- Enantioselective total synthesis of (-)-α-kainic acid
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(Figure Presented) An enantioselective total synthesis of (-)-α-kainic acid is described. Key steps are an lr-catalyzed allylic amination with a propargyllc amine to provide an enyne and a diastereoselective intramolecular Pauson-Khand reaction. Subsequent steps involve a Baeyer-Villiger reaction, reduction of the resulting lactone, and direct Jones oxidation of a silyl ether.
- Farwick, Andreas,Helmchen, Guenter
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- Algal neurotoxin biosynthesis repurposes the terpene cyclase structural fold into an N-prenyltransferase
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Prenylation is a common biological reaction in all domains of life wherein prenyl diphosphate donors transfer prenyl groups onto small molecules as well as large proteins. The enzymes that catalyze these reactions are structurally distinct from ubiquitous terpene cyclases that, instead, assemble terpenes via intramolecular rearrangements of a single substrate. Herein, we report the structure and molecular details of a new family of prenyltransferases from marine algae that repurposes the terpene cyclase structural fold for the N-prenylation of glutamic acid during the biosynthesis of the potent neurochemicals domoic acid and kainic acid. We solved the X-ray crystal structure of the prenyltransferase found in domoic acid biosynthesis, DabA, and show distinct active site binding modifications that remodel the canonical magnesium (Mg2+)-binding motif found in terpene cyclases. We then applied our structural knowledge of DabA and a homologous enzyme from the kainic acid biosynthetic pathway, KabA, to reengineer their isoprene donor specificities (geranyl diphosphate [GPP] versus dimethylallyl diphosphate [DMAPP]) with a single amino acid change. While diatom DabA and seaweed KabA enzymes share a common evolutionary lineage, they are distinct from all other terpene cyclases, suggesting a very distant ancestor to the larger terpene synthase family.
- Chekan, Jonathan R.,McKinnie, Shaun M. K.,Moore, Bradley S.,Noel, Joseph P.
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- High-pressure Diels-Alder approach to natural kainic acid
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The first Diels-Alder based synthesis of (-)-kainic acid is described. Danishefsky's diene and a vinylogous malonate derived from 4-hydroxyproline combine under high pressure to afford a key bicyclic intermediate with virtually no loss of enantiopurity. This adduct can be converted into the natural product with complete stereocontrol.
- Pandey, Sushil K.,Orellana, Arturo,Greene, Andrew E.,Poisson, Jean-Francois
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- Total Synthesis of (-)-α-Kainic Acid
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N-Alkylation of the β-amino acid derivative 16, derived from (L)-aspartic acid, by the allylic chloride 12b followed by deprotection and lactonization leads to the nine-membered azalactone 18.Enolate Claisen rearrangement of this leads stereospecifically, via a boat-like transition state (cf. 6), to the pyrrolidine acid 19; subsequent one-carbon homologation, oxidation and deprotection affords (-)-(α)-kainic acid 1.
- Cooper, Jeremy,Knight, David W.,Gallagher, Peter T.
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- Enantioselective total synthesis of (-)-kainic acid and (+)-acromelic acid C: Via Rh(i)-catalyzed asymmetric enyne cycloisomerization
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A diversity-oriented 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 of (+)-acromelic acid C. Rh(i)-catalyzed asymmetric enyne cycloisomerization served as the key reaction in this strategy for the rapid construction of highly functionalized lactam, and the resulting vinyl acetate moiety was further utilized as a versatile building block for the installation of both isopropylidene and 2-pyridone units existing in natural kainoids.
- Lei, Honghui,Xin, Shan,Qiu, Yifan,Zhang, Xumu
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Read Online
- Scalable Biosynthesis of the Seaweed Neurochemical, Kainic Acid
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Kainic acid, the flagship member of the kainoid family of natural neurochemicals, is a widely used neuropharmacological agent that helped unravel the key role of ionotropic glutamate receptors, including the kainate receptor, in the central nervous system. Worldwide shortages of this seaweed natural product in the year 2000 prompted numerous chemical syntheses, including scalable preparations with as few as six-steps. Herein we report the discovery and characterization of the concise two-enzyme biosynthetic pathway to kainic acid from l-glutamic acid and dimethylallyl pyrophosphate in red macroalgae and show that the biosynthetic genes are co-clustered in genomes of Digenea simplex and Palmaria palmata. Moreover, we applied a key biosynthetic α-ketoglutarate-dependent dioxygenase enzyme in a biotransformation methodology to efficiently construct kainic acid on the gram scale. This study establishes both the feasibility of mining seaweed genomes for their biotechnological prowess.
- Chekan, Jonathan R.,McKinnie, Shaun M. K.,Moore, Malia L.,Poplawski, Shane G.,Michael, Todd P.,Moore, Bradley S.
