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.
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