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DOI: 10.1055/s-0031-1290091
Facile N-Urethane-Protected α-Amino/Peptide Thioacid Preparation Using EDC and Na2S
Publication History
Publication Date:
07 December 2011 (online)
Abstract
We report herein an efficient protocol for the synthesis of N-urethane-protected α-amino/peptide thioacids from their corresponding acids mediated by EDC and Na2S. The fast reaction under mild conditions enabled the process to be completed in shorter duration with good yield circumventing column purification. The chemistry is compatible with a wide variety of urethane protecting groups, side-chain functionalities, and sterically hindered amino acids.
Key words
N-urethane-protected α-amino thioacids - carbodiimides - sodium sulfide
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General Procedure for the Preparation of Peptide Acids
A solution of Nα-protected amino acid (1 mmol) in dry CH2Cl2 (5 mL) was cooled to 0 ˚C, EDC (1 mmol), HOBt (1.2 mmol), and O,N-bis-TMS-amino acid (1.5 mmol) were added. The reaction mixture was stirred for 3-4 h (TLC analysis), and then evaporation of the solvent and acidification with 1 M HCl furnished pure peptide acid.
- 27b For the preparation of O,N-bis-TMS-amino
acids, see:
Tantry SJ.Vasanthakumar G.-R.Sureshbabu VV. Lett. Pept. Sci. 2003, 10: 51
References and Notes
General Procedure
for the Synthesis of Amino/Peptide Thioacids
To
a DMF solution of an acid (1.0 mmol), EDC (1.1 equiv) was added
at 0 ˚C under a nitrogen atmosphere. After stirring
for 10 min, finely ground Na2S (3 equiv) was added to
the reaction mixture which was allowed for stir for 3-4
h until the disappearance of the starting material (TLC analysis).
The residue was dissolved in EtOAc (15 mL), and the solution was
then carefully acidified at 0 ˚C to a pH of 3 by
using 1 M KHSO4. The organic layer was then immediately
separated and removed under reduced pressure. The crude product
was triturated with Et2O or recrystallized with THF-H2O
to obtain pure thioacid.
Fmoc-Ile-COSH
Yellow
solid; mp 81-83 ˚C. IR (KBr): νmax = 1689,
1739, 2550, 3342 cm-¹. R
f
= 0.39
(EtOAc-n-hexane = 60:40).
RP-HPLC: t
R = 15.2
(60-100% MeCN, 30 min). ESI-HRMS:
m/z calcd for C21H23NO3S:
392.1296 [M + Na]+;
found: 392.1290. ¹H NMR (400 MHz, CDCl3): δ = 0.88
(t, J = 5.6 Hz,
3 H), 0.98 (d, J = 3.8
Hz, 3 H), 1.12-1.24 (m, 2 H), 2.38-2.47 (m, 1
H), 4.28 (d, J = 6.7
Hz, 1 H), 4.37 (d, J = 7.1
Hz, 1 H), 4.61 (d, J = 4.4
Hz, 2 H), 5.91 (br s, 1 H), 7.43 (br s, 1 H), 7.26-7.84
(m, 8 H). ¹³C NMR (100 MHz, CDCl3): δ = 10.8, 14.3,
24.1, 37.0, 46.4, 65.9, 72.8, 125.9, 127.3, 128.6, 128.9, 139.2,
142.6, 155.2, 197.2.
Fmoc-Ala-Phe-COSH
White
solid; mp 126-128 ˚C. IR (KBr): νmax = 1681,
1748, 1768, 2549, 3328 cm-¹. R
f
= 0.53
(CHCl3-MeOH = 80:20). RP-HPLC: t
R = 11.4 (60-100% MeCN,
30 min). ESI-HRMS: m/z calcd
for C27H26N2O4S: 497.1511 [M + Na]+; found:
497.1501. ¹H NMR (400 MHz, CDCl3): δ = 1.2
(d, J = 4.8
Hz, 3 H), 2.6 (d, J = 5.6
Hz, 2 H), 2.8 (br s, 1 H), 3.38 (t, J = 7.4
Hz, 1 H), 3.6 (br s, 1 H), 3.9 (t, J = 6.9
Hz, 2 H), 4.1 (m, 1 H), 4.3 (m, 1 H), 6.32 (br s, 1 H), 7.1 (br
s, 1 H), 7.2-7.9 (m, 13 H). ¹³C
NMR (100 MHz, CDCl3): δ = 17.2, 37.4,
46.8, 51.2, 67.9, 69.7, 125.7, 126.8, 127.2, 127.9, 128.4, 128.9,
131.2, 139.1, 141.4, 143.2, 155.7, 172.1, 197.2.
Chiral-HPLC analyses were carried out employing Chiralpak IA, 250 × 4.6 mm; solvent: hexane-EtOH (7:3); flow rate: 1.0 mL/min.