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p. 8454 - 8457
(2019/05/21)
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- Synthesis of (±)-β-Allokainic Acid
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The total synthesis of kainoid alkaloid, (+/–)-β-allokainic acid is reported. The key step is a vinylogous Cloke–Wilson rearrangement followed by Lewis acid and transition metal induced transformations to prepare a highly functionalized pyrrolidine suitable for conversion to the target molecule.
- Piotrowski, Mathew L.,Kerr, Michael A.
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p. 3122 - 3126
(2019/06/08)
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- Synthesis of Kainoids and C4 Derivatives
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A unified stereoselective synthesis of 4-substituted kainoids is reported. Four kainic acid analogues were obtained in 8-11 steps with up to 54% overall yields. Starting from trans-4-hydroxy-l-proline, the sequence enables a late-stage modification of C4 substituents with sp2 nucleophiles. Stereoselective steps include a cerium-promoted nucleophilic addition and a palladium-catalyzed reduction. A 10-step route to acid 21a was also established to enable ready functionalization of the C4 position.
- Tian, Zhenlin,Menard, Frederic
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p. 6162 - 6170
(2018/05/23)
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- Total synthesis of (-)-kainic acid and (+)-: Allo -kainic acid through SmI2-mediated intramolecular coupling between allyl chloride and an α,β-unsaturated ester
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A 3,4-disubstituted pyrrolidine ring was effectively cyclized through SmI2-mediated reductive coupling between allyl chloride and an α,β-unsaturated ester, although little has been reported about SmI2-promoted C-C bond formation of an allyl chloride with an α,β-unsaturated ester. Selection of either the 3,4-cis- or 3,4-trans-selective cyclization can be accomplished simply by changing the additives from NiI2 to HMPA during reductive cyclization conducted in H2O-THF. Total synthesis of (-)-kainic acid and (+)-allo-kainic acid, which are pyrrolidine alkaloids used in neuroscience and neuropharmacology as useful molecular probes, was successfully achieved by using the stereo-complementary ring closure reactions promoted by SmI2 for the construction of the 2,3,4-trisubsituted pyrrolidine scaffold of kainoids.
- Suzuki, Junya,Miyano, Natsumi,Yashiro, Shunpei,Umezawa, Taiki,Matsuda, Fuyuhiko
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p. 6557 - 6566
(2017/08/16)
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- Synthetic method of kainic acid
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The invention discloses a synthetic method of kainic acid. The synthetic method comprises the steps of carrying out single-step series connection N-allylation-SN2' reaction on (S)-5-oxo-tetrahydrofuran-3-carbamic acid benzyl ester as a raw material to construct a kainic acid core framework-trans-2,3-cis-3,4-trans-trisubstituted pyrrolidine intermediate, reducing and oxidizing an ester group in the intermediate into an aldehyde group, carrying out Horner-Wordsworth-Emmons reaction and mercury ion accelerated methanol hydrolysis reaction to obtain the ester group added with a carbon atom, finally carrying out ester exchange, oxidization and hydrolysis, so as to obtain kainic acid. The synthetic method has the beneficial effects that the raw material cost is low, the reaction steps are short, the operation process is simple and convenient, the total yield of kainic acid is high, the synthetic cost of kainic acid can be greatly lowered, and the industrial production of kainic acid is hopefully realized.
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Paragraph 0012
(2016/10/07)
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- Substrate stereocontrol in the intramolecular organocatalyzed tsuji-trost reaction: Enantioselective synthesis of allokainates
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Organocatalyzed Tsuji-Trost cyclization of 3b proceeds with asymmetric induction and allows for stereoselective synthesis of (+)-allokainic acid. The stereochemical outcome of the cyclization was predicted by calculations.
- Vulovic, Bojan,Gruden-Pavlovic, Maja,Matovic, Radomir,Saicic, Radomir N.
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supporting information
p. 34 - 37
(2014/01/23)
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- Short total synthesis of (-)-kainic acid
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A short total synthesis of (-)-kainic acid has been developed involving a novel diastereofacial differentiating Cu-catalyzed Michael addition-cyclization reaction, which provided access to a chiral pyrroline in a highly stereoselective manner. The chiral pyrroline was converted to (-)-kainic acid via the stereoselective 1,4-reduction of the pyrroline double bond in three steps.
