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

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.

amino acids - acylation - glutathione - peptides - drugs

References and Notes

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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.

<A NAME="RS00510ST-20">20</A>

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.