Kainic acid and Biological importence

Views:
 
Category: Entertainment
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

Slide 1:

Synthetic Approaches to Kainic acid And their Biological Relevance Graduate Seminar Dubbu Sateesh 13207071 Supervisor: Prof. Y. D. Vankar Department of Chemistry IIT Kanpur 1

Slide 2:

Outline : History of Kainoids Biological importance of Kainoids Types of Kainoids and their derivatives Introduction of Kainic acid Synthetic approaches to Kainic acid Isolation of Kainic acid 2

Slide 3:

History of kainoids : Kainiod was originally isolated from seaweed  in 1953 . It was  called " Kainin-sou " or " Makuri " in Japan . " Kainin-sou " is used as an  anthelmintic  in Japan. All kainoids are neuroactive . The structure of Kainic acid is closely related to other excitatory amino acids, such as domoic acid and acromelic acid and thus these compounds are often categorized as kainoids . Kainoids are a naturally occurring pyrrolidine with dicarboxylic acid substituents at C-2, C-3 and alkyl group at C-4 position. 3

Slide 4:

Biological Importance of kainoids Kainoids has been aroused by their potent biological effects of Insecticidal and Anthelmintic (anti-intestinal worm) properties have long been reported and applied therapeutically . Kainoid has been widely used as a tool in neuropharmacology for simulating central nervous system (CNS) disorders, such as epilepsy, Alzheimer’s disease, and Huntington’s chorea. Kainoid exerts its neuroexcitotoxic and epileptogenic properties by acting on kainate receptors (KARs). 4

Slide 5:

The mode of kainoid biological action is thought to arise from their structural similarity to glutamic acid of a mammalian central nervous system neurotransmitter. Binding is influenced strongly by C4 stereochemistry, C4 substituent and molecular conformation. 5

Slide 6:

Types of kainoids and their derivatives 6

Slide 7:

Domoic acid: Domoic acid, was first isolated in 1958 from a Japanese red alga Chondria armata by Daigo and co-workers. In the late 1980 Nomoto and co-workers reported the isolation of isodomoic acids A, B, C and D and domoilactones from the same organism. Chondria armata in sea Chondria armata in Herbarium sheet 7

Slide 8:

Wright and co-workers isolated domoic acid, the C(5’)- epimer of domoic acid, as well as isodomoic acids D-F, from cultivated mussels Mytilus edulis in Canada. Recently, Arakawa and co-workers isolated isodomoic acids G and H from Chondria armata . Domoic acid, as well as isodomoic acids A-C, have been shown to exhibit a very strong insecticidal property against American cockroaches Periplaneta americana . 8

Slide 9:

Types of domoic acid: 9

Slide 10:

Acromelic acid: In 1983, Shirahama and Matsumoto isolated Acromelic acid A and Acromelic acid B from Clitocybe acromelalga (Japanese name, dokusasako ) These amino acids exhibit remarkably potent neuro -excitatory activity via activation of ionotropic glutamate receptors in the brain. Acromelic acids are almost more potent than domoic acid and kainic acid Clitocybe acromelalga 10

Slide 11:

Types of Acromelic acid : Acromelic acid 11

Slide 12:

(-)- Kainic acid was first isolated by Murakami and co-workers in 1953 from the Japanese marine algae Digenea simplex. Introduction of Kainic acid: Digenea simplex Centrocerus clavulatum 12

Slide 13:

Isolation of Kainic acid : Supernatant Kainic acid containing fraction Kainic acid Frozen algal material 13

Slide 14:

Kainic acid has also been isolated from other species of red algae, such as Alsidium helminthochorton ( Calaf et al. 1989), Caloglossa leprieurii (Pei-Gen and Shan-Lin 1986), Centroceras clavulatum ( Impellizezeri et al. 1975), and certain strains of Palmaria palmata ( Laycook et al. 1989). Kainic acid was used as an antihelminth compound to remove worms from the gut. Aqueous extracts of this alga have been used in East Asian countries as vermifuge medicines. 14

Slide 15:

Kainic acid is an extremely potent neuroexcitor , binding specifically at the kainate receptor and leading to specific neuronal death. Both the anthelmintic and neuroexcitatory properties of kainic acid are dependent on the cis C-3–C-4 relative stereochemistry: allokainic acid, the C-4 epimer , is inactive as an anthelmintic and has lower neuroexcitatory activity than kainic acid. Despite its importance in neuroscience, this compound remains quite expensive due to limited availability. 15

Synthetic Approaches to Kainic acid:

Synthetic Approaches to Kainic acid 16

Slide 17:

Oppolzer’s Synthesis key step for this synthesis is Stereocontrolled intramolecular ene reaction. Oppolzer et al . J. Am. Chem. Soc . 1982 , 104 , 4978-4979 The first enantioselective synthesis of kainic acid was developed by Oppolzer and co-workers. 17

