Modular Strategy for the Collective Total Synthesis of Pandanus amaryllifolius Alkaloids: Pandanusines A and B and Pandamarine

Abstract

Pandanus amaryllifolius produces structurally unique alkaloids, including pandanusines A and B and pandamarine, featuring rare diazaspirocyclic γ-lactam frameworks. Herein, we report concise total syntheses of these three natural products based on a modular copper(I)-catalyzed reaction. Readily accessible γ-hydroxy-γ-lactams were prepared from iodoacrylic acids, terminal alkynes, and primary amines and subsequently transformed through N-acyliminium ion intermediates to construct diazaspirocyclic backbones. This strategy enabled the synthesis of (±)-pandanusine B in four steps (40% overall yield) and (±)-pandanusine A in five steps (26.5% overall yield) after optimization of the protecting group strategy. The methodology was further extended to the total synthesis of the more complex alkaloid pandamarine. These results demonstrate the synthetic potential of γ-hydroxy-γ-lactams as versatile precursors for the rapid construction of architecturally complex alkaloid scaffolds. Furthermore, the absolute configurations of both HPLC-separated enantiomers of pandanusine A and B were unambiguously determined through a combination of vibrational and electronic circular dichroism analyses and DFT and TD-DFT calculations.