- Oe, Kentaro,Ohfune, Yasufumi,Shinada, Tetsuro
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p. 2550 - 2553
(2014/05/20)
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- A unified strategy for kainoid synthesis
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A unified strategy for kainoid synthesis was developed. The key features of the strategy involve a Claisen-Ireland rearrangement to construct the contiguous stereogenic centers and a palladium-catalyzed formation of the pyrrolidine ring with complete stereoselectivity. The present protocol has enabled rapid access to a wide range of kainoids with diverse types of substituents (alkenyl, aryl, and alkyl groups) at the 4-position of the pyrrolidine ring, starting from the common intermediate and appropriate acetic acid derivatives. To test the generality of the strategy, we have accomplished the syntheses of kainic acid, o-methoxyphenyl derivative (MFPA), and a novel cyclopropyl derivative (CPKA), using 3-methylbut-3-enoic acid, 2-(2-methoxyphenyl)acetic acid, and 2-cyclopropylacetic acid, respectively.
- Fujii, Masaya,Yokoshima, Satoshi,Fukuyama, Tohru
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p. 4823 - 4836
(2014/08/05)
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- A short scalable route to (-)-α-kainic acid using Pt-catalyzed direct allylic amination
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An increased supply of scarce or inaccessible natural products is essential for the development of more sophisticated pharmaceutical agents and biological tools, and thus the development of atom-economical, step-economical and scalable processes to access these natural products is in high demand. Herein we report the development of a short, scalable total synthesis of (-)-α-kainic acid, a useful compound in neuropharmacology that is, however, limited in supply from natural resources. The synthesis features sequential platinum-catalyzed direct allylic aminations and thermal ene-cyclization, enabling the gram-scale synthesis of (-)-α-kainic acid in six steps and 34% overall yield.
- Zhang, Ming,Watanabe, Kenji,Tsukamoto, Masafumi,Shibuya, Ryozo,Morimoto, Hiroyuki,Ohshima, Takashi
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supporting information
p. 3937 - 3941
(2015/10/19)
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- Total synthesis of (-)-α-Kainic acid via chirality transfer through Ireland-Claisen rearrangement
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The total synthesis of (-)-α- Kainic acid is accomplished using a linear strategy involving Noyori asymmetric reduction and chirality transfer through Ireland-Claisen rearrangement as key steps.
- Reddy, Naredla Kesava,Chandrasekhar, Srivari
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p. 3355 - 3360
(2013/07/05)
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- Diastereoselective rhodium-catalyzed ene-cycloisomerization reactions of alkenylidenecyclopropanes: Total synthesis of (-)-α-kainic acid
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The rhodium-catalyzed ene-cycloisomerization of alkenylidenecyclopropanes provides an atom-economical approach to five-membered carbo- and heterocycles that contain two new stereogenic centers. A key and striking feature of this protocol is that the alkene geometry does not impact the efficiency and diastereocontrol, which provides excellent synthetic versatility. For instance, (E)- and (Z)-allylic alcohols furnish the corresponding aldehydes with similar efficiency and selectivity. This process facilitates the construction of a key intermediate in an eight-step total synthesis of (-)-α-kainic acid.
- Evans, P. Andrew,Inglesby, Phillip A.
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supporting information; experimental part
p. 3635 - 3638
(2012/04/17)
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- Total synthesis of (-)-(α)-kainic acid via a diastereoselective intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne
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An enantioselective synthesis of (-)-(α)-kainic acid in 15 steps with an overall yield of 24% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with complete diastereoselectivity via an unprecedented SmI2-catalyzed intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone and an alkyne. Double bond isomerization was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(α)-kainic acid.
- Luo, Zhi,Zhou, Bing,Li, Yuanchao
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supporting information; experimental part
p. 2540 - 2543
(2012/07/14)
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- A Diels-Alder-based total synthesis of (-)-kainic acid
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An efficient synthesis of (-)-kainic acid, through a high-pressure-promoted Diels-Alder cycloaddition of a vinylogous malonate derived from 4-hydroxyproline, is described. The bicyclic adduct could be converted into the natural product with complete stereocontrol.
- Orellana, Arturo,Pandey, Sushil K.,Carret, Sebastien,Greene, Andrew E.,Poisson, Jean-Francois
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experimental part
p. 5286 - 5296
(2012/08/27)
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- Chirality transfers through sequential sigmatropic rearrangements of allylic vicinal diols: Development and application to total synthesis of (-)-kainic acid
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A detailed description is presented of two sequential sigmatropic rearrangements starting from enantiopure allylic vicinal diols. Starting from the same allylic diol, the sequential Claisen/Claisen rearrangement can install two identical functional groups in a one-pot reaction, whereas, the sequential Claisen/Overman rearrangement can introduce two different functional groups, both occurring without protecting group manipulation. Both sequential reactions proceeded with complete stereoselectivity, which was easily predictable by the judicious choice of two factors regarding the allylic diols: (1) the stereochemistry of the hydroxy groups and (2) the geometry of the olefin. To demonstrate this sequential rearrangement methodology, we accomplished the total synthesis of (-)-kainic acid, whose three contiguous stereocenters were completely established by three chirality transfer reactions (SN2' and sequential Claisen/Overman reactions) of flexible acyclic intermediates derived from D-arabinose. A detailed investigation is described of two sequential sigmatropic rearrangements from allylic diols. Starting from the same allylic diol, either two identical functional groups (Claisen/Claisen) or two different functional groups (Claisen/Overman) were diastereoselectively installed. The reaction was successfully applied to the total synthesis of (-)-kainic acid.
