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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

  • 1a Kent SBH. Chem. Soc. Rev.  2009,  38:  338 
    Google Scholar
  • 1b Muir TW. Annu. Rev. Biochem.  2003,  72:  249 
    Google Scholar
  • 2 Crich D. Sasaki K. Rahaman MdY. Bowers AA. J. Org. Chem.  2009,  74:  3886 
    Google Scholar
  • 3a Haung H. Carey RI. J. Peptide Res.  1998,  51:  290 
    Google Scholar
  • 3b Hadad CM. Rablen PR. Wiberg KB. J. Org. Chem.  1998,  63:  8668 
    Google Scholar
  • 4 Barlett KN. Kolakowski RV. Katukojvala S. Williams LJ. Org. Lett.  2006,  8:  823 
    Google Scholar
  • 5a Blake J. Int. J. Pept. Protein Res.  1981,  17:  273 
    Google Scholar
  • 5b Yamashiro D. Blake J. Int. J. Pept. Protein Res.  1981,  18:  383 
    Google Scholar
  • 5c Mitin YV. Zapevalova NP. Int. J. Pept. Protein Res.  1990,  35:  352 
    Google Scholar
  • 6a Wu X. Stockdill JL. Wang P. Danishefsky SJ. J. Am. Chem. Soc.  2010,  132:  4098 
    Google Scholar
  • 6b Rao Yu. Li X. Danishefsky SJ. J. Am. Chem. Soc.  2009,  131:  12924 
    Google Scholar
  • 7a Park S.-D. Oh J.-H. Lim D. Tetrahedron Lett.  2002,  43:  6309 
    Google Scholar
  • 7b Fazio F. Wong C.-H. Tetrahedron Lett.  2003,  44:  9083 
    Google Scholar
  • 7c Mckervey MA. O’Sullivan MB. Mayers PL. Green RH. J. Chem. Soc., Chem. Commun.  1993,  94 
    Google Scholar
  • 8a Shangguna N. Katukojvala S. Greenberg R. Williams LJ. J. Am. Chem. Soc.  2003,  125:  7754 
    Google Scholar
  • 8b Merkx R. van Haren MJ. Rijkers Drik TS. Liskamp RMJ. J. Org. Chem.  2007,  72:  4574 
    Google Scholar
  • 9 Crich D. Sasaki K. Org. Lett.  2009,  11:  3514 
    Google Scholar
  • 10 Assem N. Natarajan A. Yudin AK. J. Am. Chem. Soc.  2010,  132:  10986 
    Google Scholar
  • 11 Crich D. Sharma I. Angew. Chem. Int. Ed.  2009,  48:  2355 
    Google Scholar
  • 12 Fu X. Jiang S. Li C. Xin J. Yang Y. Ji R. Bioorg. Med. Chem. Lett.  2007,  17:  465 
    Google Scholar
  • 13 Kolb J. Beck B. Almstetter M. Heck S. Herdtweck E. Dömling A. Mol. Diversity  2003,  6:  297 
    Google Scholar
  • 14 Yazmin T. Rosa-Bauza Berst F. Ellman JA. ChemBioChem.  2007,  8:  981 
    Google Scholar
  • 15a Le H.-T. Gallard J.-F. Mayer M. Guittet E. Michelot R. Bioorg. Med. Chem.  1996,  4:  2201 
    Google Scholar
  • 15b Hoeg-Jensen T. Jakobsen H. Olsen CE. Holm A. Tetrahedron Lett.  1991,  32:  7617 
    Google Scholar
  • 15c Hoeg-Jensen T. Holm A. Sorensen H. Synthesis  1994,  383 
    Google Scholar
  • 16a Crich D. Sana K. Guo S. Org. Lett.  2007,  9:  4423 
    Google Scholar
  • 16b Crich D. Sharma I. Angew. Chem. Int. Ed.  2009,  48:  2355 
    Google Scholar
  • 17 Rao Y. Li X. Nagorny P. Hayashida J. Danishefsky SJ. Tetrahedron Lett.  2009,  50:  6684 
    Google Scholar
  • 18 Monfardini I. Huang J.-W. Beck B. Cellitti JF. Pellecchai M. Dömling A. J. Med. Chem.  2011,  54:  890 
    Google Scholar
  • 19 Schwabacher AW. Maynard TL. Tetrahedron Lett.  1993,  34:  1269 
    Google Scholar
  • 20 Tan X.-H. Yang R. Wirjo A. Liu C.-F. Tetrahedron Lett.  2008,  49:  2891 
    Google Scholar
  • 21 Zhang X. Lu X.-W. Liu C.-F. Tetrahedron Lett.  2008,  49:  6122 
    Google Scholar
  • 22 Shigenaga A. Sumikawa Y. Tsuda S. Sato S. Otaka A. Tetrahedron  2010,  66:  3290 
    Google Scholar
  • 23a Wang P. Danishefsky SJ. J. Am. Chem. Soc.  2010,  132:  17045 
    Google Scholar
  • 23b Wang P. Li X. Zhu J. Chen J. Yuan Y. Wu X. Danishefsky SJ. J. Am. Chem. Soc.  2011,  133:  1597 
    Google Scholar
  • 24 Pan J. Nelmi O. Devarie B. Xian M. Org. Lett.  2011,  13:  1092 
    Google Scholar
  • 25 Goyal N. Synlett  2010,  335 ; and references cited therein
    Google Scholar
  • 26 Sureshbabu VV. Lalithamba HS. Narandra N. Hemantha HP. Org. Biomol. Chem.  2010,  8:  835 
    Google Scholar
  • 27a

    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 
    Google Scholar
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.