Slide 18:

Synthesis : Oppolzer et al . J. Am. Chem. Soc . 1982 , 104 , 4978-4979 (-)- Kainic acid 18 5% solution Syn selenoxide elimination Ene reaction

Slide 19:

Clayden’s Synthesis Clayden et al. Chem. Commun ., 2000 , 317–318 C umylamine De- aromatising cyclisation of a lithiated N-benzyl p - anisamide Synthesis: 19 N-benzyl p - anisamide

Slide 20:

Clayden et al. Chem. Commun ., 2000 , 317–318 (-)- Kainic acid 20 Syn selenoxide elimination

Slide 21:

Lautens’s Synthesis Lautens et al . Org. Lett ., 2005, 7 , 3045-3047 Retrosynthesis : (-)- Kainic acid N,N- diphenylmethylene cyclopropyl amide 21 Diastereoselective methylene cyclopropane ring expansion

Slide 22:

Lautens et al . Org. Lett ., 2005, 7 , 3045-3047 Synthesis: N,N - diphenylmethylene cyclopropyl amide Chiral sulfinimine 22

Slide 23:

Lautens et al . Org. Lett ., 2005, 7 , 3045-3047 (-)- Kainic acid 23

Slide 24:

Fukuyama et al. Eur. J. Org. Chem. 2014 , 4823-36 Retrosynthesis : Fukuyama’s Synthesis (-)- Kainic acid 24 Claisen -Ireland rearrangement

Slide 25:

Synthesis: Fukuyama et al. Eur. J. Org. Chem. 2014 , 4823-36 25

Slide 26:

Fukuyama et al. Eur. J. Org. Chem. 2014 , 4823-36 26 Claisen -Ireland rearrangement

Slide 27:

Fukuyama et al. Eur. J. Org. Chem. 2014 , 4823-36 27 Reductive cleavage

Chida’s Synthesis:

Chida’s Synthesis Readily available and inexpensive starting material D- arabinose The key step Claisen & Overman rearrangement. Noritaka chida et al. Org. Lett . 2010 , 12 , 24 Synthetic Plan towards (-)- Kainic acid: 28

Slide 29:

Noritaka chida et al. Org. Lett . 2010 , 12 , 24 Synthesis: D- arabinose 29

Slide 30:

30 Overman Rearrangement Eschenmoser-Claisen Rearrangement

Slide 31:

31 (-)- Kainic acid Noritaka chida et al. Org. Lett . 2010 , 12 , 24

Slide 32:

Li’s Synthesis Retrosynthesis : Yuanchao Li et al . Org. Lett., 2012 , 14 , 2540–2543 (-)- Kainic acid 32 Intramolecular (3+2) Cycloaddition reaction

Slide 33:

Synthesis: D-serine methyl ester hydrogen chloride 33

Slide 34:

Yuanchao Li et al . Org. Lett., 2012 , 14 , 2540–2543 (-)- Kainic acid 15 steps with overall yield is 24%. 34

Slide 35:

Retrosynthesis : Cohen et al. Org. Lett., 2007, 9 , 3825-3828 Cohen’s Synthesis (-)- Kainic acid The key step Pd-catalyzed Zn- ene cyclization 35 Michael addition

Slide 36:

Synthesis of KA by using a Pd-Catalyzed Zn- ene Cyclization of an Allyl Sulfone : Cohen et al. Org. Lett., 2007, 9 , 3825-3828 36

Slide 37:

Synthesis of KA by using a Pd-Catalyzed Zn- ene Cyclization of an Allyl Chloride: Cohen et al. Org. Lett., 2007, 9 , 3825-3828 37

Slide 38:

38 Overall yield of this synthesis is 48%

Slide 39:

Fukuyama et al. Org. Lett., 2011 , 13, 2068-2070 Fukuyama’s Synthesis Synthetic Plan for (-)- Kainic acid : 39

Slide 40:

Synthesis : Fukuyama et al. Org. Lett., 2011 , 13, 2068-2070 40 Curtius rearrangement Pinnick oxidation

Slide 41:

Fukuyama et al. Org. Lett., 2011 , 13, 2068-2070 41

Slide 42:

Conclusion : 42 Different types of Kainoids and their biological importance have been discussed. Domoic acid, Acromelic acid and kainic acids are known to have neuroexcitatory properties , and are being used for the treatment of epilepsy disease. Due to their limited availability from natural sources, synthesis of these Kainoids is quite challenging due to its highly functionalized trisubstituted pyrrolidine ring with three contiguous chiral centers. In literature, several total syntheses and synthetic approaches are known which involve minimum 15 steps and still there is a huge scope for the synthetic organic chemists to develop novel synthesis with minimum number of steps.

Slide 43:

43

authorStream Live Help