Stereoselective Synthesis of Polysubstituted Tetrahydrofurans by Radical Cyclization of Epoxides Using a Transition-Metal Radical Source. Application to the Total Synthesis of (±)-Methylenolactocin and (±)-Protolichesterinic Acid

Abstract

Radical cyclization reactions of substituted α-(prop-2-ynyloxy) epoxides using bis(cyclopentadienyl)titanium(III) chloride as the radical source resulted in polysubstituted tetrahydrofurans. Titanium(III) species were prepared in situ from commercially available titanocene dichloride and zinc dust in tetrahydrofuran. Upon radical cyclization, 2-aryl epoxides 3a−e afforded only trans products 4a−e whereas the 2-alkyl epoxides 3f−h formed a mixture of isomeric products 4f−h in a ratio of 5:1. Some of the aryl tetrahydrofuran derivatives have already been used for the synthesis of bioactive furofuran lignans. 2-Pentyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4f) and 2-tridecyl-3-(hydroxymethyl)-4-methylenetetrahydrofuran (4g) have been transformed to two antitumor antibiotics (±)-methylenolactocin (1f) and (±)-protolichesterinic acid (1g), respectively, in good overall yield.