Biopatterned Reorganization of Alkaloids Enabled by Ring-Opening Functionalization of Tertiary Amines

Biosynthetic processes often involve reorganization of one family of natural products to another. Chemical emulation of nature's rearrangement-based structural diversification strategy would enable the conversion of readily available natural products to other value-added secondary metabolites. However, the development of a chemical method that can be universally applied to structurally diverse natural products is nontrivial. Key to the successful reorganization of complex molecules is a versatile and mild bond-cleaving method that correctly places desired functionality, facilitating the target synthesis. Here, we report a ring-opening functionalization of a tertiary amine that can introduce desired functionalities in the context of alkaloids reorganization. The semistability of the difluoromethylated ammonium salt, accessed by the reaction of tertiary amine and in situ generated difluorocarbene, enabled the attack at the a-position by various external nucleophiles. The utility and generality of the method is highlighted by its applications in the transformation of securinega, iboga, and sarpagine alkaloids to neosecurinega, chippiine/ dippinine, and vobasine-type bisindole alkaloids, respectively. During the course of these biosynthetically inspired reorganizations, we could explore chemical reactivities of biogenetically relevant precursors.

Automated summary

Biosynthetic processes often involve reorganizing one family of natural products to another, and chemically emulating nature's strategy can lead to value-added products. The key to successful reorganization of complex molecules is finding a versatile and mild bond-cleaving method that can correctly introduce desired functionalities.