Synthesis of Indolizidine Alkaloids via the Intramolecular Imino Diels-Alder Reaction

An intramolecular imino Diels-Alder strategy has been developed for total synthesis of the indolizidine alkaloids δ-coniceine (1), tylophorine (2), elaeokanine A (3), and elaeokanine B (4). In all cases, an acyl imine dienophile was generated thermally in situ from a methylol acetate precursor. Diene-methylol acetate 8 has been cyclized via 10 to lactam 11, which was converted to δ-coniceine. Similarly, intermediate methylol acetate 18 was transformed via 19 and 20 to pentacyclic lactam 21, and then to tylophorine. In the syntheses of elaeokanine A and B, a masked diene precursor, in the form of a dihydrothiophene dioxide system, was prepared. Thus, compound 35 was cyclized via intermediate 23b to afford bicyclic lactams 37 and 39 in a 5:4 ratio. These products were subsequently converted to 3 and 4.