- Kitamoto, Katsunori,Nakayama, Yasuaki,Sampei, Mana,Ichiki, Masato,Furuya, Naoya,Sato, Takaaki,Chida, Noritaka
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p. 4217 - 4231
(2012/10/08)
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- Highly enantioselective alkenylation of cyclic α,β-unsaturated carbonyl compounds as catalyzed by a rhodium-diene complex: Application to the synthesis of (S)-pregabalin and (-)-α-kainic acid
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Rhod to addition: An efficient asymmetric conjugate-addition reaction of alkenyltrifluoroborates and α,β-unsaturated carbonyl compounds, as catalyzed by a rhodium-diene complex, was developed. The products were obtained in high yield and high levels of enantioselectivity. The methodology was applied to a concise synthesis of (S)-pregabalin and (-)-α-kainic acid (see scheme).
- Yu, Hong-Jie,Shao, Cheng,Cui, Zhe,Feng, Chen-Guo,Lin, Guo-Qiang
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supporting information
p. 13274 - 13278,5
(2012/12/12)
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- Highly enantioselective alkenylation of cyclic α,β-unsaturated carbonyl compounds as catalyzed by a rhodium-diene complex: Application to the synthesis of (S)-pregabalin and (-)-α-kainic acid
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Rhod to addition: An efficient asymmetric conjugate-addition reaction of alkenyltrifluoroborates and α,β-unsaturated carbonyl compounds, as catalyzed by a rhodium-diene complex, was developed. The products were obtained in high yield and high levels of enantioselectivity. The methodology was applied to a concise synthesis of (S)-pregabalin and (-)-α-kainic acid (see scheme).
- Yu, Hong-Jie,Shao, Cheng,Cui, Zhe,Feng, Chen-Guo,Lin, Guo-Qiang
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supporting information
p. 13274 - 13278
(2013/01/15)
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- Total synthesis of (±)-kainic acid: A photochemical C-H carbamoylation approach
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A novel photochemical C-H 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.
- Kamon, Takuma,Irifune, Yayoi,Tanaka, Tetsuaki,Yoshimitsu, Takehiko
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supporting information; experimental part
p. 2674 - 2677
(2011/07/07)
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- Progress in the synthesis of (-)-α-kainic acid
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Causing neuronal death, kainic acid and its derivatives are toxic to several known animal species, including rats. Kainic acid and its derivatives have been shown to cause neuroexcitatory activity observed in several neurological disorders. In this research project, a synthetic route that involves control of the stereochemistry to synthesize a pure stereoisomer of kainic acid is proposed. The pure stereoisomer possesses certain medical properties of interest to pharmacological companies. This laboratory synthesis is gaining popularity and increasing importance all over the world because extraction from seaweeds, where kainic acid is found, does not produce reasonable yields. This laboratory procedure will attempt to synthesize kainic acid using an ENE reaction in the final step of the 12 steps as shown in the graphical abstract. Taylor & Francis Group, LLC.
- Choony, Nandeo,James, Lisa,Rabun, Courtney
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p. 2539 - 2543
(2011/09/12)
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- A general synthetic approach to the amnesic shellfish toxins: Total synthesis of (-)-isodomoic acid B, (-)-isodomoic acid E and (-)-isodomoic acid F
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The alkynylpyrrolidine 4 was made via a dearomatising cyclisation of an aromatic amide, and was elaborated by stannylcupration and palladium-catalysed coupling to achieve the first total synthesis of three members of the isodomoic acid family; the same alkyne can be envisaged as a precursor to several more of this class of amnesic shellfish toxins. The Royal Society of Chemistry.
- Lemiere, Gilles,Sedehizadeh, Simon,Toueg, Julie,Fleary-Roberts, Nadia,Clayden, Jonathan
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supporting information; experimental part
p. 3745 - 3747
(2011/05/04)
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- A Practical Synthesis of (-)-Kainic Acid
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A highly practical stereoselective total synthesis of (-)-kainic acid is described. This synthesis features the stereoselective alkylation of an iodolactone intermediate that was efficiently prepared from (P)-carvone and introduction of carboxylic acid by hydrolysis of a nitrile accompanied by epimerizaion. This synthetic route enabled us to obtain 14.6 g of (-)-kainic acid.
