Synthesis of Alkaloid 223A and a Structural Revision

Toyooka, Naoki; Fukutome, Ayako; Nemoto, Hideo; Daly, John W.; Spande, Thomas F.; Garraffo, H. Martin; Kaneko, Tetsuo

doi:10.1021/ol025775m

Cited by 58 publications

(41 citation statements)

References 13 publications

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“…In 1997, John Daly and coworkers reported the first trisubstituted indolizidine alkaloid 223A along with three higher homologues, isolated from the Panamanian population of the frog Dendrobates pumilio Schmidt and proposed the structure to be 2 (Figure 1). 4 Later, Toyooka et al, reporting the first total synthesis of this natural product, revised the structure of the natural product to 1 and assigned the originally proposed structure 2 to 6- epi -223 A 5…”

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Asymmetric Total Synthesis of Alkaloids 223A and 6-epi-223A

et al. 2009

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A concise and asymmetric total synthesis of the title compound is described. The key ring system was constructed using an intramolecular Schmidt reaction on a norbornenone derivative, which was subsequently subjected to ring-opening metathesis followed by reduction. An unusual isomerization of the C-6 ethyl group afforded the desired stereochemistry of the natural product. The synthesis is readily adaptable to analogue production.

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“…To date, four total syntheses of alkaloid 223A (1) 5,6a–6c and two total syntheses of 6- epi - 223A (2) 6a,7 have been reported. Each of these routes employed imaginative and modern synthetic procedures but nonetheless required ≥10 synthetic steps to prepare this seemingly simple natural product.…”

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Asymmetric Total Synthesis of Alkaloids 223A and 6-epi-223A

et al. 2009

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“…Among these alkaloids, indolizidine 223A, the first member of a new trisubstituted indolizidine class of amphibian alkaloids, was isolated by Daly and co-workers [2] from the skin extract of a Panamanian population of the frog Dendrobates pumilio Schmidt (Dendrobatidae). The first total synthesis of alkaloid 223A reported by the groups of Toyooka and Daly [3] allowed the determination of the correct structure. Recently, this natural product was shown to exhibit blocking effects on nicotinic acetylcholine receptors.…”

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“…[4] To date, five syntheses of indolizidine 223A have been reported. [3,5] Most of them involve the elaboration of a chiral tetrasubstituted piperidine intermediate and its subsequent cyclization into the corresponding indolizidine. Recently, Aubé et al…”

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Total Synthesis of Indolizidine (+)‐223A

Fellah

Lhommet

2011

Eur J Org Chem

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“…[1] Furthermore, b-enamino esters are employed as key starting reagents for the synthesis of substituted pyra-Quinones represent one of the most widely distributed structural classes in nature, [17] and compounds belonging to this class can be found in a large number of important pharmacophores [18] associated with anti-cancer, antibacterial, antimalarial, fungicidal, and antiparasitic agents. The current method provides a highly favorable synthetic strategy for the efficient construction of important therapeutic agents containing polysubstituted aromatic core structures.…”

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The Construction of Polysubstituted Aromatic Core Derivatives via a Cycloaddition/Oxidative Aromatization Sequence from Quinone and β‐Enamino Esters

Huang

et al. 2014

Adv Synth Catal

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An unexpected strategy has been discovered for the construction of polysubstituted aromatic core derivatives from the reaction of quinones or N-substituted maleimides with b-enamino esters by a cycloaddition/oxidative aromatization sequence that provides products contrary to those delivered by the Nenitzescu reaction. The current method provides a highly favorable synthetic strategy for the efficient construction of important therapeutic agents containing polysubstituted aromatic core structures.b-Enamino esters are versatile intermediates, which are often used for the synthesis of heterocycles, and compounds of this class are also common pharmacophores in a number of important medicinal agents. [1] Furthermore, b-enamino esters are employed as key starting reagents for the synthesis of substituted pyra-Quinones represent one of the most widely distributed structural classes in nature, [17] and compounds belonging to this class can be found in a large number of important pharmacophores [18] associated with anti-cancer, antibacterial, antimalarial, fungicidal, and antiparasitic agents. [19] Based on the recent resurgence of interest in the functionalization of quinone structures [20] and the application of b-enamino esters in organic synthesis, [21] we became interested in further exploring the reactions of b-enamino esters with quinones.During the course of our research in this area, an unexpected product, diethyl 9,10-anthraquinone-1,3dicarboxylate (3a), was discovered involving the reaction of 1,4-naphthoquinone (1a) with ethyl-3-(methylamino)acrylate (2a) [Eq. (2)]. Contrary to similar work reported by MenØndez et al. [Eq.(1)], [22] however, where the Nenitzescu reaction was used to obtain fused indoles, our own work led to the formation of a different product 3a, with the difference in the products being attributed to the presence of an H atom instead of a methyl group at the R 2 position of the b-enamino esters under the same conditions as reported by MenØndez (Table 1, entry 1).Furthermore, among various kinds of naturally occurring substances, quinone derivatives are common and very important. [23] For example, rhein, [24] physcion, [23d,25] aloe-emodin; [26] emodin [27] and chrysophanol [28] exhibit antifungal activity. [23d,29] Especially emodin, which is purified from the Chinese medicinal herb rhubarb, has inhibitory activity against ERK phosphorylation in PC3 cells induced by EGF. [30] Moreover, aloe-emodin might represent a conceptually new lead antitumor drug taking into account its unique cytotoxicity profile and mode of action. [26a] Besides, DMAC, aloesaponarin I and aloesaponarin II also show good antibacterial activity (Figure 1). [31] Based on this initial result and the significance of these unexpected polysubstituted aromatic cores in related drugs, we became interested in developing a greater understanding of this reaction between 1,4-

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Synthesis of Alkaloid 223A and a Structural Revision

Cited by 58 publications

References 13 publications

Asymmetric Total Synthesis of Alkaloids 223A and 6-epi-223A

Asymmetric Total Synthesis of Alkaloids 223A and 6-epi-223A

Total Synthesis of Indolizidine (+)‐223A

The Construction of Polysubstituted Aromatic Core Derivatives via a Cycloaddition/Oxidative Aromatization Sequence from Quinone and β‐Enamino Esters

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