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.