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Synlett 2010(9): 1337-1340  
DOI: 10.1055/s-0029-1219837
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Efficient and Selective Syntheses of S-Acyl and N-Acyl Glutathiones

Alan R. Katritzky*a, Nader E. Abo- Dyaa,b, Srinivasa R. Talaa, Ebrahim H. Ghazvini-Zadeha, Kiran Bajaja, Said A. El-Fekyb
a Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax: +1(352)3929199; e-Mail: katritzky@chem.ufl.edu;
b Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
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Publication History

Received 8 February 2010
Publication Date:
16 April 2010 (online)

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Abstract

Selective syntheses of S-acyl glutathiones are achieved in 79-98% yields using 1-acyl-1H-benzotriazoles in the presence of potassium bicarbonate in aqueous methanol at 20 ˚C. N-Acylation of S-(p-nitrobenzoyl) glutathione with 1-acyl-1H-benzotriazoles followed by deprotection of the p-nitrobenzoyl groups under mild conditions gave 63-78% yields of N-acyl glutathiones. These methodologies should be useful for the S-acylation and N-acylation of peptides and glycopeptides.

Key words

amino acids - acylation - glutathione - peptides - drugs

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General Procedure for the Preparation of Compounds 3a-e
To a solution of GSH (1 equiv) in H2O (3 mL), a solution of 1-acyl-1H-benzotriazole (1 equiv) in MeOH (8 mL) was added, and the mixture was stirred for 5 min at r.t. An aq KHCO3 solution (2 equiv) in H2O (1 mL) was added dropwise to the reaction mixture at a rate of 0.2 mL/min. The reaction progress was monitored by TLC (disappearance of 1-acyl-1H-benzotriazoles, which have R f values in the range from 0.6-0.7 using solvent mixture of hexanes-EtOAc (2:1) as eluent; together with the appearance of benzotriazole at R f value 0.45), which indicated the completion of the reaction within 10-15 min. MeOH was evaporated under reduced pressure and dilute HCl (6 M)/Na2HPO4 (1 N) was added until pH of the mixture was adjusted to 5. The precipitate formed was collected on a Buchner funnel, was washed with H2O, EtOAc, and hexanes to afford the desired compound.

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General Procedure for the Preparation of Compounds 5a-e A solution of 1-acyl-1H-benzotriazole (1 equiv) in MeCN
(5 mL) and Et3N (2 equiv) was added to a solution of 3f
(1 equiv) in MeCN-H2O (1 mL - 2 drops). The reaction mixture was stirred at r.t. for 1.5 h. After completion of the reaction (by TLC as described above for compounds 3a-e), the pH was adjusted to 3 using HCl (6 M). MeCN was evaporated under reduced pressure, and the resulting crude was triturated with Et2O (5 mL) until a friable solid was formed. The solid was filtered and washed with additional amount of Et2O (2 mL) and dried to give the desired compound.

20

General Procedure for the Preparation of Compounds 6a-e
Pyrrolidine (3 equiv) was added to a stirred solution of 5a-e (1 equiv) in anhyd THF and MeOH (3:1, 4 mL). The mixture was stirred at 20 ˚C for 4 h. The solvents were then evaporated, and the resulting crude solid was dissolved in H2O (2 mL) and MeOH (0.2 mL). The resulting solution was acidified to pH 1 using HCl (6 M) and stirred for 30 min. The precipitate was filtered and washed with Et2O to afford the desired product.