Vinylogous urethanes in alkaloid synthesis. Applications to the synthesis of racemic indolizidine 209B and its (5R*,8S*,8aS*)-(±) diastereomer, and to (−)-indolizidine 209B

Abstract

Syntheses of racemic (5R*,8R*,8aS*)-8-methyl-5-pentylindolizidine (indolizidine 209B) (±)-1 and its hitherto unknown (5R*,8S*,8aS*) diastereomer (±)-20 were accomplished in eight steps from pyrrolidine-2-thione and ethyl oct-2-enoate. Key steps included cyclisations exploiting the nucleophilicity of vinylogous urethanes derived from ethyl (2E)-{1-[1-(2-hydroxyethyl)hexyl]pyrrolidin-2-ylidene}acetate 8, and stereoselective reduction of the carbon–carbon double bond of a bicyclic vinylogous urethane 11. An enantioselective modification of the route involving initial conjugate addition of the anion of (R)-(+)-N-benzyl-1-phenylethylamine to tert-butyl (2E)-oct-2-enoate resulted in a formal synthesis of (−)-indolizidine 209B.