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/

Radical cyclization reactions of substituted alpha-(prop-2-ynyloxy) ep oxides using bis(cyclopentadienyl)-titanium(III) chloride as the radic al source resulted in polysubstituted tetrahydrofurans. Titanium(III) species were prepared in situ from commercially available titanocene d ichloride and zinc dust in tetrahydrofuran, Upon radical cyclization, 2-aryl epoxides 3a-e afforded only trans products 4a-e whereas the 2-a lkyl epoxides 3f-h formed a mixture of isomeric products 4f-h in a rat io of 5:1. Some of the aryl tetrahydrofuran derivatives have already b een used for the synthesis of bioactive furofuran lignans. entyl-3-(hy droxymethyl)-4-methylenetetrahydrofuran (4f) and decyl-3-(hydroxymethy l)-4-methylenetetrahydrofuran (4g) have been transformed to two antitu mor antibiotics (+/-)-methylenolactocin (1f) and (+/-)-protolichesteri nic acid (1g), respectively, in good overall yield.