Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Villiger reaction, reduction of the resulting lactone, and direct jones oxidation of a silyl ether. The michael reaction in organic synthesis the michael reaction has been used widely in organic synthesis for its cc bondforming ability. Overall, a set of new chemical tools for kainate receptors is reported. The biochemical mechanisms of the excitotoxicity of kainic acid. Kainic acid is a natural marine product originally isolated from the red marine alga d. An intermolecular sn2 substitution was excluded due to the competitive facile elimination of tsoh. The principal one is the presence of an alkene in the target, which of course cannot be present during the rutheniumpromoted ringdegradation step. Request pdf on jul 1, 2016, hongwei shi and others published formal total synthesis of. Thus, kainduced neurodegeneration in rodents has been used as a model for exploring the pathogenesis of excitotoxicity in neurodegenerative disorders. Kainic acid has a few features that make the strategy for its synthesis differ somewhat from that for the synthesis of 2. Base induced fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by wittig methylenation gave the kainoid derivative 18. A short total synthesis of kainic acid has been developed involving a novel diastereofacial differentiating cucatalyzed michael additioncyclization reaction, which provided access to a. The intermediate pyrrolidine 6 was easily transformed to aakainic acid in few steps, scheme 129.
A highly practical total synthesis of kainic acid has been accomplished. Kainic acid is used to study mechanisms of excitationinduced apoptosis and epilepsy. Key steps are an ircatalyzed allylic amination with a propargylic amine to provide an enyne and a diastereoselective intramolecular pauson. Since its isolation in 1953, kainic acid has been the target of many synthetic chemists, and a plethora of total syntheses have been. Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. The present paper deals with an improved synthesis of cipa and cipb and their transformation into ciopa and ciopb, the corresponding amido derivatives figure 2. Total syntheses of kainic acid stathakis 2012 european.
Results and discussion according to a literature report,9 the synthesis of cipa and cipb, as pure enantiomers, has. All that remains for the synthesis of kainic acid 1. Your browser doesnt seem to have a pdf viewer, please download the pdf to view this item. Nov 24, 2010 kainic acid ka, an analog of excitotoxic glutamate, can elicit selective neuronal death in the brain of rodents, of which the pathological changes partially mimic neurodegeneration in the cns. Two alternative protocols for the construction of the. Kainic acid definition of kainic acid by medical dictionary. Implications for natural origins of atropabyssomicin c. Citations are publications that use tocris products. An excitatory amino acid receptor agonist selective for the kainate receptor subtype k i 21 nm for. Classics in total synthesis iimore targets, strategies. The pausonkhand reaction is an important reaction in the field of organic chemistry.
This article reported an eight steps formal total synthesis of. The key transformations include an efficient tandem nallylations n 2. Dec 21, 2007 one of the main challenges of the synthesis is the installation of cis3,4 stereochemistry in kainic acid, which is a crucial factor for biological activity. Bachi and artem melman department of organic chemistry. Particularly, the synthetic endeavours towards the building of kainic acid reported during the period 2012 till mid 2015 have. However, at least some of the enantiopurity is lost in most of the existing reactions used in synthetic organic chemistry. It is employed in the traditional sense where an enolate reacts with an. Bachi and artem melman department of organic chemistry, the weitmann institute of science, rehovot 76100, ismel abstract. Limo n et al 2019 electrophysiological evaluation of extracellular spermine and alkaline ph on synaptic human gabaa receptors.
The preparation of the fused bicycle 14 is reported together with its photocyclisation to the dioxinone 2. The molecular formula of ka are c 10 h 15 no 4 and the molar mass of ka is 2. One of the biggest challenges in asymmetric synthesis is to prevent racemization of enantiopure starting materials. Khand reaction directed towards the synthesis of dicyclopentapentalenes.
This longawaited graduate level book, written by one of the worlds leading organic chemists in collaboration with two of his former and present coworkers, adopts a refreshingly unique approach to synthesis planning and execution. Kainic acid ka is a known potent neuroexcitotoxin, although the biochemical mechanism producing its underlying neurotoxic effect is not quite clear. Biochemphysiol actions kainic acid monohydrate is an agonist at the kainate class of ionotropic glutamate receptors, which induces seizures and neurodegeneration in vivo and is used to induce experimental epilepsy in rodents and study the mechanisms of. The molecular structure of kainic acid 2carboxy4isopropenylpyrrolidin3ylacetic acid, ka. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the red alga digenea simplex. Studies towards a total synthesis of kainic acid request pdf. The two ionotropic glutamate receptor agonists kainic acid ka and dihydrokainic acid dhk have been used as research tools in various in vivo central nervous system disease models in rodents, as well as being. Kainic acid via chirality transfer through irelandclaisen rearrangement. Naturally enantiopure proteinogenic amino acids that can be transformed into many useful intermediates in.
A diversityoriented synthetic strategy was developed for the total synthesis of kainoid amino acids, which led to the enantioselective synthesis of kainic acid and the first total synthesis. Kainic acid, c 10 h 15 o 4 n, has an intense anthelmintic effect, about ten times that of santonin, without. They named it kainic acid after kaininso, the japanese name of the mother alga. Recent progress in syntheses and biological activities of kainic. A fully functionalized trisubstituted pyrrolidine ring was constructed by ringclosing metathesis of an acrylate derivative followed by an intramolecular michael addition of the resultant. The importance of this reaction originates from its high value in transforming simple components into the synthetically useful cyclopentenone unit, in which a high degree of.
Materials and methods animals and treatments twenty adult wistar rats, weighing 180200 g, were used in the present study. Key steps are an ircatalyzed allylic amination with. Benzotriazolylalkylalkenylamines and samarium diiodide. A novel photochemical ch carbamoylation of an octahydroisoindole derivative with phnco has allowed the authors to provide a unique access to a highly functionalized proline motif from which total synthesis of kainic acid, a bioactive marine alkaloid, has been accomplished. Kainate receptors, or kainic acid receptors kars, are ionotropic receptors that respond to the neurotransmitter glutamate. Information and translations of kainic acid in the most comprehensive dictionary definitions resource on the web. Structure of kainic acid and its isomer, allokainic acid nature. The synthesis features the stereoselective alkylation of an. Molecules free fulltext the 9phenyl9fluorenyl group. Histopathological examination of gerbil brains 24 h after systemic injection of ka revealed severe neuronal lesions in different regions of the brain,expecially the cerebellar and hippocampal areas.
The glutamatergic neurotransmitter system is involved in important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases. Pdf download buy article permissions and reprints all articles of this category an enantioselective synthesis of. A diversityoriented synthetic strategy was developed for the total synthesis of kainoid amino acids, which led to the enantioselective synthesis of. It is a potent central nervous system stimulant, and has been developed as the prototype neuroexcitatory amino acid for the induction of seizures in experimental animals, at a typical dose of 1030 mgkg in mice. Enantioselective total synthesis of a kainic acid mario d. Two broad categories of glutamate receptors glurs, that is, iglurs and metabotropic glurs mglurs, differ with reference to their functions. It involves the transitionmetal catalysed cycloaddition of an alkyne, an alkene and carbon monoxide, to produce cyclopentenones.
The journal of organic chemistry 20, 78 7, 33553360. Diastereoselective synthesis of pyrrolidines by 5exotrig cyclizations of. Rh i catalyzed asymmetric enyne cycloisomerization served as the key reaction in this st. In neurobiology, it is used as a research tool to destroy neurons and as an activator of glutamate receptors. Enantioselective total synthesis of akainic acid mario d. Excelent east to understand on mdma, and methamphetamine synthesis.
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