Synthetic Approaches to Kainic acid

And their Biological Relevance

Graduate Seminar

Dubbu Sateesh

13207071

Supervisor: Prof. Y. D. Vankar

Department of Chemistry

IIT Kanpur

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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

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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.

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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).

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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.

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Types of kainoids and their derivatives

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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

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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.

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Types of domoic acid:

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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

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Types of Acromelic acid :

Acromelic acid

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(-)-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 clavulatum12

Isolation of Kainic acid :

Supernatant

Kainic acid containing fraction

Kainic acid

Frozen algal material

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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.

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Kainic acid is an extremely potent neuroexcitor, bindingspecifically at the kainate receptor and leading to specificneuronal death.

Both the anthelmintic and neuroexcitatory properties of kainicacid are dependent on the cis C-3–C-4 relative stereochemistry:allokainic acid, the C-4 epimer, is inactive as an anthelminticand has lower neuroexcitatory activity than kainic acid.

Despite its importance in neuroscience, this compound remains quite expensive due to limited availability.

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Synthetic Approaches to Kainic acid

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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.

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Synthesis:

Oppolzer et al. J. Am. Chem. Soc. 1982, 104, 4978-4979

(-)-Kainic acid

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5% solution

Syn selenoxide eliminationEne reaction

Clayden’s Synthesis

Clayden et al. Chem. Commun., 2000, 317–318

Cumylamine

De-aromatising cyclisation of a lithiated N-benzyl p-anisamide

Synthesis:

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N-benzyl p-anisamide

Clayden et al. Chem. Commun., 2000, 317–318

(-)-Kainic acid

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Syn selenoxide elimination

Lautens’s Synthesis

Lautens et al. Org. Lett., 2005, 7, 3045-3047

Retrosynthesis :

(-)-Kainic acid

N,N-diphenylmethylene cyclopropyl amide

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Diastereoselective methylene cyclopropane ring expansion

Lautens et al. Org. Lett., 2005, 7, 3045-3047

Synthesis:

N,N-diphenylmethylenecyclopropyl amide

Chiral sulfinimine

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Lautens et al. Org. Lett., 2005, 7, 3045-3047

(-)-Kainic acid

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

Retrosynthesis:

Fukuyama’s Synthesis

(-)-Kainic acid

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Claisen-Ireland rearrangement

Synthesis:

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

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

Claisen-Ireland rearrangement

Fukuyama et al. Eur. J. Org. Chem. 2014, 4823-3627

Reductive cleavage

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:

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Noritaka chida et al. Org. Lett. 2010, 12, 24

Synthesis:

D-arabinose

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Overman Rearrangement

Eschenmoser-Claisen Rearrangement

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(-)-Kainic acid

Noritaka chida et al. Org. Lett. 2010, 12, 24

Li’s Synthesis

Retrosynthesis:

Yuanchao Li et al. Org. Lett., 2012, 14, 2540–2543

(-)-Kainic acid

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Intramolecular (3+2) Cycloaddition reaction

Synthesis:

D-serine methyl ester

hydrogen chloride

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Yuanchao Li et al. Org. Lett., 2012, 14, 2540–2543

(-)-Kainic acid

15 steps with overall yield is 24%.

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Retrosynthesis:

Cohen et al. Org. Lett., 2007, 9, 3825-3828

Cohen’s Synthesis

(-)-Kainic acid

The key step Pd-catalyzed Zn-ene cyclization

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Michael addition

Synthesis of KA by using a Pd-Catalyzed Zn-ene Cyclization of an Allyl Sulfone:

Cohen et al. Org. Lett., 2007, 9, 3825-382836

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

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Overall yield of this synthesis is 48%

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

Fukuyama’s Synthesis

Synthetic Plan for (-)-Kainic acid :

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Synthesis:

Fukuyama et al. Org. Lett., 2011, 13, 2068-207040

Curtius rearrangementPinnick oxidation

Fukuyama et al. Org. Lett., 2011, 13, 2068-207041

Conclusion :

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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.

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