Total synthesis of (±)-dysibetaine CPa

doi:10.1016/j.tetlet.2011.06.034

Tetrahedron Letters

Volume 52, Issue 34, 24 August 2011, Pages 4402-4404

Dedicated to the memory of Professor Tetsuo Shiba

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Abstract

The cyclopropane-containing amino acid, dysibetaine CPa, isolated from Micronesian marine sponge, has been synthesized in 4.53% total yield over 12 steps starting from maleic anhydride to study the biological function in detail, by taking advantage of electron-withdrawing 4-nitrophenyl group.

Graphical abstract

Introduction

Micronesian marine sponge Lendenfeldia chondrodes contains various structurally novel neuroactive amino acids such as dysiherbaines (DHs),¹ dysibetaines (DBs),2, 3 and cribronic acid.⁴ While DH has been shown to be highly potent agonist selective to ionotropic glutamate receptors such as GluR5 and GluR6,⁵ pharmacological activities of the other metabolites have not been well investigated because of the limited quantities that are available. Here, we report the synthesis of (±)-dysibetaine CPa (1),³ (Fig. 1) by the route dysibetaine CPb (2) and various structural analogs would be also synthesized in both racemic and optically active forms, to study the absolute stereochemistry as well as the structure–activity relationships.⁶

Section snippets

Results and discussion

Dysibetaine CPa (1) is an optically active cyclopropane betaine consists of trimethylammonium carboxylate, that contains an additional free carboxylic acid. In this study, we planned to adopt symmetric imide 5 as a synthetic intermediate, so that enantioselective hydrolytic or reductive cleavage can realize the asymmetric synthesis of 1 in the future.

Construction of the succinimide-fused cyclopropane ring was performed first as shown in Scheme 1. Condensation of N-(4-nitrophenyl)maleimide (4),⁷

Conclusion

In summary, we have successfully synthesized dysibetaine CPa (1) in 4.53% total yield over 12 steps starting from maleic anhydride by taking advantage of electron-withdrawing 4-nitrophenyl group. Current efforts are directed toward the synthesis of the analogs¹⁴ and dysibetaine CPb (2) in both racemic and optically active forms, as well as their biological functions.¹⁵

Acknowledgment

Financial support from the Yamada Science Foundation is gratefully acknowledged.

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Citation Excerpt :
Then the absolute stereochemistry was unambiguously determined by single-crystal X-ray diffraction analysis of the 4-bromobenzoate 16 (Scheme 4).21 After substitution of the hydroxy group with bromide (CBr4, PPh3) in 82% yield (3→13, Scheme 3), introduction of quaternary ammonium group was conducted stepwise (Me2NH,3,4 120 °C, 99% for 14; dimethyl sulfate,22 40 °C, 73% for 15) because of the poor reactivity of 13 toward Me3N. Acidic hydrolysis of 15 followed by purification by ion-exchange chromatography (Dowex 1-X8) successfully gave (−)-dysibetaine CPa ((−)-1) in 80% yield.
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Total synthesis of (±)-dysibetaine CPa

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

Acknowledgment

J. Org. Chem.

J. Chem. Soc., Perkin Trans. 1

Tetrahedron

Arch. Pharm. Res.

Tetrahedron Lett.

J. Am. Chem. Soc.

Org. Lett.

Tetrahedron Lett.