- Takita, Satoshi,Yokoshima, Satoshi,Fukuyama, Tohru
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supporting information; experimental part
p. 2068 - 2070
(2011/06/22)
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- A practical synthesis of (-)-kainic acid
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A highly practical total synthesis of (-)-kainic acid has been accomplished. The synthesis features the stereoselective alkylation of an iodolactone intermediate efficiently prepared from (+)-carvone and introduction of carboxylic acid by hydrolysis of a nitrile accompanied by epimerization. Georg Thieme Verlag Stuttgart. New York.
- Takita, Satoshi,Yokoshima, Satoshi,Fukuyama, Tohru
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experimental part
p. 3848 - 3858
(2012/01/06)
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- Di- and trisubstituted γ-lactams via Rh(II)-carbenoid reaction of N -Cα-branched, N -Bis(trimethylsilyl)methyl α-diazoamides. Synthesis of (±)-α-allokainic acid
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Acyclic N-Cα-branched, N-bis(trimethylsilyl)methyl (N-BTMSM) diazoamides undergo regio-, chemo-, and diastereoselective Rh(II)-carbenoid C-H insertion to give 4,5-disubstituted and 3,4,5-trisubstituted γ-lactams. The conformational influence of
- Zhang, Bao,Wee, Andrew G. H.
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supporting information; experimental part
p. 5386 - 5389
(2011/03/17)
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- Novel sequential sigmatropic rearrangements of allylic diols: Application to the total synthesis of ( - )-kainic acid
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Sequential sigmatropic rearrangements (Claisen/Claisen and Claisen/Overman) of enantiopure allylic diols are described. The reactions proceeded in complete diastereoselectivity without protecting group manipulations. The sequential Claisen/Overman rearrangement was successfully applied to the total synthesis of ( - )-kainic acid.
- Kitamoto, Katsunori,Sampei, Mana,Nakayama, Yasuaki,Sato, Takaaki,Chida, Noritaka
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p. 5756 - 5759
(2011/03/23)
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- Total synthesis of (-)-kainic acid via intramolecular michael addition: A second-generation route
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A total synthesis of (-)-kainic acid starting from the commercially available 2-azetidinone is described. The key δ-lactone intermediate was concisely prepared from the commercially available azetidinone through the Reformatsky-type reaction and an introduction of a glycine moiety. The construction of the functionalized pyrrolidine ring was executed by a one-pot sequential elimination-Michael addition protocol of a β-amino-δ- lactone intermediate with high diastereoselectivity.
- Sakaguchi, Hiroshi,Tokuyama, Hidetoshi,Fukuyama, Tohru
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supporting information; experimental part
p. 1711 - 1714
(2009/04/10)
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- Asymmetric synthesis of (-)- and (+)-kainic acid using a planar chiral amide as a chiral building block
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Both enantiomers of kainic acid have been synthesized from enantioenriched planar chiral cyclic amide 2a. The C3 and C4 stereocenters in the pyrrolidine ring were constructed by transannular Cope rearrangement of 2a, and the carboxyl group at the C2 position was introduced through lithiation followed by a carboxylation in the presence of an external chiral ligand.
- Tomooka, Katsuhiko,Akiyama, Toshiyuki,Man, Phewluangdee,Suzuki, Masaki
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supporting information; experimental part
p. 6327 - 6329
(2009/04/07)
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- Total syntheses of (-)-α-kainic acid and (+)-α-allokainic acid via stereoselective C-H insertion and efficient 3,4-stereocontrol
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(Chemical Equation Presented) Reported herein is a novel approach to the total syntheses of (-)-α-kainic acid and (+)-α-allokainic acid, where the stereochemistries on C(2), C(3), and C(4) of the pyrrolidine core were introduced efficiently and selectively. A regio- and stereoselective C-H insertion reaction was utilized to prepare the γ-lactam as an intermediate. A Michael-type cyclization of phenylsulfone with a conjugated acetylenic ketone was developed to prepare the tricyclic ketone as a key intermediate for (-)-α-kainic acid. Subsequently, a stereoselective dephenylsulfonylation was carried out successfully to secure the cis relationship at C(3) and C(4) centers. An unprecedented acetylation on the phenylsulfone, followed by a stereoselective dephenylsulfonylation, secured the trans relationship at C(3) and C(4) centers in (+)-α-allokainic acid.
- Young, Chun Jung,Cheol, Hwan Yoon,Turos, Edward,Kyung, Soo Yoo,Kyung, Woon Jung
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p. 10114 - 10122
(2008/03/28)
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- Stereocontrolled total synthesis of (-)-kainic acid. Regio- and stereoselective lithiation of pyrrolidine ring with the (+)-sparteine surrogate
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(Chemical Equation Presented) A stereocontrolled total synthesis of (-)-kainic acid is described. cis-3,4-Disubstituted pyrrolidine ring was constructed by [3 + 2] cycloaddition of azomethine ylide with chiral butenolide. The crucial introduction of carboxyl group at the C-2 position was executed by regio- and stereoselective lithiation of the pyrrolidine ring in the presence of a (+)-sparteine surrogate followed by trapping with carbon dioxide.
