A re-evaluation of the use of Rink, BAL, and PAL resins and linkers

QSAR and Combinatorial Science

Volumn 23, Issue 2-3, 2004, Pages 145-152

  Yraola, Francesc ^a   Ventura, Rubén ^a   Vendrell, Marc ^a   Colombo, Aina ^b   Fernàndez, Joan Carles ^b   De La Figuera, Natalia ^b   Fernández Forner, Dolors ^b   Royo, Miriam ^a   Forns, Pilar ^b   Albericio, Fernando ^c,d  

^a Barcelona Science Park   (Spain)

^b Almirall and Prodesfarma ^*  (Spain)

^c BELLVITGE BIOMEDICAL RESEARCH INSTITUTE IDIBELL   (Spain)

^d UNIVERSITY OF BARCELONA   (Spain)

Author keywords

AM Linker; Combinatorial Chemistry; Handle; Side reaction; Solid phase

Indexed keywords

AMINO ACIDS; BIOCHIPS; BYPRODUCTS;

AM LINKER; AMINE DERIVATIVES; BENZYLAMINES; COMBINATORIAL CHEMISTRY; GUANIDINE DERIVATIVE; HANDLE; RE-EVALUATION; SIDE REACTIONS; SOLID PHASIS; SOLID-PHASE;

RESINS;

AMINE; AMINOMETHYL RESIN; BACKBONE AMIDE LINKER RESIN; GUANIDINE DERIVATIVE; PEPTIDE AMIDE LINKER RESIN; PHENYLALANINAMIDE; PHENYLALANINE; RESIN; RINK RESIN; TRYPTOPHANAMIDE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; COMBINATORIAL CHEMISTRY; PRIORITY JOURNAL; PROTON NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS;

EID: 8444252690     PISSN: 1611020X     EISSN: None     Source Type: Journal    
DOI: 10.1002/qsar.200420013     Document Type: Article

References (35)

