A Facile Synthesis of NODASA-Functionalized Peptide

 

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Abstract

Herein, we report a mild and efficient synthesis of a NODASA-functionalized peptide, which was initiated with a Michael addition reaction between monomethyl fumarate and 1,4,7-triazacyclononane.

• References and Notes

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• 15 General Procedure for the Synthesis of 1-Amino-2-benzyl-15-[4,7-bis(2-tert-butoxy-2-oxoethyl)-1,4,7-triazonan-1-yl]-11-(4-hydroxybenzyl)-1,4,7,10,13-pentaoxo-3,6,9,12-tetra-azahexadecan-16-oic Acid (5) The functionalized peptide on resin 4; 0.0125 mmol was swelled in 1.0 ml CH₂Cl₂ for 5 min followed by filtration, and 1.0 mL of 1 M LiOH (dissolved in MeOH and THF in 1:1 ratio) was added. The reaction was carried out for a period of 30 min at room temperature. The completion of the reaction was monitored by cleaving an aliquot of the compound from the resin and checked by LC–MS as well as analytical HPLC. The resin was washed with about 5.0 mL of THF (2×), DMF (2×), and CH₂Cl₂ (2×) consecutively. Compound 5 (0.0125 mmol) was deprotected and cleaved from the resin using a cocktail of 1.0 mL TFA/H₂O/thioanisole (95:2.5:2.5) over 2 h. The resin was removed by filtration and washed with 1 mL TFA. Further, TFA was evaporated with the aid of N₂ gas bubbling through the mixture. The peptide was then precipitated in 5.0 mL of ice-cold Et₂O. The precipitated peptide was centrifuged and the Et₂O solution was decanted. It was then dissolved in 1.0 mL of water and freeze dried without further purification which gave a yield of 84%. The purity of the synthesis was checked by analytical RP-HPLC which showed 100% purity and characterized by LC–MS. HRMS (ESI⁺): m/z calcd. for C₃₆H₄₉N₈O₁₂ [M + H]: 785.3464; found: 785.3434

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