Natural Product-Derived Chiral Pyrrolidine-2,5-diones, Their Molecular Structures and Conversion to Pharmacologically Important Skeletons

The versatility of the natural products (2S,3S)- and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (1 and 2), isolated in large amounts from tropical plant sources, has been demonstrated by the construction of 3-substituted and 3,4-disubstituted chiral pyrrolidine-2,5-diones. The absolute configurations of chiral pyrrolidine-2,5-diones have been ascertained using chiroptical spectroscopic methods and/or single-crystal XRD data. A combination of different reaction strategies delivering a diverse matrix of fused heterocyclic ring systems is presented. The pyrrolo­[2,1-a]­isoquinoline alkaloid (+)-crispine A possesses a wide range of pharmacological activities including antidepressant, antiplatelet, antileukemic, and anticancer activities. The analogues of indolizino­[8,7-b]­indole alkaloids (+)- and (−)-harmicine show strong antileishmanial, antinociceptive, PDE5-inhibitory, antimalarial, and antiviral activities. The bicyclic furo­[2,3-b]­pyrrolo skeleton is present in many natural products. Thus, the uniqueness of relatively cheap, naturally occurring chiral 2-hydroxycitric acid lactones as chirons has been demonstrated by the construction of some important molecular skeletons that are otherwise difficult to synthesize.