Development of norbenzomorphan derived sigma 2 receptor ligands and the synthesis of (±) gliocladin C and related epipolythiodiketopiperazine alkaloids




Hodges, Timothy Robert

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A novel set of norbenzomorphan derivatives were discovered to bind to the sigma receptors with varying affinity and subtype selectivity. The structure activity relationships (SAR) for this class of compounds were thoroughly investigated by synthesizing new analogs that explored unique areas of chemical space. Substituents were systematically altered in length, substitution pattern, hydrophobic bulk, flexibility, and electronic character, resulting in a variety of ligands with excellent affinity and subtype selectivity for the sigma 2 receptor. It was also found that a dramatic switch in sigma receptor subtype selectivity could be achieved by altering the substitution pattern of the core arene ring in the norbenzomorphan scaffold. These SAR efforts culminated in a sigma 2 receptor selective ligand that was shown to have efficacy in a mouse model of traumatic brain injury (TBI). This was the first example of the effects that sigma 2 receptor modulation has on TBI, thereby making the sigma 2 receptor a unique potential target for novel therapeutics. In a separate project, the total synthesis of (±)-gliocladin C was completed in nine steps and ~15% overall yield. A novel three-step sequence was developed to facilitate the synthesis of a unique diketopiperazine nucleophile that was subsequently reacted with isatin. Lewis acid promoted ionization of the resulting 3-hydroxyoxindole triggered a Friedel-Crafts-like reaction with N-silylated indole to form a key stereogenic quaternary center. A selective reduction of the oxindole amide was achieved using an unusual combination of a Lewis acid and alane. This reaction was optimized to afford the pyrroloindoline framework on a ~1 g scale. The synthesis was completed with a challenging two-step oxidative cleavage of an enamide olefin to unveil the trioxopiperazine moiety of gliocladin C. Two related epipolythiodiketopiperazine alkaloids, (±) gliocladine C and (±) T988C, were also accessed via formal syntheses by diverging from a common synthetic intermediate.



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