Discovery and Application of New Organocatalytic Modalities from Natural Product Libraries

Natural products have historically been evaluated for their biological activities in pharmaceutical development; however, their potential as asymmetric catalysts has been rarely explored. In this study, we screened our natural product library for catalytic activity and identified three naturally occurring alkaloids—gardnerine, spiradine A, and calycanthine—that effectively catalyze an asymmetric Michael reaction between oxindole and nitrostyrene. Among them, (+)-calycanthine, characterized by its unique aminal structure, was further investigated. Concise synthetic and extraction protocols were developed to access both enantiomers of calycanthine. Subsequent derivatization of this alkaloid led to improved enantioselectivity in the model reaction. Computational studies revealed that the aminal moiety of the catalyst activates both nucleophiles and electrophiles through multiple hydrogen-bonding interactions, including non-classical hydrogen bonds between the carboxylic acid group and the aminal C-H.