Total Synthesis of Shearinines D and G: A Convergent Approach to Indole Diterpenoids

Carreira, Erick M.; Hauser, Nicole; Imhof, Michael A.; Eichenberger, Sarah S.; Kündig, Tomas

doi:10.1002/ange.202112838

Cited by 6 publications

(5 citation statements)

References 73 publications

(62 reference statements)

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“…The related aza-version of AchR was realized successfully to provide functionalized piperidinones/piperidines . Although AchR remains an effective method for de novo synthesis of various saccharides, the synthetic utility of (aza-)AchR has been expanded greatly in the total synthesis of natural products, as summarized in four recent reviews by Ghosh et al, Mhaske et al, Trushkov et al, and Pattenden et al Scheme presents some selected examples of natural products achieved recently with (aza-)AchR by other research groups (Ghosh et al, Zakarian et al, Srihari et al, Phillips et al, Prasad et al, O’Doherty et al, Padwa et al, Liebeskind et al, Qi et al, Takahashi et al, Li et al, and Carreira et al). In this Account, we will focus on our work on three aspects of AchR: green chemistry for AchR, novel transformations of AchR products, and an AchR-based synthetic strategy for the total synthesis of natural products.…”

Section: Introductionmentioning

confidence: 99%

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

2022

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Metrics & MoreArticle Recommendations CONSPECTUS:The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, smallmolecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges. This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries. We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck−Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.

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Section: Introductionmentioning

confidence: 99%

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

2022

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“…With a key step completed, carbazole 15 was subjected to Sharpless dihydroxylation conditions at low temperature. Extended reaction time (16 h) allowed the intermediate furan diol 16 to further undergo Achmatowicz rearrangement [18][19][20] in the same vessel, affording diol 17 in 40% yield with a d.r. of 3:1 favoring the desired diastereomer.…”

Section: Scheme 1 Enantiospecific Synthesis Of 10mentioning

confidence: 99%

“…17 Recently, Carreira and co-workers have disclosed the first total synthesis of shearinines, which feature complex substitutions at indole C5 and C6. 18 Shearilicine (1) incorporates a highly oxidized terminal ring, which is a structural feature closely associated with the most biologically active constituents of the class. 8 Despite the structural diversity within this extensive indole diterpenoid class, shearilicine (1) is the first carbazole-containing metabolite within the family.…”

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confidence: 99%

Total Synthesis of (+)-Shearilicine

Kim

Zhu

Harada

et al. 2022

Preprint

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Herein we report the first total synthesis of the indole diterpenoid natural product shearilicine by an 11-step sequence. This synthesis features the development of a generalizable core precursor to the highly oxidized subclass of indole diterpenoids that are particularly notable for their potent and selective inhibition of Big Potassium (BK) ion channels. In order to access the target molecule in an enantiospecific fashion, a native chiral auxiliary strategy was employed by exploiting the directing ability of the isopropylidene moiety of (R)-carvone, followed by the subsequent cleavage of this functionality. The formation of the key carbazole substructure was accomplished through a mild intramolecular Heck cyclization. Computational evaluation of the relevant transition state revealed a complex network of non-covalent interactions between the substrate and ligands.

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“…6 That particular moiety also occurs in shearinine D, of which the Carreira group recently reported an elegant total synthesis. 7 Common to a larger part of the indole diterpenoid family is the tetracyclic indeno [1,2-b]indole partial structure highlighted in Fig. 1, which is found frequently among the nodulisporic acids, paspalines, paxillines, terpendoles, shearinines, janthitrems, and lolitrems.…”

Section: Introductionmentioning

confidence: 99%

“…In both routes, the indole section is assembled by subsequent Pd-catalyzed anellation of a protected o-stannylaniline to an alkenyltriflate functionality. 7,10 This strategy was developed by Kuwahara in 2012 during their total synthesis of paspalinine. 11 A recent approach to the trans-system by Nishikawa and coworkers features a tandem palladium-catalyzed cyclization of an N-tosylated o-alkynylaniline precursor.…”

Section: Introductionmentioning

confidence: 99%