- Morita, Yasuhiro,Tokuyama, Hidetoshi,Fukuyama, Tohru
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p. 4337 - 4340
(2007/10/03)
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- Novel approach to the (-)-sparteine-mediated synthesis of kainoids: Total synthesis of (-)-α-kainic acid by (-)-sparteine-mediated deprotonation
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We report a new synthesis of kainoids via allyllithium compounds using an intramolecular cycloalkylation as the key step. Preparation of different substituted pyrrolidines was carried out by using carbamates, that react with the chiral base n-BuLi/(-)-sparteine with strong selection between the diastereotopic protons adjacent to the carbamate group in favour for the pro-S proton. (-)-α-Kainic acid was synthetized from D-serine methyl ester hydrochloride, based on a (-)-sparteine-mediated asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti-SN′S E′ intramolecular cycloalkylation, leads to the pyrrolidine ring precursor of (-)-α-kainic acid, in high yield and diastereoselectivity. Related approaches, starting from L-glutamic acid failed. The intermediate pyrrolidine was further transformed to (-)-α-kainic in three steps. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Martinez, M. Montserrat,Hoppe, Dieter
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p. 1427 - 1443
(2007/10/03)
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- Total synthesis of (-)-(α)-kainic acid via a diastereoselective methylenecyclopropane ring expansion
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(Chemical Equation Presented) A concise and enantioselective synthesis of (-)-(α)-kainic acid in 13 steps with an overall yield of 15% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with excellent diastereoselectivity (>20:1) via a Mgl 2-mediated ring expansion of a tertiary methylenecyclopropyl amide. A selective hydroboration was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(α)-kainic acid.
- Scott, Mark E.,Lautens, Mark
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p. 3045 - 3047
(2007/10/03)
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- Ruthenium-catalyzed cycloisomerizations of diynols
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A wide variety of diynols containing tertiary, secondary, and primary propargylic alcohols undergo a cycloisomerization reaction to form dienones and dienals in the presence of a catalytic amount of [CpRu(CH3CN) 3]PF6. The
- Trost, Barry M.,Rudd, Michael T.
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p. 4763 - 4776
(2007/10/03)
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- Stereocontrolled syntheses of kainoid amino acids from 7-azabicyclo[2.2.1] heptadienes using tandem radical addition-homoallylic radical rearrangement
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N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1] hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, α-kainic acid 12, α-isokainic acid 14, and α-dihydroalloka
- Hodgson, David M.,Hachisu, Shuji,Andrews, Mark D.
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p. 8866 - 8876
(2007/10/03)
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- Total synthesis of (-)-α-kainic acid by (-)-sparteine-mediated asymmetric deprotonation-cycloalkylation
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(Chemical Equation Presented) We report a new enantioselective synthesis of (-)-α-kainic acid from D-serine methyl ester hydrochloride, based on a (-)-sparteine-mediated asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti SN′SE′ intramolecular cycloalkylation, leads to the pyrrolidine ring precursor of (-)-α-kainic acid, in high yield and diastereoselectivity. The intermediate pyrrolidine was further transformed to (-)-α-kainic acid in three steps.
- Martinez, M. Montserrat,Hoppe, Dieter
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p. 3743 - 3746
(2007/10/03)
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- Total synthesis of (+/-)-kainic Acid with an aza-[2,3]-Wittig sigmatropic rearrangement as the key stereochemical determining step.
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A flexible route to the kainoid skeleton is exemplified by the synthesis of (+/-)-kainic acid from 3-butyn-1-ol. The route relies on the aza-[2,3]-Wittig sigmatropic rearrangement to efficiently install the relative stereochemistry between C2-C3. The C4 s
- Anderson, James C,Whiting, Matthew
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p. 6160 - 6163
(2007/10/03)
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- Synthesis of (-)-kainic acid using chiral lithium amides in an asymmetric dearomatizing cyclization
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Chiral lithium amide bases are able to deprotonate N-benzyl-N-cumyl anisamides enantioselectively to yield enantiomerically enriched benzylic organolithiums. These spontaneously undergo dearomatising cyclisation to yield, in high enantiomeric excess enantiomerically enriched partially saturated isoindolones, which in some cases may be recrystallised to enantiomeric purity. These isoindolone derivatives are converted in nine steps, among them a surprisingly regioselective Baeyer-Villiger reaction, to (-)-kainic acid.
