RESUMEN
A total synthesis of tetrodotoxin was accomplished. A Diels-Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four-step sequence involving a Curtius rearrangement, or a three-step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin.
Asunto(s)
Tetrodotoxina/síntesis química , Alquinos/química , Técnicas de Química Sintética , Guanidina/química , Nitrilos/química , Nitrógeno/química , Tetrodotoxina/químicaRESUMEN
Advanced intermediates for the syntheses of tetrodotoxin reported by the groups of Fukuyama, Alonso, and Sato were prepared. Key steps include the toluene dioxygenase mediated dihydroxylation of either iodobenzene or benzyl acetate. The resulting diene diols were transformed into Fukuyama's intermediate in six steps, into Alonso's intermediate in nine steps, and into Sato's intermediate in ten steps.
Asunto(s)
Oxidorreductasas/química , Tetrodotoxina/síntesis química , Compuestos de Bencilo/química , Hidroxilación , Yodobencenos/química , Estructura Molecular , Tetrodotoxina/químicaRESUMEN
The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.
Asunto(s)
Bloqueadores de los Canales de Sodio/síntesis química , Tetrodotoxina/análogos & derivados , Tetrodotoxina/síntesis química , Benzoquinonas/síntesis química , Benzoquinonas/química , Técnicas de Química Sintética , Bloqueadores de los Canales de Sodio/química , Estereoisomerismo , Tetrodotoxina/químicaRESUMEN
Tetrodotoxin (TTX) is a potent neurotoxin found in a number of marine creatures including the pufferfish, where it is synthesized by bacteria and accumulated through the food chain. It is a potent and selective blocker of some types of voltage-gated Na+ channel (NaV channel). 4,9-Anhydrotetrodotoxin (4,9-anhydroTTX) was purified from a crude mixture of TTX analogues (such as TTX, 4-epiTTX, 6-epiTTX, 11-oxoTTX and 11-deoxyTTX) by the use of liquid chromatography-fluorescence detection (LC-FLD) techniques. Recently, it has been reported that 4,9-anhydroTTX selectively blocks the activity of NaV1.6 channels with a blocking efficacy 40-160 times higher than that for other TTX-sensitive NaV1.x channel isoforms. However, little attention has been paid to the molecular properties of the α-subunit in NaV1.6 channels and the characteristics of binding of 4,9-anhydroTTX. From a functional point of view, it is important to determine the relative expression of NaV1.6 channels in a wide variety of tissues. The aim of this review is to discuss briefly current knowledge about the pharmacology of 4,9-anhydroTTX, and provide an analysis of the molecular structure of native NaV1.6 channels. In addition, chemical aspects of 4,9-anhydroTTX are briefly covered.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.6/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/análogos & derivados , Animales , Humanos , Ratones , Ratones Noqueados , Canal de Sodio Activado por Voltaje NAV1.6/genética , Bloqueadores de los Canales de Sodio/síntesis química , Tetrodotoxina/síntesis química , Tetrodotoxina/farmacologíaRESUMEN
The first total synthesis of chiriquitoxin, the most structurally complex analogue of tetrodotoxin isolated from a Costaâ Rican dart frog, has been accomplished from a newly designed intermediate for a variety of tetrodotoxin derivatives. The synthesis includes the third total synthesis of tetrodotoxin in this laboratory, and its intermediate was transformed into chiriquitoxin by a stereocontrolled aldol reaction with a D-camphor-derived lactone for installation of the unique side chain, and a new deprotection of methylthiomethyl (MTM) ether by using a Pummerer rearrangement.
Asunto(s)
Piel/química , Tetrodotoxina/síntesis química , Aldehídos/química , Animales , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Bufonidae/metabolismo , Lactonas/química , Piel/metabolismo , Estereoisomerismo , Tetrodotoxina/químicaRESUMEN
A fully stereocontrolled 1,3-diol orthoesterification and a water-promoted intramolecular Henry addition, combined with the previously reported formal (3 + 3) annulation of α-nitro-α,ß-enals and 2,2-dimethyl-1,3-dioxan-5-one, provided for a short convergent pathway to the dioxaadamantane core of (±)-tetrodotoxin.
