Occurrence and Minimization of Cysteine Racemization during Stepwise Solid-Phase Peptide Synthesis

Journal of Organic Chemistry

Volumn 62, Issue 13, 1997, Pages 4307-4312

  Han, Yongxin ^a,c   Albericio, Fernando ^b   Barany, George ^a  

^a University of Minnesota   (United States)

^b UNIVERSITY OF BARCELONA   (Spain)

^c HYBRIDON INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000277428     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo9622744     Document Type: Article

References (48)

1. Reviews: (a) Bodanszky, M. Principles of Peptide Synthesis, 2nd ed.; Springer-Verlag: Berlin, 1993. (b) Sakakibara, S. Biopolymers Wept, Sci.) 1995, 37, 17-28.
2. Reviews: (a) Bodanszky, M. Principles of Peptide Synthesis, 2nd ed.; Springer-Verlag: Berlin, 1993. (b) Sakakibara, S. Biopolymers Wept, Sci.) 1995, 37, 17-28.
3. Reviews: (a) Barany, G.; Merrifield, R. B. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, NY, 1979; Vol. 2, pp 1-284, (b) Atherton, E.; Sheppard, R. C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press: Oxford, 1989. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides. A User's Guide; Grant, G. A., Ed.; W. H. Freeman and Co.: New York, 1992; pp 77-183. Merrifield, B. In Peptides: Synthesis, Structures, and Applications; Gutte, B., Ed.; Academic Press, Inc.: San Diego, CA, 1995; pp 93-169.
4. Reviews: (a) Barany, G.; Merrifield, R. B. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, NY, 1979; Vol. 2, pp 1-284, (b) Atherton, E.; Sheppard, R. C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press: Oxford, 1989. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides. A User's Guide; Grant, G. A., Ed.; W. H. Freeman and Co.: New York, 1992; pp 77-183. Merrifield, B. In Peptides: Synthesis, Structures, and Applications; Gutte, B., Ed.; Academic Press, Inc.: San Diego, CA, 1995; pp 93-169.
5. Reviews: (a) Barany, G.; Merrifield, R. B. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, NY, 1979; Vol. 2, pp 1-284, (b) Atherton, E.; Sheppard, R. C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press: Oxford, 1989. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides. A User's Guide; Grant, G. A., Ed.; W. H. Freeman and Co.: New York, 1992; pp 77-183. Merrifield, B. In Peptides: Synthesis, Structures, and Applications; Gutte, B., Ed.; Academic Press, Inc.: San Diego, CA, 1995; pp 93-169.
6. Reviews: (a) Barany, G.; Merrifield, R. B. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, NY, 1979; Vol. 2, pp 1-284, (b) Atherton, E.; Sheppard, R. C. Solid Phase Peptide Synthesis: A Practical Approach; IRL Press: Oxford, 1989. Fields, G. B.; Tian, Z.; Barany, G. In Synthetic Peptides. A User's Guide; Grant, G. A., Ed.; W. H. Freeman and Co.: New York, 1992; pp 77-183. Merrifield, B. In Peptides: Synthesis, Structures, and Applications; Gutte, B., Ed.; Academic Press, Inc.: San Diego, CA, 1995; pp 93-169.
7. Review: Kemp, D. S. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, NY, 1979; Vol. 1, pp 315-381.
8. (a) Bodanszky, M.; Bodanszky, A. Chem. Commun. 1967, 591-592.
9. (b) Kovacs, J.; Mayers, G. L.; Johnson, R. H.; Ghatak, U. R. Chem. Commun. 1968, 1066-1067.
10. (c) Mayers, G. L.; Kovacs, J. Chem. Commun. 1970, 1145-1146.
11. (d) Kovacs, J.; Mayers, G. L.; Johnson, R. H.; Cover, R. E.; Ghatak, U. R. J. Org. Chem. 1970, 35, 1810-1815.
12. (e) Barber, M.; Jones, J. H.; Witty, M. J. J. Chem. Soc., Perkin Trans. 1 1979, 2425-2428.
13. (a) Atherton, E.; Hardy, P. M.; Harris, D. E.; Matthews, B. H. in Peptides 1990: Proceedings of the Twenty-First European Peptide Symposium; Giralt, E., Andreu, D., Eds.; ESCOM Science Publishers: Leiden, The Netherlands, 1991; pp 243-244.
