Total synthesis of atropodiastereomers of heterodimeric Amaryllidaceae alkaloids: narcipavline and narcikachnine.

Abstract

We report the first asymmetric total synthesis of recently isolated heterodimeric Amaryllidaceae alkaloids, narcipavlines A (1a) and B (1b), and narcikachnines A (2a) and B (2b), thereby confirming their absolute stereochemistry. These alkaloids showcase a unique heterodimeric structure, amalgamating two distinct types of Amaryllidaceae alkaloids: the cis-hydrodibenzofuran containing tetracyclic galantamine core (6a) and the galanthindole core (7) featuring a biaryl axis. The presence of this biaryl axis, coupled with the substantial galantamine core (6a) at the ortho substituents, imposes constraints on free rotation around the C-C axis, resulting in atropisomerism, an exceedingly rare phenomenon in nature. Key steps in the synthesis encompass the utilization of a one-pot double reductive amination approach for the establishment of C-N-C bonds to merge both the galantamine (6a) and galanthindole (7) cores. Additionally, the Mitsunobu reaction and intramolecular Heck cyclization have emerged as pivotal techniques for crafting the tricyclic hydrodibenzofuran core [(-)-13], incorporating an all-carbon quaternary stereogenic center.