Synlett 2013; 24(14): 1818-1824
DOI: 10.1055/s-0033-1339347
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Cysteine Protease Inhibitors CPI-2081a and CPI-2081b Using a Controlled SPPS Byproduct Forming Reaction

Amanda M. Heapy
a   School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1010, New Zealand
b   Centre for Brain Research, The University of Auckland, 85 Park Road, Auckland, 1023, New Zealand
,
Mike Dragunow
b   Centre for Brain Research, The University of Auckland, 85 Park Road, Auckland, 1023, New Zealand
,
Margaret A. Brimble*
a   School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1010, New Zealand
b   Centre for Brain Research, The University of Auckland, 85 Park Road, Auckland, 1023, New Zealand
c   School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland, 1010, New Zealand   Fax: +64(9)3737422   eMail: m.brimble@auckland.ac.nz
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Publikationsverlauf

Received: 16. April 2013

Accepted: 10. Juni 2013

Publikationsdatum:
24. Juli 2013 (online)


Abstract

An efficient first synthesis of the cysteine protease inhibitors CPI-2081a and CPI-2081b is described. These naturally occurring penta-peptides exhibit extensive amino acid modifications including N-terminal acylation, S-tert-butylation and C-2 ­p-hydroxy­benzyl alkylation of the tryptophan indole ring in CPI-2081b. Both compounds were synthesised by using Fmoc SPPS. In the case of CPI-2081b a SPPS side reaction was optimized to allow straightforward synthetic access to this p-hydroxybenzylated tryptophan-containing natural product.

Supporting Information

 
  • References and Notes

  • 2 Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
  • 3 Albericio F, Kruger H. Future Med. Chem. 2012; 4: 1527
    • 4a Zompra AZ, Galanis AS, Werbitzky O, Alerricio F. Future Med. Chem. 2009; 1: 361
    • 4b Gracia SR, Grau K, Sewald N. Future Med. Chem. 2009; 1: 1289
  • 5 Singh JP, Tamang S, Rajamohanan PR, Jima NC, Chakraborty G, Kundu GC, Gaikwad SM, Khan MI. J. Med. Chem. 2010; 53: 5121
  • 6 Merrifield RB. J. Am. Chem. Soc. 1963; 85: 2149
  • 7 Isidro-Llobet A, Alvarez M, Albericio F. Chem. Rev. 2009; 109: 2455
    • 8a Majchrzak MW, Zobel JN, Obradovich DJ. Synth. Commun. 1997; 27: 3201
    • 8b Li M, Roswell DF, White EH. Biochem. Biophys. Res. Commun. 1993; 196: 907
    • 8c Ungemach F, Dipierro M, Weber R, Cook JM. Tetrahedron Lett. 1979; 3225
    • 8d Ogawa H, Sasaki T, Irie H, Yajima H. Chem. Pharm. Bull. 1978; 26: 3144
  • 9 Giraud M, Cavelier F, Martinez J. J. Pept. Sci. 1999; 5: 457
  • 10 CPI-2081a (1): The assembled peptide sequence, [Ac-Leu-Cys(tBu)-Trp-Ala-Phe-WANG-PS] was cleaved from the resin by gently agitating with a mixture of TFA/TIS/H2O/2,2′-(ethylenedioxy)diethanethiol (94:1:2.5:2.5, 4 mL) for 3 h. The supernatant containing the crude peptide was isolated from the resin by filtration and the resin was further washed with neat TFA (2 × 1 mL). The TFA filtrate was diluted with H2O and MeCN (1:1, 40 mL), lyophilized to dryness, and purified by HPLC to afford 1 as a colourless solid. [α]D –22.13 (c 0.36, MeOH); IR: 3294, 1640, 1537 cm–1; HRMS (ESI): m/z calcd for C38H53N6O7S: 737.3691; found: 737.3678. See the Supporting Information for complete procedures and analytical data.
  • 11 CPI-2081b (2): The assembled peptide sequence [Ac-Leu-Cys(tBu)-Trp-Ala-Phe-WANG-PS] was cleaved from the resin by gently agitating with neat TFA under a variety of conditions (Table 1). The supernatant containing the crude peptide was isolated from the resin by filtration and the resin was further washed with neat TFA (2 × 1 mL). The TFA filtrate mixture was diluted with H2O and MeCN (1:1, 40 mL), lyophilized to dryness, and purified by flash column silica chromatography. [α]D –17.26 (c 0.17, MeOH); IR: 3313, 1641, 1530 cm–1; HRMS (ESI): m/z calcd C45H58N6NaO8S: 865.3929; found: 865.3932. See the Supporting Information for complete procedures and analytical data.