A diversityoriented synthetic strategy was developed for the total synthesis of kainoid amino acids, which led to the enantioselective synthesis of. The molecular structure of kainic acid 2carboxy4isopropenylpyrrolidin3ylacetic acid, ka. Key steps are an ircatalyzed allylic amination with a propargylic amine to provide an enyne and a diastereoselective intramolecular pauson. Implications for natural origins of atropabyssomicin c. Key steps are an ircatalyzed allylic amination with.
The principal one is the presence of an alkene in the target, which of course cannot be present during the rutheniumpromoted ringdegradation step. Since its isolation in 1953, kainic acid has been the target of many synthetic chemists, and a plethora of total syntheses have been. The michael reaction in organic synthesis the michael reaction has been used widely in organic synthesis for its cc bondforming ability. It is employed in the traditional sense where an enolate reacts with an. Limo n et al 2019 electrophysiological evaluation of extracellular spermine and alkaline ph on synaptic human gabaa receptors. A short total synthesis of kainic acid has been developed involving a novel diastereofacial differentiating cucatalyzed michael additioncyclization reaction, which provided access to a. Kainate receptors, or kainic acid receptors kars, are ionotropic receptors that respond to the neurotransmitter glutamate. An excitatory amino acid receptor agonist selective for the kainate receptor subtype k i 21 nm for. An intermolecular sn2 substitution was excluded due to the competitive facile elimination of tsoh. Glutamate is produced by the cells metabolic processes and there are four major.
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. Information and translations of kainic acid in the most comprehensive dictionary definitions resource on the web. 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. 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. The synthesis features the stereoselective alkylation of an. Kainic acid has a few features that make the strategy for its synthesis differ somewhat from that for the synthesis of 2. A fully functionalized trisubstituted pyrrolidine ring was constructed by ringclosing metathesis of an acrylate derivative followed by an intramolecular michael addition of the resultant. Bloodbrain barrier permeability and brain uptake mechanism.
Enantioselective total synthesis of akainic acid mario d. However, at least some of the enantiopurity is lost in most of the existing reactions used in synthetic organic chemistry. Your browser doesnt seem to have a pdf viewer, please download the pdf to view this item. 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. Pdf download buy article permissions and reprints all articles of this category an enantioselective synthesis of. Thus, kainduced neurodegeneration in rodents has been used as a model for exploring the pathogenesis of excitotoxicity in neurodegenerative disorders. 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. Synthesis of natural products and the development of. Khand reaction directed towards the synthesis of dicyclopentapentalenes. Journal of the american chemical society, 129, 429440. Bachi and artem melman department of organic chemistry.
Citations are publications that use tocris products. Kainic acid is a natural marine product originally isolated from the red marine alga d. One of the biggest challenges in asymmetric synthesis is to prevent racemization of enantiopure starting materials. 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. Molecules free fulltext the 9phenyl9fluorenyl group.
All that remains for the synthesis of kainic acid 1. 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. 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. In neurobiology, it is used as a research tool to destroy neurons and as an activator of glutamate receptors. Diastereoselective synthesis of pyrrolidines by 5exotrig cyclizations of. The pausonkhand reaction is an important reaction in the field of organic chemistry. Enantioselective total synthesis of a kainic acid mario d. The intermediate pyrrolidine 6 was easily transformed to aakainic acid in few steps, scheme 129. Recent progress in syntheses and biological activities of kainic. The journal of organic chemistry 20, 78 7, 33553360. 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. Materials and methods animals and treatments twenty adult wistar rats, weighing 180200 g, were used in the present study. Kainic acid definition of kainic acid by medical dictionary. Naturally enantiopure proteinogenic amino acids that can be transformed into many useful intermediates in.
Bachi and artem melman department of organic chemistry, the weitmann institute of science, rehovot 76100, ismel abstract. Overall, a set of new chemical tools for kainate receptors is reported. They named it kainic acid after kaininso, the japanese name of the mother alga. Kainic acid, or kainate, is an acid that naturally occurs in some seaweed.
Request pdf on jul 1, 2016, hongwei shi and others published formal total synthesis of. Studies towards a total synthesis of kainic acid request pdf. Benzotriazolylalkylalkenylamines and samarium diiodide. Volume 59, issue 18, 28 april 2003, pages 33073314. Among them, the total synthesis of kainic acid 1 has been studied extensively, and more than 35 total. Villiger reaction, reduction of the resulting lactone, and direct jones oxidation of a silyl ether. Following an introductory look at the concept of synthesis, the authors discuss the why, what, and how of organic synthesis as they apply to natural products. Synthesis of kainic acid derivatives and their application as kainate.
Kainic acid ka is a known potent neuroexcitotoxin, although the biochemical mechanism producing its underlying neurotoxic effect is not quite clear. 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. Kainic acid is used to study mechanisms of excitationinduced apoptosis and epilepsy. It involves the transitionmetal catalysed cycloaddition of an alkyne, an alkene and carbon monoxide, to produce cyclopentenones. Results and discussion according to a literature report,9 the synthesis of cipa and cipb, as pure enantiomers, has. Rh i catalyzed asymmetric enyne cycloisomerization served as the key reaction in this st. Particularly, the synthetic endeavours towards the building of kainic acid reported during the period 2012 till mid 2015 have. This article reported an eight steps formal total synthesis of.
Kainic acid via chirality transfer through irelandclaisen rearrangement. Two broad categories of glutamate receptors glurs, that is, iglurs and metabotropic glurs mglurs, differ with reference to their functions. The key transformations include an efficient tandem nallylations n 2. The biochemical mechanisms of the excitotoxicity of kainic acid.
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. Total syntheses of kainic acid stathakis 2012 european. The molecular formula of ka are c 10 h 15 no 4 and the molar mass of ka is 2. Base induced fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by wittig methylenation gave the kainoid derivative 18.
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. Structure of kainic acid and its isomer, allokainic acid nature. Kainic acid, c 10 h 15 o 4 n, has an intense anthelmintic effect, about ten times that of santonin, without. Two alternative protocols for the construction of the. 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. A highly practical total synthesis of kainic acid has been accomplished. Classics in total synthesis iimore targets, strategies.