A General Strategy for the Catalytic,Highly Enantio‐ and Diastereoselective Synthesis of Indolizidine‐Based Alkaloids

Sixteen indolizidine‐based alkaloids (IBAs) that were isolated as poison constituents of the skin of frogs were synthesized in a highly flexible and stereoselective manner. As a key step, a three‐component, organocatalytic, highly enantio‐ and diastereoselective vinylogous Mukaiyama–Mannich reaction was employed furnishing optically highly enriched butyrolactams as central intermediates on a multigram scale. The attached six‐membered ring was constructed through cyclization of the pendant enoate moiety onto the pyrrolidine ring. The absolute configuration of the bridgehead chiral center and the adjacent 8‐position was established in the initial vinylogous Mannich reaction, whereas the 3‐ and 5‐substituents were introduced through organometallic addition at a late stage of the synthesis with full stereochemical control from the substrate. With this strategy, simple as well as even more complex alkaloids were accessible in good overall yields as single stereoisomers. These syntheses also served to establish the absolute and relative configuration of those IBAs that had never been synthesized before.