Asunto(s)
Adamantano/química , Adamantano/síntesis química , Dioxanos/química , Dioxanos/síntesis química , Tetrodotoxina/química , Tetrodotoxina/síntesis química , EstereoisomerismoRESUMEN
Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products due to its densely functionalized structure and potent toxicity. Despite its small molecular size (MW 319 g mol⻹), tetrodotoxin has long been well known as a formidable molecule in natural product synthesis. We have devoted more than twenty years to developing synthetic strategies for this molecule, resulting in the preparation of a variety of analogues of tetrodotoxin for biological experiments. This account describes a brief history of tetrodotoxin research and an overview of our synthetic efforts toward tetrodotoxin with the underlying logic and strategy.
Asunto(s)
Productos Biológicos/síntesis química , Tetrodotoxina/síntesis química , Animales , Productos Biológicos/química , Reacción de Cicloadición , Ciclohexanos/química , Guanidina/química , Lactonas/síntesis química , Lactonas/química , Modelos Moleculares , Estereoisomerismo , Tetraodontiformes/metabolismo , Tetrodotoxina/químicaRESUMEN
We describe an improved synthesis of (-)-5,11-dideoxytetrodotoxin from an enone, which was used for synthesis of tetrodotoxin and its analogues in this laboratory. One of the major modifications was to establish a two-step guanidinylation of trichloroacetamide of a highly functionalized intermediate, which allowed us to prepare (15)N(2)-labeled 5,11-dideoxytetrodotoxin for biosynthetic investigations.
Asunto(s)
Tetrodotoxina/análogos & derivados , Tetrodotoxina/síntesis química , Acetamidas/química , Cloroacetatos/química , Guanidina/química , Estructura Molecular , EstereoisomerismoRESUMEN
A route to a racemic diene intermediate for the synthesis of tetrodotoxin is described. Key steps of the sequence leading to such a compound include the oxidative amidation of a phenol, a Cu(II)-catalyzed cyclocondensation of a nitroketone with an olefin (Machetti-DeSarlo reaction), and a nucleophilic fragmentation of the resulting isoxazoline. Several unusual reactions encountered in the course of this study are thoroughly discussed.
Asunto(s)
Derivados del Benceno/química , Tetrodotoxina/síntesis química , Catálisis , Cobre/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Estructura Molecular , Tetrodotoxina/químicaRESUMEN
Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its α-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives.
Asunto(s)
Tetrodotoxina , Bloqueadores del Canal de Sodio Activado por Voltaje , Catálisis , Reacción de Cicloadición , Guanidina/química , Rutenio/química , Estereoisomerismo , Tetrodotoxina/síntesis química , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis químicaRESUMEN
This contribution reviews all the synthetic work on tetrodotoxin that has appeared in the literature through June 2011.
Asunto(s)
Tetrodotoxina/síntesis química , Reacción de Cicloadición/métodos , Tetrodotoxina/químicaRESUMEN
[reaction: see text] The first total synthesis of 5,6,11-trideoxytetrodotoxin (1) and its 4-epimer were achieved. The synthesis is characterized by the stereoselective construction of the quaternary amino carbon center at C8a by an asymmetric transferring Strecker synthesis and the highly efficient conversion of cyanohydrin 4 to 1 via intramolecular cyclization reactions.
Asunto(s)
Nitrilos/química , Tetrodotoxina/análogos & derivados , Estructura Molecular , Estereoisomerismo , Tetrodotoxina/síntesis química , Tetrodotoxina/químicaRESUMEN
A formal total synthesis of (±)-tetrodotoxin that relies on the bimolecular oxidative amidation of a phenol is described, and a structural correction of the Sato lactone, an important tetrodotoxin intermediate, is provided. This work lays the foundation for an ultimate enantioselective synthesis.