14. (b) Fujiwara, Y.; Akaji, K.; Kiso, Y. In Peptide Chemistry 1993; Okada, Y., Ed.; Protein Research Foundation: Osaka, 1994; pp 29-32.
15. (a) Solé, N. A.; Han, Y.; Vágner, J.; Gross, C. M.; Tejbrant, J.; Barany, G. In Peptides-Chemistry, Structure and Biology: Proceedings of the Fourteenth American Peptide Symposium; Kaumaya, P. T. P., Hodges, R. S., Eds.; Mayflower Scientific Ltd.: Kingswinford, England, 1996; pp 113-114.
16. (b) Han, Y.; Barany, G. J. Org. Chem. 1997, 62, 3841.
17. (a) Hudson, D. J. Org. Chem. 1988, 53, 617-624,
18. (b) Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; Gera, L.; Masada, R. I.; Hudson, D.; Barany, G. J. Org. Chem. 1990, 55, 3730-3743.
19. Independent of our work, cysteine racemization in stepwise Fmoc solid-phase peptide synthesis has been noted and discussed: (a) Musiol, H.-J.; Siedler, F.; Quarzago, D.; Moroder, L. Biopolymer 1994, 34, 1553-1562. (b) Kaiser, T.; Nicholson, G.; Kohlbau, H. J.; Voelter, W. Tetrahedron Lett. 1996, 37, 1187-1190.
20. Independent of our work, cysteine racemization in stepwise Fmoc solid-phase peptide synthesis has been noted and discussed: (a) Musiol, H.-J.; Siedler, F.; Quarzago, D.; Moroder, L. Biopolymer 1994, 34, 1553-1562. (b) Kaiser, T.; Nicholson, G.; Kohlbau, H. J.; Voelter, W. Tetrahedron Lett. 1996, 37, 1187-1190.
21. Review: Andreu, D.; Albericio, F.; Solé, N. A.; Munson, M. C.; Ferrer, M.; Barany, G. In Methods in Molecular Biology, Pennington, M. W., Dunn, B. M., Eds.; Humana Press: Totowa, NJ, 1994; Vol. 35; pp 91-169.
22. Assemblies of linear and cyclized oxytocin by Fmoc chemistry, using a variety of coupling protocols, have been described in ref 10b and several earlier publications from our laboratory: (a) Albericio, F.; Hammer, R. P.; García-Echeverría, C.; Molins, M. A.; Chang, J. L.; Munson, M. C.; Pons, M.; Giralt, E.; Barany, G. Int. J. Peptide Protein Res. 1991, 37, 402-413. (b) Munson, M. C.; García-Eeheverria, C.; Albericio, F.; Barany, G. J. Org. Chem. 1992, 57, 3013-3018. Han, Y.; Bontems. S. L.; Hegyes, P.; Munson, M. C.; Minor, C. A.; Kates, S. A.; Albericio, F.; Barany, G. J. Org. Chem. 1996, 61, 6326-6339,
23. Assemblies of linear and cyclized oxytocin by Fmoc chemistry, using a variety of coupling protocols, have been described in ref 10b and several earlier publications from our laboratory: (a) Albericio, F.; Hammer, R. P.; García-Echeverría, C.; Molins, M. A.; Chang, J. L.; Munson, M. C.; Pons, M.; Giralt, E.; Barany, G. Int. J. Peptide Protein Res. 1991, 37, 402-413. (b) Munson, M. C.; García-Eeheverria, C.; Albericio, F.; Barany, G. J. Org. Chem. 1992, 57, 3013-3018. Han, Y.; Bontems. S. L.; Hegyes, P.; Munson, M. C.; Minor, C. A.; Kates, S. A.; Albericio, F.; Barany, G. J. Org. Chem. 1996, 61, 6326-6339,
24. Assemblies of linear and cyclized oxytocin by Fmoc chemistry, using a variety of coupling protocols, have been described in ref 10b and several earlier publications from our laboratory: (a) Albericio, F.; Hammer, R. P.; García-Echeverría, C.; Molins, M. A.; Chang, J. L.; Munson, M. C.; Pons, M.; Giralt, E.; Barany, G. Int. J. Peptide Protein Res. 1991, 37, 402-413. (b) Munson, M. C.; García-Eeheverria, C.; Albericio, F.; Barany, G. J. Org. Chem. 1992, 57, 3013-3018. Han, Y.; Bontems. S. L.; Hegyes, P.; Munson, M. C.; Minor, C. A.; Kates, S. A.; Albericio, F.; Barany, G. J. Org. Chem. 1996, 61, 6326-6339,
25. (a) Barany, G.; Albericio, F.; Solé, N. A.; Griffin., G. W.; Kates, S. A.; Hudson, D. In Peptides 1992: Proceedings of the Twenty-Second European Peptide Symposium; Schneider C. H., Eberle, A. N., Eds.; ESCOM Science Publishers: Leiden, The Netherlands, 1993; pp 267-268,
26. (b) Zalipsky, S.; Chang, J. L.; Albericio, F.; Barany, G. Reactive Polymers 1994, 22, 243-258 and references cited therein.
