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Novel Strategies to Transform a Commercially Available Iboga Alkaloid to Post-Iboga Alkaloids
(PhD candidate HyeonggeunLim, Professor Sunkyu Han, PhD candidate Sikwang Seong) KAIST chemists have synthesized seven different iboga and post-iboga natural products from commercially available catharanthine by mirroring nature’s biosynthetic post-modification of the iboga skeleton. They devised a novel strategy to biosynthesize the natural products via a series of selective and efficient oxidation and rearrangement reactions. This will serve as a stepping stone for developing therapeutic medications against cancer and narcotics addiction. The research team, led by Professor Sunkyu Han, conceptualized and coined the term “Post-Iboga” alkaloids to describe the natural products that are biosynthetically derived from iboga-type alkaloids, which are composed of rearranged indole and/or isoquinuclidine backbones. Iboga alkaloids have attracted significant attention from the scientific community due to their intriguing polycyclic structures and potential therapeutic uses against drug addictions. Nature has evolved to add architectural repertoires to this family of secondary metabolites by diversifying the iboga frameworks. Notable examples are the FDA-approved anticancer drugs vinblastine and vincristine, both derived by the oxidative dimerization of catharanthine and vindoline subunits. Admittedly, synthetic foci toward the biosynthetic iboga-derivatives have historically been on these aforementioned dimeric natural products. Recent natural product isolation studies on Tabernaemontana corymbosa and Ervatamia officinalis species have resulted in discoveries of various secondary metabolites that are biosynthetically derived from iboga alkaloids. These recent outbursts of iboga-derived natural product isolation reports have kindled interests toward these family of natural products. The research team utilized (+)-catharanthine, the starting material for the industrial production of the anticancer drug Navelbine®. Well-orchestrated oxidations at the C19 position and the indole moiety of the catharanthine derivative, followed by differential rearrangements under acidic conditions, provided synthetic samples of voatinggine and tabertinggine respectively. On the other hand, opportune oxidations at the C19 position and the alpha position of the tertiary amine moiety of the catharantine derivative, followed by a transhemiaminalization, produced the first synthetic sample of chippiine/dippinine-type natural product, dippinine B. It is important to note that the chippiine and dippinine-type alkaloids have been targeted among synthetic chemists for over 30 years but had not succumbed to synthesis prior to this report. Professor Han believes that their study will serve as a blueprint for further explorations of the synthesis, biosynthesis, and pharmacology of this emerging family of natural products. This study was published in Chem on November 15, 2018 (DOI: 10.1016/j.chempr.2018.10.009).
Total Synthesis of Flueggenine C via an Accelerated Intermolecular Rauhut-Currier Reaction
The first total synthesis of dimeric securinega alkaloid (-)-flueggenine C was completed via an accelerated intermolecular Rauhut–Currier (RC) reaction. The research team led by Professor Sunkyu Han in the Department of Chemistry succeeded in synthesizing the natural product by reinventing the conventional RC reaction. The total synthesis of natural products refers to the process of synthesizing secondary metabolites isolated from living organisms in the laboratory through a series of chemical reactions. Each stage of chemical reaction needs to be successful to produce the final target molecule, and thus the process requires high levels of patience and creativity. For that reason, the researchers working on natural products total synthesis are often called “molecular artists”. Despite numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas, whose monomeric units are connected by a putative enzymatic RC reaction, has not been reported to date. The team used a Rauhut-Currier (RC) reaction, a carboncarbon bond forming a reaction between two Michael acceptors first reported by Rauhut and Currier in 1963, to successfully synthesize a dimeric natural product, flueggenine C. This new work featured the first application of an intermolecular RC reaction in total synthesis. The conventional intermolecular RC reaction was driven non-selectively by a toxic nucleophilic catalyst at a high temperature of over 150°C and a highly concentrated reaction mixture, and thus has never been applied to natural products total synthesis. To overcome this long-standing problem, the research team placed a nucleophilic moiety at the γ-position of the enone derivative. As a result, the RC reaction could be induced by the simple addition of a base at ambient temperature and dilute solution, without the need of a nucleophilic catalyst. Using this newly discovered reactivity, the team successfully synthesized the natural product (-)-flueggenine C from commercially available amino acid derivative in 12 steps. Professor Han said, “Our key finding regarding the remarkably improved reactivity and selectivity of the intermolecular RC reaction will serve as a significant stepping stone in allowing this reaction to be considered a practical and reliable chemical tool with broad applicability in natural products, pharmaceuticals, and materials syntheses. ” This research was led by Ph.D. candidate Sangbin Jeon and was published in The Journal of the American Chemical Society (JACS) on May 10. This research was funded by KAIST start-up funds, HRHR (High-Risk High-Return), RED&B (Research, Education, Development & Business) projects, the National Research Foundation of Korea, and the Institute for Basic Science. (Figure 1: Representative dimeric/oligomeric securinega alkaloids) (Figure 2: Our reinvented Rauhut-Currier reaction) (Figure 3: Total Synthesis of (-)-flueggenine C)
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