- Clayden, Jonathan,Menet, Christel J,Tchabanenko, Kirill
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p. 4727 - 4733
(2007/10/03)
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- Facile synthesis of (+)-α-allokainic acid via Pd-catalyzed hydrogenolysis of allyl acetate derived from trans-4-hydroxy-L-proline
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Pd(PPh3)4/PPh3-catalyzed hydrogenolysis of 3a derived from trans-4-hydroxy-L-proline using ammonium formate as a hydride reagent, provides olefin 4 as a major product, which is hydrolyzed to give (+)-α-allokainic acid.
- Ma, Dawei,Wu, Wengen,Deng, Ping
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p. 6929 - 6931
(2007/10/03)
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- Asymmetric Total Synthesis of (-)-α-Kainic Acid Using an Enantioselective, Metal-Promoted Ene Cyclization
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(Matrix Presented) A short and efficient asymmetric total synthesis of the title compound 1, which is an important neurotransmitter, has been achieved. The synthesis features a metal-promoted, enantioselective ene reaction that provides entry into the kainic acid ring system from very simple precursors. Moreover, the zirconium-mediated Strecker reaction, which represents an outgrowth of earlier amide-to-imine methodology developed in our laboratory, demonstrates remarkable chemoselectivity and stereoselectivity.
- Xia, Qian,Ganem, Bruce
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p. 485 - 487
(2007/10/03)
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- The stereoselective preparation of substituted pyrrolidines using titanium- And zirconium-mediated diene metallabicyclisation methodology: The total synthesis of (-)-α-kainic acid
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Zirconium- and titanium-mediated diene metallabicyclisation-elimination-functionalisation have been compared, contrasted and utilised for the preparation of 3,4-disubstituted and 2,3,4-trisubstituted pyrrolidines in high yield and excellent stereoselectivity. The zirconium-mediated methodology has been employed as the key step in a partial synthesis of (-)-α-kainic acid starting from D-serine, but the key metallabicyclisation sequence proceeded with poor stereocontrol. By contrast, the total synthesis of (-)-α-kainic acid starting from L-serine was accomplished using a titanium-mediated cyclisation sequence which proceeded with excellent stereocontrol. Novel kainoids and piperidines are also reported. The Royal Society of Chemistry 2000.
- Campbell, Andrew D.,Raynham, Tony M.,Taylor, Richard J. K.
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p. 3194 - 3204
(2007/10/03)
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- Synthesis of (±)-kainic acid by dearomatising cyclisation of a lithiated N-benzyl p-anisamide
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N-Benzyl p-anisamide 6, on lithiation with Bu(t)Li in the presence of HMPA, undergoes a stereoselective anionic cyclisation with loss of aromaticity to give a bicyclic enone which may be converted in nine steps to (±)-kainic acid.
- Clayden, Jonathan,Tchabanenko, Kirill
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p. 317 - 318
(2007/10/03)
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- Radical cyclization in heterocycle synthesis. Part 10: A concise synthesis of (-)-kainic acid via sulfanyl radical addition-cyclization-elimination reaction
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Sulfanyl radical addition-cyclization-elimination of diallylamines in the presence of thiophenol and AIBN gave the 2,3,4-trisubstituted pyrrolidine in high yield. This reaction was extended to a radical cyclization using a catalytic amount of thiophenol. A successful application was demonstrated by the asymmetric synthesis of (-)-kainic acid. (C) 2000 Elsevier Science Ltd.
- Miyata, Okiko,Ozawa, Yoshiki,Ninomiya, Ichiya,Naito, Takeaki
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p. 6199 - 6207
(2007/10/03)
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- A stereodivergent approach to (-)-α-kainic acid and (+)-α-allokainic acid utilizing the complementarity of alkyne and allene cyclizations
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A formal synthesis of (+)-α-allokainic acid and a total synthesis of (-)-α-kainic acid were carried out using a short, efficient, and highly stereoselective approach. From an alkyne precursor, a nickel-catalyzed cyclization and a palladium-catalyzed rearrangement were utilized in the synthesis of (+)-α-allokainic acid. From an allene precursor, a nickel-catalyzed cyclization was utilized in the synthesis of (-)-α-kainic acid. The allene cyclization used in the latter sequence was the first example of a metal-catalyzed cyclization of this type.
- Chevliakov, Maxim V.,Montgomery, John
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p. 11139 - 11143
(2007/10/03)
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- New enantioseleetive approach to the total synthesis of (-)-α-Kainic Acid
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The total synthesis of (-)-α-Kainic Acid 1 has been accomplished using ethyl N-Boc-pyroglutamate 2 as starting material. The isopropenyl appendage was achieved from the elimination of the dimethylcarbinol introduced at C-4 via an aldol condensation of the lactam enolate of 2 and acetone. The acetate group at C-3 of the kainic acid structure was introduced via diethyl malonate Michael addition reaction to the 2,3-didehydroprolinate 8. This Michael addition reaction proceeds with complete stereocontrol over the newly generated stereogenic centres. Inversion of the configuration at C-3 in 9 through double bond formation followed by hydrogenation, neutral decarboxylation and further epimerization of the C-2 stereogenic centre in 12, gave rise to the desired natural product.
