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.

Key words

amino acids - acylation - glutathione - peptides - drugs

References and Notes

• 1 Pompella A. Visvikis A. Paolicchi A. Tata VD. Casini AF. Biochem. Pharmacol.  2003,  66:  1499 
• 2 Bernardi D. Battaglia E. Krisch G. Bioorg. Med. Chem. Lett.  2006,  16:  1601 
• 3 Al-Timari A. Douglas KT. Biochim. Biophys. Acta  1986,  870:  160 
• 4 Donnerstag B. Ohlenschläger G. Cinatl J. Amrani M. Hofmann D. Flindt S. Treusch G. Träger L. Cancer Lett.  1996,  110:  63 
• 5 Vogel J.-U. Cinatl J. Dauletbaev N. Buxbaum S. Treusch G. Cinatl J. Gerein V. Doerr HW. Med. Microbiol. Immunol.  2005,  194:  55 
• 6 Fraternale A. Paoletti MF. Casabianca A. Orlandi C. Schiavano GF. Chiarantini L. Clayette P. Oiry J. Vogel J.-U. Cinatl J. Magnani M. Antiviral Res.  2008,  77:  120 
• 7 Grillo MP. Hua F. Drug Metab. Dispos.  2003,  31:  1429 
• 8 Bernardi D. Ba LA. Kirsch G. Synthesis  2007,  140 
• 9 Stadtman ER. Methods Enzymol.  1957,  3:  931 
• 10 Galzigna L. inventors; WO  9200320. 
• 11 Clelland JD. Thornalley PJ. J. Chem. Soc., Perkin Trans. 1  1991,  3009 
• 12 Chen H.-JC. Hsieh C.-J. Shen L.-C. Chang C.-M. Biochemistry  2007,  46:  3952 
• 13 Karwatsky J. Daoud R. Cai J. Gros P. Georges E. Biochemistry  2003,  42:  3286 
• 14 Kiwada H, Akimoto M, Araki M, Tsuji M, and Kato Y. inventors; JP  63002922. 
• 15 Katritzky AR. Tala SR. Abo-Dya N. Gyanda K. El-Gendy BE. Abdel-Sammi ZK. Steel PJ. J. Org. Chem.  2009,  74:  7165 
• 16a Katritzky AR. Suzuki K. Wang Z. Synlett  2005,  1656 
• 16b Katritzky AR. Angrish P. Suzuki K. Synthesis  2006,  411 
• 16c Katritzky AR. Angrish P. Hür D. Suzuki K. Synthesis  2005,  397 
• 16d Katritzky AR. Suzuki K. Singh SK. He H.-Y. J. Org. Chem.  2003,  68:  5720 
• 16e Katritzky AR. He H.-Y. Suzuki K. J. Org. Chem.  2000,  65:  8210 
• 16f Katritzky AR. Wang M. Yang H. Zhang S. Akhmedov NG. ARKIVOC  2002,  (viii):  134 
• 16g Katritzky AR. Shestopalov AA. Suzuki K. ARKIVOC  2005,  (vii):  36 
• 16h Katritzky AR. Tala SR. Singh SK. Synthesis  2006,  3231 
• 16i Katritzky AR. Chen Q.-Y. Tala SR. Org. Biomol. Chem.  2008,  6:  2400 
• 16j Katritzky AR. Angrish P. Todadze E. Synlett  2009,  2392 
• 17 Ané A. Josse S. Naud S. Lacône V. Vidot S. Fournial A. Kar A. Pipelier M. Dubreuil D. Tetrahedron  2006,  62:  4784 

18

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.

19

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.