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Synlett 2012(1): 89-92  
DOI: 10.1055/s-0031-1290091
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Facile N-Urethane-Protected α-Amino/Peptide Thioacid Preparation Using EDC and Na2S

T. M. Vishwanatha, M. Samarasimhareddy, Vommina V. Sureshbabu*
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore - 560 001, India
e-Mail: sureshbabuvommina@rediffmail.com, hariccb@gmail.com, hariccb@hotmail.com; e-Mail: hariccb@hotmail.com;
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Publication History

Received 28 June 2011
Publication Date:
07 December 2011 (online)

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Facile N-Urethane-Protected α-Amino/Peptide Thioacid Preparation Using EDC and Na2SSynlett 2012; 2012(03): 482-482
DOI: 10.1055/s-0030-1290331

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

    References and Notes

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28

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.

29

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.

30

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.

31

Chiral-HPLC analyses were carried out employing Chiralpak IA, 250 × 4.6 mm; solvent: hexane-EtOH (7:3); flow rate: 1.0 mL/min.