Reversible backbone protection enables combinatorial solid-phase ring-closing metathesis reaction (RCM) in peptides

Organic Letters

Volumn 4, Issue 1, 2002, Pages 59-61

  Schmiedeberg, Niko ^a   Kessler, Horst ^a  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALKENE; AMINO ACID; CYCLOPEPTIDE;

ARTICLE; CHEMISTRY; COMBINATORIAL CHEMISTRY; CYCLIZATION; OXIDATION REDUCTION REACTION; SYNTHESIS;

ALKENES; AMINO ACIDS; COMBINATORIAL CHEMISTRY TECHNIQUES; CYCLIZATION; OXIDATION-REDUCTION; PEPTIDES, CYCLIC;

EID: 0037050468     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol016891c     Document Type: Article

References (30)

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3. (a) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606-9614.
4. (b) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, J. P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643.
5. Schafmeister, C. E.; Po, J.; Verdine, G. L. J. Am. Chem. Soc. 2000, 122, 5891-5892.
6. 30).
7. Schmiedeberg, N.; Bürgle, M.; Wilhelm, O. G.; Lottspeich, F.; Graeff, H.; Schmitt, M.; Magdolen, V.; Kessler, H. Peptides for the New Millenium, Proceedings of the 16th American Peptide Symposium, Minneapolis, 1999; Fields, G. B., Tam, J. P., Barany, G., Eds.; Kluwer: Dordrecht, 2000; pp 543-545.
8. Schmiedeberg, N.; Bürgle, M.; Wilhelm, O. G.; Lottspeich, F.; Graeff, H.; Schmitt, M.; Magdolen, V.; Kessler, H. Peptides for the New Millenium, Proceedings of the 16th American Peptide Symposium, Minneapolis, 1999; Fields, G. B., Tam, J. P., Barany, G., Eds.; Kluwer: Dordrecht, 2000; pp 543-545.
9. Automated peptide synthesis was performed via Fmoc/tBu strategy on tritylpolystyrene resin as described in Magdolen, V.; Bürgle, M.; Arroyo de Prada, N.; Schmiedeberg, N.; Riemer, C.; Schroeck, F.; Kellermann, J.; Degitz, K.; Wilhelm, O. G.; Schmitt, M.; Kessler, H. Biol. Chem. 2001, 382, 1197-1205.
10. In a typical RCM reaction, about 130 mg of peptidyl resin (0.17 mmol/g) was suspended in 4 mL of dry DCM under an atmosphere of argon, 30 mg of 1 (0.04 mmol) was added in one portion, and the mixture was shaken at room temperature or refluxed for 12 h. Afterwards the resin was filtered and washed twice with DCM and methanol.
11. (a) Rich, D. H.; Tam, J. P. Tetrahedron Lett. 1977, 9, 749-750.
12. (b) Goldring, W. P. D.; Hodder, A. S.; Weiler, L. Tetrahedron Lett. 1998, 39, 4955-4958.
13. (c) Creighton, C. J.; Reitz, A. B. Org. Lett. 2001, 3, 893-895.
14. (a) Reichwein, J. F.; Wels, B.; Kruijtzer, J. A. W.; Versluis, C.; Liskamp, R. M. J. Angew. Chem., Int. Ed. 1999, 38, 3684-3687.
15. (b) Hirohashi, M.; Tamamura, H.; Otaka, A.; Ibuka, T.; Arakaki, R.; Nakashima, H.; Fujii, N. Peptides, Proceedings of the 25th European Peptide Symposium, Budapest 1998; Bajusz, S., Hudecz, F., Eds.; Akadémiai Kiadó: Budapest, 1999; pp 662-663.
16. (b) Hirohashi, M.; Tamamura, H.; Otaka, A.; Ibuka, T.; Arakaki, R.; Nakashima, H.; Fujii, N. Peptides, Proceedings of the 25th European Peptide Symposium, Budapest 1998; Bajusz, S., Hudecz, F., Eds.; Akadémiai Kiadó: Budapest, 1999; pp 662-663.
17. (a) Haack, T.; Mutter, M. Tetrahedron Lett. 1992, 33, 1589-1592.
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19. (c) Miranda, L. P.; Meutermans, W. D. F.; Smythe, M. L.; Alewood, P. F. J. Org. Chem. 2000, 65, 5460-5468.
20. Me, Mepro)-OH building block was prepared as described in Wöhr, T.; Wahl, F.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X.; Mutter, M. J. Am. Chem. Soc. 1996, 118, 9218-9227 or purchased from NovaBiochem, Läufelfingen.
21. Furthermore, the identical backbone protected but otherwise C-terminal shortened peptidyl resins lacking residues His and Trp already react at room temperature.
22. After the RCM reaction, the cleavage of protected peptides from the resin requires triple treatment with DCM/TFE/HOAc (8:1:1) with extended reaction times of 1 h, respectively.
23. About 40 mg of the crude peptide was dissolved in 2 mL ot ACN/ TEA; 25 equiv DTT was added; the solution was incubated for 2 h, filtered, and dropped in 20 mL of water; and the precipitated peptide was collected by centrifugation, washed with water, and lyophilized from dioxane.
24. Wilhelm, O. G.; Kessler, H.; Bürgle, M.; Potthoff, N.; Schmiedeberg, N. PCT Int. Appl. EP00/06905, 2001.
25. Racemic olefinic amino acids were either purchased as the free amino acid (aminopentenic acid, Aldrich) and subsequently Fmoc protected or synthesized starting from diethyl acetamidomalonate and the appropriate alkenyl bromide as described in Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc., Perkin Trans. 1 1998, 16, 2485-2499. As found in peptidylresins 4 and 5 and in 14 and 16 (using enantiomencally pure allylglycine, x = 1, data not shown), we considered the approach with x = 1 as not suitable for combinatorial purposes because of a too high degree of unreacted peptide in some cases together with very low reaction rates during reduction (see further syntheses of 21-24a,b).
26. Ripka, A. S.; Bohacek, R. S.; Rich, D. H. Bioorg. Med. Chem. Lett. 1998, 8, 357-360 and ref 3b.
27. (a) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron 1976, 32, 2157-2162.
28. (b) Lacombe, P.; Castagner, B.; Gareau, Y.; Ruel, R. Tetrahedron Lett. 1998, 39, 6785-6786.
29. Reference 4. Typically 8 mg of peptide in 500 μL of NMP was added to about 30 equiv of trisylhydrazide and 1.6 equiv of DIEA (referring to trisylhydrazide) and the mixture was shaken at 50°C for 24 h. The procedure was then repeated once for 48 h.
30. 2O, which is mainly responsible for the low yields of the target molecules.