27. (a) Friedman, M.; Krull, L. H.; Cavins, J. F. J. Biol. Chem. 1970, 245, 3868-3871.
28. (b) Nimura, N.; Ogura, H.; Kinoshita, T. J. Chromatogr. 1980, 202, 375-379.
29. (c) Kinoshita, T.; Kasahara, Y.; Nimura, N. J. Chromatogr. 1981, 210, 77-81.
30. (d) Brückner, H.; Keller-Hoehl, C. Chromatographia 1990, 30, 621-629.
31. (e) Adamson, G. J.; Hoang, T.; Crivici, A.; Lajoie, G. A. Anal. Biochem. 1992, 202, 210-214.
32. (f) Siedler, F.; Weyher, E.; Moroder, L. J. Pept. Sci, 1996, 2, 271-275.
33. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
34. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
35. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
36. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
37. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
38. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
39. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
40. The development and applications of the revelant coupling reagents are reported by the following: (a) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219-1222. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 1269-1272. Hudson, D. J. Org. Chem. 1988, 53, 617-624. Foumier, A.; Wang, C. T.; Felix, A. M. Int. J. Pept. Protein Res. 1988, 31, 86-97. (e) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1219-1222. (f) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398. (g) Carpino, L. A.; El-Fahan, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203. (h) Kates, S. A.; Minor, C. A.; Shroff, H.; Haaseth, R. C.; Triolo, S.; El-Faham, A.; Carpino, L. A.; Albericio, F. In Peptides 1994: Proceedings of the Twenty-Third European Peptide Symposium; Maia, H. L. S., Ed.; ESCOM Science Publishers: Leiden, The Netherlands, 1995; pp 248-249.
41. Although initial reports (ref 17e-g) snowed the structures of HBTU and HATU as uronium salts, it has been shown more recently that both compounds crystallize as aminium salts (guanidinium N-oxides). See: (a) Abdelmoty, I.; Albericio, F.; Carpino, L. A.; Foxman, B. M.; Kates, S. A. Lett. Pept. Sci. 1994, 1, 57-67. (b) Henklein, P.; Costisella, B.; Wray, V.; Domke, T.; Carpino, L. A.; El-Faham, A.; Kates, S. A.; Abdelmoty, I.; Foxman, B. M. In Peptides 1996: Proceedings of the Twenty-Fourth European Peptide Symposium; Ramage, R., Epton, R., Eds.; Mayflower Scientific Ltd.: Kingswinford, England, 1996; in press.
42. Although initial reports (ref 17e-g) snowed the structures of HBTU and HATU as uronium salts, it has been shown more recently that both compounds crystallize as aminium salts (guanidinium N-oxides). See: (a) Abdelmoty, I.; Albericio, F.; Carpino, L. A.; Foxman, B. M.; Kates, S. A. Lett. Pept. Sci. 1994, 1, 57-67. (b) Henklein, P.; Costisella, B.; Wray, V.; Domke, T.; Carpino, L. A.; El-Faham, A.; Kates, S. A.; Abdelmoty, I.; Foxman, B. M. In Peptides 1996: Proceedings of the Twenty-Fourth European Peptide Symposium; Ramage, R., Epton, R., Eds.; Mayflower Scientific Ltd.: Kingswinford, England, 1996; in press.
43. Collidine (TMP) was recommended by Carpino as a useful base to minimize racemization in HATU-mediated coupling of peptide segments: Carpino, L. A.; El-Faham, A. J. Org. Chem. 1994, 59, 695-698.
44. Kuroda, H.; Chen, Y.; Kimura, T.; Sakakibara, S. Int. J. Peptide Protein Res. 1992, 40, 294-299.
45. (a) Rich, D. H.; Singh, J. In The Peptides; Gross, E., Meienhofer, J., Eds.; Academic Press: New York, 1979; Vol. 1, pp 241-261.
46. (b) Merrifield, R. B.; Vizioli, L.D.; Boman, H. G. Biochemistry 1982, 21, 5020-5031.
47. Kisfaludy, L.; Schön, I. Synthesis 1983, 325-427.
48. Fmoc-Cys(Trt)-OPfp and Fmoc-Cys(Acm)-OPfp were commercially available, and Fmoc-Cys(Xan)-OPfp and Fmoc-Cys(Tmob)-OPfp were prepared as described in the Experimental Section.