Transition-metal- or oxidant-promoted deconstructive functionalizations of noncyclic carbon–nitrogen bonds are well established, usually only leaving one moiety functionalized toward the final prod...

Deconstructive Functionalizations of Unstrained Carbon-Nitrogen Cleavage Enabled by Difluorocarbene.

Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to access unique chemical space. Here, we report a highly efficient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues.

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Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer.

(-)-Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine by heating, enabling biocatalytic production of these compounds. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Therefore, this discovery provides insight into enantioselective enzymatic formal Diels-Alder reactions.

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Biosynthesis of an Anti-Addiction Agent from the Iboga Plant.

The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs

Total synthesis of alkaloids using both chemical and biochemical methods.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

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 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.

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

Post-iboga alkaloids are secondary metabolites that are biosynthetically derived from iboga-type alkaloids via rearrangements of the indole and/or isoquinuclidine moieties. Herein, we categorize post-iboga alkaloids into five types based on the biosynthetic mode of transformation of the iboga scaffold. We then describe reported syntheses of post-iboga alkaloids, including our laboratory’s recent contributions, based on our own categorization. 1	Introduction 1.1	Iboga and Post-Iboga Alkaloids 1.2	Classification of Post-Iboga Alkaloids 1.2.1	Introduction to Type I Post-Iboga Alkaloids 1.2.2	Introduction to Type II Post-Iboga Alkaloids 1.2.3	Introduction to Type III Post-Iboga Alkaloids 1.2.4	Introduction to Type IV Post-Iboga Alkaloids 1.2.5	Introduction to Type V Post-Iboga Alkaloids 2	Syntheses of Post-Iboga Alkaloids 2.1	Syntheses of Type I Post-Iboga Alkaloids 2.1.1	Syntheses of Monomeric Type I Post-Iboga Alkaloids 2.1.2	Syntheses of Dimeric Type I Post-Iboga Alkaloids 2.2	Syntheses of Type II Post-Iboga Alkaloids 2.3	Synthetic Studies Toward Type III Post-Iboga Alkaloids 2.4	Syntheses of Type IV Post-Iboga Alkaloids 2.5	Synthesis of Type V Post-Iboga Alkaloids 3	Conclusion and Outlook

Syntheses of Post-Iboga Alkaloids

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. In this chapter, we disclose the full synthetic story 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 delineate full details that enabled the first synthesis of chippiine-/dippinine-based type III post-iboga alkaloid dippinine B.

Sikwang Seong

Papers

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

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

Syntheses of Post-Iboga Alkaloids

Synthesis of types II and III post-iboga alkaloids