Asunto(s)
Amidas/química , Amidas/síntesis química , Lactonas/química , Fenoles/química , Tetrodotoxina/síntesis química , Estructura Molecular , Oxidación-Reducción , Estereoisomerismo , Tetrodotoxina/químicaRESUMEN
This report describes the stereocontrolled total synthesis of the multi-functionalized cyclitol derivative, tetrodotoxin, containing eight asymmetric carbons and different types of branched-chains, from myo-inositol and D-glucose using three different methods. The tetrodotoxin derivatives possess a relatively small molecular weight but unique structural and chemical properties. Selection of the appropriate synthetic method may be useful not only for compounds related to TTX (including related derivatives), but also for other highly complex multi-functionalized cyclitols containing branched-chains.
Asunto(s)
Técnicas de Química Sintética/métodos , Ciclitoles/síntesis química , Glucosa/química , Inositol/química , Tetrodotoxina/síntesis química , Ciclitoles/química , Estructura Molecular , Estereoisomerismo , Tetrodotoxina/químicaRESUMEN
[structure: see text] 8,11-Dideoxytetrodotoxin, an unnatural tetrodotoxin analogue, was synthesized in a highly stereoselective manner from a common intermediate in our synthetic studies on tetrodotoxin. The synthesis features neighboring group participation of trichloroacetamide for stereoselective hydroxylation, protection of ortho ester, and guanidine installation with Boc-protected isothiourea.
Asunto(s)
Tetrodotoxina/análogos & derivados , Tetrodotoxina/síntesis química , Estereoisomerismo , Tetraodontiformes , Tetrodotoxina/químicaRESUMEN
Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products owing to its complex structure and potent biological activity, which leads to fatal poisoning. Continuous synthetic studies on tetrodotoxin and its analogues to elucidate biologically interesting issues associated with tetrodotoxin have led to the development of versatile routes for a variety of tetrodotoxin derivatives. With the aim of investigating the structure-activity relationship of tetrodotoxin with voltage-gated sodium channels, this study describes the first total syntheses of 5-deoxytetrodotoxin, a natural analogue of tetrodotoxin, and 8-deoxytetrodotoxin, an unnatural analogue, from a newly designed, versatile intermediate in an efficient manner. An estimation of the biological activities of these compounds reveals the importance of the hydroxy groups at the C-5 and C-8 positions on the inhibition of voltage-gated sodium channels.
Asunto(s)
Tetrodotoxina/análogos & derivados , Animales , Técnicas de Química Sintética , Masculino , Ratones Endogámicos , Relación Estructura-Actividad , Tetraodontiformes , Tetrodotoxina/síntesis química , Tetrodotoxina/química , Tetrodotoxina/farmacología , Tetrodotoxina/toxicidad , Pruebas de Toxicidad , Veratridina/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
This report describes the stereocontrolled total synthesis of the multi-functionalized cyclitol derivative, tetrodotoxin, containing eight asymmetric carbons and different types of branched-chains, from myo-inositol and D-glucose using three different methods. The tetrodotoxin derivatives possess a relatively small molecular weight but unique structural and chemical properties. Selection of the appropriate synthetic method may be useful not only for compounds related to TTX (including related derivatives), but also for other highly complex multi-functionalized cyclitols containing branched-chains.
Asunto(s)
Ciclitoles/síntesis química , Glucosa/química , Inositol/química , Tetrodotoxina/síntesis química , EstereoisomerismoRESUMEN
A stereoselective and efficient total synthesis of optically active tetrodotoxin (TTX) is described. A polyfunctionalized key cyclitol compound containing branched-chains for the synthesis of TTX was prepared from D-glucose employing the Henry reaction (Nitro aldol reaction) as the key transformation. Stereoselective construction of the alpha-azido-aldehyde branched-chain was achieved via the key spiro alpha-chloroepoxide intermediate.