- Rubio, Almudena,Ezquerra, Jesus,Escribano, Ana,Remuinan, Modesto Jesus,Vaquero, Juan Jose
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p. 2171 - 2174
(2007/10/03)
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- An Enantioselective Synthesis of (-)-α-Kainic Acid via Thiyl Radical Addition-Cyclization-Elimination Reaction
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An enantioselective synthesis of (-)-α-kainic acid has been achieved via the route involving thiyl radical addition-cyclization-elimination reaction.
- Miyata, Okiko,Ozawa, Yoshiki,Ninomiya, Ichiya,Naito, Takeaki
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p. 275 - 276
(2007/10/03)
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- Stereoselective synthesis of (-)-α-kainic acid and (+)-α-allokainic acid via trimethylstannyl-mediated radical carbocyclization and oxidative destannylation
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(-)-α-Kainic acid (1) and its C4 epimer (+)-α-allokainic acid (2) have been prepared from L-serine. The requisite stereochemical array in (-)-α-kainic acid (1) was introduced using a trimethylstannyl radical carbocyclization of a diene, which gave the 2,3-trans/3,4-cis and 2,3-trans/3,4-trans componnds in a 2.8:1 ratio and in high yield. The destannylation of the trisubstituted pyrrolidine nucleus was achieved via an oxidative cleavage of the C-Sn bond with ceric ammonium nitrate. This provided a dimethyl acetal that was further transformed into the intended α-kainic acid. When the same radical carbocyclization was attempted on a triene, the 2,3-trans/3,4-trans and the 2,3-trans/3,4-cis adducts were obtained in a 2.5:1 ratio, respectively. This approach was used to synthesize (+)-α-allokainic acid.
- Hanessian, Stephen,Ninkovic, Sacha
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p. 5418 - 5424
(2007/10/03)
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- Stereoselective synthesis of (±)-α-kainic acid using free radical key reactions
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Thiol-mediated free radical isomerization of a deliberately substituted but-3-enyl isocyanide 12a, and n-Bu3SnH/AIBN-mediated free radical cyclization of a deliberately substituted but-3-enyl isothiocyanate 22, afforded, respectively, the (ethylthio)pyrroline 13a and the thiopyroglutamates 5 and 23. Reduction, protection, and deprotection of these heterocyclic compounds afforded proline derivatives 6 and 25 which contain all the structural elements of α-kainic acid (1) except the C-2 acetic acid moiety. These intermediates were stereospecifically converted into (±)-α-kainic acid using a new method of temporary sulfur connection. Accordingly, CH2CO2Me is linked to the chiral isopropenyl anchor and then intramolecularly connected to the pyrrolidine ring and eventually disconnected from its anchor by a sequential reductive double elimination process in which the isopropenyl double bond is restored.
- Bachi, Mario D.,Bar-Ner, Nira,Melman, Artem
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p. 7116 - 7124
(2007/10/03)
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- A Total Synthesis of (-)-α-Kainic Acid Involving a Pauson-Khand Reaction as the Key Step
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A synthetic route to (-)-α-kainic acid has been developed based on the Pauson-Khand reaction as a key step for the construction of the bicyclic ring system.In this reaction a built-in oxazolidinone ring serves as a rigid template for good diastereofacial selectivity.
- Yoo, Sung-eun,Lee, Sang Hee
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p. 6968 - 6972
(2007/10/02)
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- A Concise, Stereocontrolled Thiazolium Ylide Approach to Kainic Acid
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Racemic α-kainic acid (1) has been prepared from (1SR,2SR,5RS)-ethyl (N-(benzyloxycarbonyl)-3-aza-6-oxobicyclooctane-2-carboxylate (11) in ca. 16percent overall yield via a concise six-step synthetic sequence.Compound 11 is prepared on a large scale in 50percent yield via the cycloaddition of thiazolium ylide 9 and 2-cyclopentenone, which provides the requisite 2,3-trans, 3,4-cis stereochemical array about the trisubstituted pyrrolidine nucleus in 1.Chemoselective addition of the one-to-one adduct of MeLi and TiCl4 to the ketone functionality in 11 followed by dehydration, oxidative ring opening, and nonbasis methylenation of the stereochemically labile C4 acetate moiety with CH2I2-Zn-TiCl4 affords the fully protected penultimate intermediate 17 which is exhaustively hydrolyzed to provide 1.This represents a highly efficient and stereocontrolled preparation of (+/-)-α-kainic acid.
- Monn, James A.,Valli, Matthew J.
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p. 2773 - 2778
(2007/10/02)
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