Quinolizidine-Based Alkaloids: A General Catalytic, Highly Enantio- and Diastereoselective Synthetic Approach

Abstract

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.

Key words

vinylogous Mannich reaction - quinolizidines - natural products - organocatalysis - total synthesis - large-scale synthesis

• References

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