The stemona alkaloids, isolated from Stemonaceae plants, consist of over 100 natural products. Among these alkaloids, ca. 40 natural products belong to stemoamide-type alkaloids, and contain the tricyclic core structure of stemoamide (1) comprised of a γ-lactone, a γ-lactam, and an azepane ring. The stemoamide-type alkaloids such as saxorumamide (2), isosaxorumamide (3), and stemonine (4) are tetracyclic compounds, which have additional γ-lactone to 1. We envisioned that stemoamide (1) could serve as a common precursor to tetracyclic natural products, and considered employing two successive coupling reactions of the five-membered building blocks (Scheme 1). The first coupling reaction would be the vinylogous Michael addition of 2-oxypyrrole 8 to chiral α,β-unsaturated lactone 7. The second would be the chemoselective nucleophilic addition of the γ-lactone equivalent 10 to stemoamide (1). The key to success of our strategy was the differentiation between the γ- lactone and the γ-lactam of 1. We commenced our unified synthesis of stemoamide-type alkaloids 1 ~ 4 by synthesis of stemoamide (1) (Scheme 2). The vinylogous Michael reaction and subsequent reduction of enamide 13 smoothly proceeded to afford bicyclic compound 9. After three-step conversion from 9, we accomplished the total synthesis of 1 in 7 steps with 20.6% overall yield (Scheme 3). With stemoamide (1) in hand, we attempted the chemoselective nucleophilic addition to 1. The lactone-selective nucleophilic addition with lithiated furan 17 provided both saxorumamide (2) and isosaxorumamide (3) (Scheme 4). On the other hand, the lactamselective nucleophilic addition was achieved through chemoselective reduction with [IrCl(CO)(PPh3)2] and (Me2HSi)2O5), followed by acid-mediated vinylogous Mannich reaction with siloxyfuran 27 to afford stemonine (4) (Scheme 6).
