2,2,3-trisubstituted tetrahydrofurans and 2H-tetrahydropyrans by tandem demethoxycarbonylation Michael addition reactions

A tandem demethoxycarbonylation-Michael addition reaction has been developed as a synthetic route to highly functionalized five-and six-membered oxygen heterocycles. Methyl esters, activated toward decarboxylation 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 for 4-8 h results in chemoselective S(N)2 dealkylation of the methyl esters, decarboxylation, and cyclization of the intermediate enolates by a Michael addition to the pendent acrylate moiety. This affords tetrahydrofuran and 2H-tetrahydropyran derivatives in 60-90% yields with diastereoselectivities 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 reaction works best for the preparation of five-and six-membered rings, and cyclizations proceed most cleanly from substrates which cyclize through a tertiary enolate. Synthetic and mechanistic details are presented.