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.

Four indolizidine based alkaloids (IBAs) have been synthesized in a highly enantioselective, straightforward, and flexible manner. As a key step our previously developed Brønsted acid catalyzed vinylogous Mannich reaction was employed which easily afforded gram amounts of an optically pure central intermediate which can be converted into a wide range of diversely substituted IBAs.

Eleven quinolizidine-based alkaloids (QBAs) were synthesized in a straightforward, flexible, and stereoselective manner. As the key step, which was run on a multi-gram scale, the organocatalytic, highly enantio-and diastereoselective vinylogous Mukaiyama-Mannich reaction was used furnishing highly functionalized products carrying already two stereogenic centers. The quinolizidinone core was subsequently assembled through cyclization reactions of both ester groups with the amine moiety. Whereas the absolute configuration of the bridgehead carbon atom and the adjacent chiral center were established in the initial vinylogous Mannich reaction, the stereogenic center at the 4-position was introduced in the last step through amide activation and organometallic addition exploiting stereochemical control from the substrate. Taking advantage of this unified strategy, simple as well as more complex alkaloids were accessible in good overall yields and with high stereoselectivity. Some of the QBAs were synthesized for the first time and this study could help to assign their absolute and relative configurations.

A series of quinolizidine‐based alkaloids, e.

The presented organocatalytic, highly enantio‐ and diastereoselective vinylogous Mukaiyama‐Mannich reaction is the key step for the title strategy.

A General Organocatalytic Approach Toward the Enantioselective Total Synthesis of Indolizidine Based Alkaloids. -Indolizidine based alkaloids (V), (XI) are synthesized in a highly enantioselective straightforward, and flexible manner. Key step is the vinylogous Mannich reaction of aldehyde (I), amine (III) and dienolates (II) and (VI) which gives the desired Mannich adducts even in gram amounts. Optically pure lactams (IV) and (VII) are readily converted into diversely substituted title compounds by known methods. -(ABELS, F.; LINDEMANN, C.; KOCH, E.; SCHNEIDER*, C.; Org. Lett. 14 (2012) 23, 5972-5975, http://dx.