1. (a) C. Blackburn, F. Albericio, S. A. Kates, Drugs of the Future 1997, 22, 1007-1025;
2. (b) F. Guillier, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091-2157;
3. (c) F. Albericio, E. Giralt, In Houben-Weyl. Methods of Organic Chemistry. Vol. E 22. Synthesis of Peptides and Peptidomimetics (Eds. M. Goodman, A. Felix, L. Moroder, C. Toniolo) Georg Thieme Verlag, Stuttgart, 2001, pp. 685-709.
4. Bradley and co-workers [1b] have proposed defining a linker as an immobilized protecting group. Linkers are classified into two classes: integral linker in which the linker forms part of the solid support core (above, functionalized solid support) or grafted linker in which the linker is attached to the support (above linker or handle).
5. (a) G. Barany, R. B. Merrifield, In The Peptides (Eds. E. Gross, J. Meienhofer) Academic Press, New York, 1979, Vol. 2, pp. 1-284;
6. (b) G. Barany, F. Albericio, In Peptides - Chemistry and Biology: Proceedings of the Thirteenth American Peptide Symposium (Eds. R. S. Hodges, J. A. Smith), ESCOM, Science Publishers, Leiden, The Netherlands, 1994, pp. 1078-1080.
7. (a) F. Albericio, U. Slomczynska, G. Barany, In Forum Peptides Le Cap d'Adge 1984: Proceedings of the 1st International Forum Peptides (eds. B. Castro, and J. Martínez), Les Impressions Dohr, Nancy, France, 1986, pp. 1-5;
8. (b) F. Albericio, G. Barany, Int. J. Peptide Protein Res. 1987, 30, 206-216;
9. (c) F. Albericio, N. Kneib-Cordonier, S. Biancalana, L. Gera, R. I. Masada, D. Hudson, G. Barany, J. Org. Chem. 1990, 55, 3730-3743.
10. Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790.
11. 2 (see Ref. [5]).
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13. (a) K. J. Jensen, J. Alsina, M. F. Songster, J. Vagner, F. Albericio, G. Barany, J. Am. Chem. Soc. 1998, 120, 5441-5452;
14. (b) J. Alsina, K. J. Jensen, F. Albericio, G. Barany, Chem. Eur. J. 1999, 5, 2787-2795.
15. (a) C. G. Boojamra, K. M. Burow, J. A. Ellman, J. Org. Chem. 1995, 60, 5742-5743;
16. (b) D. Fernandez-Forner, J. M. Huerta, M. Ferrer, G. Casals, H. Ryder, E. Giralt, F. Albericio, Tetrahedron Lett. 2002, 43, 3543-3546.
17. A. R. Katritzky, L. Xie, G. Zhang, M. Griffith, K. Watson, J. S. Kiely, Tetrahedron Lett. 1997, 40, 7011-7014.
18. P. Forns, S. Sevilla, M. Erra, A. Ortega, J. C. Fernández, N. de la Figuera, D. Fernández-Forner, F. Albericio, Tetrahedron Lett. 2003, 44, 6907-6910.
19. G. R. Matsueda, J. M. Stewart, Peptides 1981, 2, 45-50.
20. MBHA resins are primarily used for the preparation of peptide amides in a Boc/Bzl strategy. Peptides are released from the resin by treatment with anhydrous HF.
21. Byproducts have been characterized by HPLC-MS and NMR.
22. F. Albericio, G. Barany, Int. J. Peptide Protein Res. 1993, 41, 307-312.
23. Novabiochem 2002/2003 Catalog, pp. 213 and 239.
24. NMR and FABMS showed that the PAL linker was incorporated onto the indole of Trp. (Diagram presentation).
25. (a) E. Atherton, D. L. Clive, R. C. Sheppard, J. Am. Chem. Soc. 1975, 97, 6584-6585;
26. (b) G. R. Matsueda, E. Haber, Anal. Biochem. 1980, 104, 215-227.
27. 2O/DCM, 15:5:5:75) gave neither the target compound nor the byproduct (by HPLC), indicating that these compounds require a high TFA concentration to be cleaved from the resin.
28. XAL-linker (Y. Han, S. L. Botems, M. C. Munson, C. A. Minor, S. A. Kates, F. Albericio, G. Barany, J. Org. Chem. 1996, 61, 6326-6339), which was developed from the XAL resin (P. Sieber, Tetrahedron Lett. 1987, 28, 2107-2110), is similar to Rink and PAL-systems but amides are released with <5% of TFA. Diagram presentation).
29. XAL-linker (Y. Han, S. L. Botems, M. C. Munson, C. A. Minor, S. A. Kates, F. Albericio, G. Barany, J. Org. Chem. 1996, 61, 6326-6339), which was developed from the XAL resin (P. Sieber, Tetrahedron Lett. 1987, 28, 2107-2110), is similar to Rink and PAL-systems but amides are released with <5% of TFA. Diagram presentation).
30. 6a, b (acyl and Fmoc derivatives) could only be released from the corresponding resins with 95% TFA, indicating that the presence of the free amine function makes the bond between the Trp and the linker more acid stable.
31. It is known that primary amines (from amino acids) can not easily be released from BAL resin. Thus, t-butyl-protected amino acids were incorporated into a BAL resin by a reductive amination and subsequent treatment with neat TFA (6 × 10 min, 25°C) removed the t-butyl group without cleavage of the amino acids anchored to the BAL resin: J. Alsina, T. S. Yokum, F. Albericio, G. Barany, Tetrahedron Lett. 2000, 41, 7277-7280.
32. While MBHA resin liberates amide peptides by treatment with anhydrous HF (see refs. [12,13]), the aminomethyl resin developed by Mitchell et al. (A. R. Mitchell, S. B. H. Kent, B. W. Erickson, R. B. Merrifield, Tetrahedron Lett. 1976, 42, 3795-3798) is totally stable to HF.
33. S. Kobayashi, M. Moriwaki, Tetrahedron Lett. 1997, 38, 4251-4254.
34. S. Löeber, P. Rodriguez-Loaiza, P. Gmeiner, Org. Lett. 2003, 5, 1753-1755
35. M. del Fresno, A. El-Faham, L. A. Carpino, M. Royo, F. Albericio, Org. Lett. 2000, 2, 3539-3542.