Asymmetric Total Synthesis of All Rugulovasine Stereoisomers and Preliminary Evaluation of Their Biological Properties

Abstract

A unified enantioselective synthesis and the biological evaluation of all rugulovasine stereoisomers are reported. The syntheses are centered on the divergent and stereochemical modular combination of each enantiomer of 4‐amino Uhle's ketone and a methacrylate derivative to build the unsaturated oxaspirolactone moiety by the Dreiding‐Schmidt reaction, followed by Fukuyama alkylation to afford the required N‐methyl secondary amine in excellent yield. The modularity of this divergent approach, the diastereoselectivities of the reactions, and the late‐stage site‐selective methylation permit the rapid asymmetric syntheses of all rugulovasine stereoisomers, including the first total syntheses of optically pure (+)‐ and (−)‐rugulovasine B and their trideuteromethylated derivatives. All enantiopure stereoisomers of rugulovasine were tested for their binding affinities to dopamine, serotonin, and adrenergic neuroreceptors, revealing their preferred selectivity for the serotonin 1 A receptor.

General acid-mediated aminolactone formation using unactivated alkenes

“…1g, bottom). These potential pitfalls include not only the originally reported internal redox event by [1,5]-hydride transfer, but also processes of elimination and water capture of the intermediate, which were initially observed in varying amounts.…”

“…1a, are of particular importance: as a result of the spirocenter, they possess interesting conformational features that directly impact their biodynamic properties. 2 For instance, the terpenoid Andirolactone 3 has shown antibiotic and cytotoxic activity; the polyketide Lambertellol A 4 possesses antifungal activity; the indole alkaloid Rugulovasine 5 shows excellent affinity to 5-HT 1A receptors; and the diterpenoid Stypolactone 6 exhibits activity towards human lung and colon carcinoma cell lines (Fig. 1a).…”