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
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General Procedure
for the Preparation of Compounds 3a-e
To
a solution of GSH (1 equiv) in H2 O (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 H2 O
(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)/Na2 HPO4 (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 H2 O, EtOAc,
and hexanes to afford the desired compound.
<A NAME="RS00510ST-19">19 </A>
General Procedure
for the Preparation of Compounds 5a-e
A solution
of 1-acyl-1H -benzotriazole (1 equiv)
in MeCN (5 mL) and Et3 N (2 equiv) was added
to a solution of 3f (1 equiv)
in MeCN-H2 O (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 Et2 O (5 mL) until a friable
solid was formed. The solid was filtered and washed with additional amount
of Et2 O (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 H2 O (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 Et2 O
to afford the desired product.