem demethoxycarbonylation-Michael addition reaction has been dev eloped as a synthetic route to highly functionalized five-and six-memb ered oxygen heterocycles. Methyl esters, activated toward decarboxylat ion by a C-2 ethoxycarbonyl group and tethered by a three-or four-atom chain to an acrylate Michael acceptor, have been prepared and used as the cyclization substrates. Treatment of these compounds with lithium chloride in DMEU (1,3-dimethyl-2-imidazolidinone) at 120 degrees C fo r 4-8 h results in chemoselective S(N)2 dealkylation of the methyl eat ers, decarboxylation, and cyclization of the intermediate enolates by a Michael addition to the pendent acrylate moiety. This affords tetrah ydrofuran and 2H-tetrahydropyran derivatives in 60-90% yields with dia stereoselectivities up to 7.5:1 in favor of the product having the C-2 ethoxycarbonyl group trans to the C-3 acetic ester side chain. The re action works best for the preparation of five-and six-membered rings, and cyclizations proceed most cleanly from substrates which cyclize th rough a tertiary enolate. Synthetic and mechanistic details are presen ted.