Synthesis of the Cysteine Protease Inhibitors CPI-2081a and CPI-2081b Using a Controlled SPPS Byproduct Forming Reaction
Received: 16. April 2013
Accepted: 10. Juni 2013
24. Juli 2013 (online)
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.
References and Notes
- 1a Cragg GM, Newman DJ, Snader KM. J. Nat. Prod. 1997; 60: 52
- 1b Newman DJ, Cragg GM. J. Nat. Prod. 2007; 70: 461
- 1c Newman DJ, Cragg GM. Natural Product Chemistry for Drug Discovery . The Royal Society of Chemistry; Cambridge: 2009: 3
- 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.