Bio-patterned reorganization approach in the synthesis of post-iboga alkaloids

Abstract

We coined the term “post-iboga” alkaloids for secondary metabolites that are biosynthetically downstream of iboga-type alkaloids with rearranged indole and/or isoquinuclidine scaffolds. We took one step further and categorized the post-iboga alkaloids into five types based on their mode of biosynthetic derivatization from the iboga framework. While there have been extensive synthetic studies on type I post-iboga alkaloids with a cleaved C16‒C21 bond from the iboga scaffold exemplified by vinblastine and cleavamine, syntheses of other types of post-iboga alkaloids have remained underdeveloped. We disclose the synthetic studies that led to the synthesis of type II post-iboga alkaloids voatinggine and tabertinggine with a cleaved N4‒C21 bond from the iboga scaffold. Furthermore, 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 α-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.