Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis

Angewandte Chemie - International Edition

Volumn 37, Issue 23, 1998, Pages 3281-3284

  Blackwell, Helen E ^a   Grubbs, Robert H ^a  

^a California Institute of Technology   (United States)

Author keywords

Carbene complexes; Helical structures; Macrocycles; Metathesis; Peptides

Indexed keywords

HEPTAPEPTIDE; MACROCYCLIC COMPOUND; OLIGOPEPTIDE; PEPTIDE; POLYPEPTIDE ANTIBIOTIC AGENT; SYNTHETIC PEPTIDE;

ARTICLE; CIRCULAR DICHROISM; COMPLEX FORMATION; CRYSTAL STRUCTURE; PEPTIDE ANALYSIS; PEPTIDE SYNTHESIS; X RAY CRYSTALLOGRAPHY;

EID: 0032542374     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1521-3773(19981217)37:23<3281::AID-ANIE3281>3.0.CO;2-V     Document Type: Article

References (50)

1. The α-helical conformation is adopted by 40% of all residues in proteins. See: T. E. Creighton, Proteins: Structures and Molecular Properties, 2nd ed., Freeman, New York, 1984, pp. 182-188.
2. D. S. Kemp, T. P. Curran, J. G. Boyd, T. J. Allen, J. Org. Chem. 1991, 56, 6683-6697, and references therein.
3. a) B. Forood, E. J. Feliciano, K. P. Nambiar, Proc. Natl. Acad. Sci. USA 1994, 90, 838-842;
4. b) H. X. Zhou, P. C. Lyu, D. E. Wemmer, N. R. Kallenbach, J. Am. Chem. Soc. 1994, 116, 1139-1140.
5. K. R. Schoemaker, P. S. Kim, E. J. York, J. M. Stewart, R. L. Baldwin, Nature 1987, 326, 563-567.
6. J. M. Scholtz, H. Qian, V. H. Robbins, R. L. Baldwin, Biochemistry 1993, 32, 9668-9676, and references therein.
7. J. C. Phelan, N. J. Skelton, A. C. Braisted, R. S. McDowell, J. Am. Chem. Soc. 1997, 119, 455-460, and references therein.
8. D. Y. Jackson, D. S. King, J. Chmielewski, S. Singh, P. G. Schultz, J. Am. Chem. Soc. 1991, 113, 9391-9392.
9. J. S. Albert, A.D. Hamilton, J. Am. Chem. Soc. 1995, 34, 984-990.
10. a) R. J. Todd, M. E. Van Dam, D. Casimiro, B. L. Haymore, F. H. Arnold, Proteins: Struct. Funct. Genet. 1991, 10, 156-161;
11. b) M. R. Ghadiri, A. K. Fernholz, J. Am. Chem. Soc. 1990, 112, 9633-9635.
12. a) S. R. Gilbertson, X. Wang, J. Org. Chem. 1996, 61, 434-435;
13. b) F. Ruan, Y. Chen, P. B. Hopkins, J. Am. Chem. Soc. 1990, 112, 9403-9404.
14. 3 = Tricyclohexylphosphane. For the synthesis of 1, see: T. E. Wilhelm, T. R. Belderrain, S. N. Brown, R. H. Grubbs, Organometallics 1997, 18, 3867-3869, and references therein.
15. a) F. P. J. T. Rutjes, H. E. Schoemaker, Tetrahedron Lett. 1997, 48, 677-680;
16. b) S. J. Miller, R. H. Grubbs, J. Am. Chem. Soc. 1995, 117, 5855-5856.
17. a) B. E. Fink, P. R. Kym, J. A. Katzenellenbogen, J. Am. Chem. Soc. 1998, 120, 4334-4344;
18. b) J. Pernerstorfer, M. Schuster, S. Blechert, Chem. Commun. 1997, 1949-1950;
19. c) S.J. Miller, H.E. Blackwell, R. H. Grubbs, J. Am. Chem. Soc. 1996, 118, 9609-9614.
20. T. D. Clark, M. R. Ghadiri, J. Am. Chem. Soc. 1995, 117, 12364-12365.
21. For a recent review of olefin metathesis in organic synthesis, see : R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413-4450.
22. I. L. Karle, P. Balaram, Biochemistry 1990, 29, 6747-6756.
23. a) I. L. Karle, J. L. Flippen-Anderson, K. Uma, P. Balaram, Biopolymers 1993, 33, 827-837;
24. b) I. L. Karle, J. L. Flippen-Anderson, K. Uma, P. Balaram, Proteins: Struct. Funct. Genet. 1990, 7, 62-73.
25. 6.
26. For general reviews on Aib-containing peptides, see: a) reference [16]; b) I. L. Karle, Biopolymers 1996, 40, 157-180;
27. c) C. Toniolo, E. Benedetti, Macromolecules 1991, 24, 4004-4009.
28. H. Sugano, M. Miyoshi, J. Org. Chem. 1976, 41, 2352-2353.
29. All L-amino acids were used. See: M. Bodansky, Peptide Chemistry, Springer, New York, 1988, pp. 55-146, and references therein.
30. Both RCM reactions appeared quantitative by thin-layer chromatography. The yields are reduced only by the isolation procedure. Lower catalyst loadings (5-10 mol%) gave a reduced yield of macrocyclic products. This is often observed for RCM macrocyclizations and is believed to be rooted in the apparently accelerated decomposition of the ruthenium methylidene catalyst species at high dilution. For a review of macrocyclization by RCM, see reference [15].
31. 1H NMR integration.
32. Full details of the RCM procedure and subsequent hydrogenation, along with complete spectral data for key compounds, is included in the supporting information.
33. M. Goodman, I. Listowsky, Y. Masuda, F. Boardman, Biopolymers 1963, 1, 33-42. Details of our CD spectral analyses are given in the supporting information.
34. For examples of small helical Aib-containing peptides exhibiting similar CD ellipticities in TFE, see: a) A. Banerjee, S. Raghothama, P. Balaram, J. Chem. Soc. Perkin Trans. 2 1997, 2087-2094;
35. b) I. L. Karle, A. Banerjee, S. Bhattachrjya, P. Balaram, Biopolymers 1996, 38, 515-526.
36. 10-helical peptides, while R ≈ 1 for largely α-helical peptides.
37. The average R value for 3,4,7, and 8 is 0.3. See: C. Toniolo, A. Polese, F. Formaggio, M. Crisma, J. Kamphuis, J. Am. Chem. Soc. 1996, 118, 2744-2745.
38. 10-helix (or vice versa) upon ring closure. See: G. Yoder, A. Polese, R. A. G. D. Silva, F. Formaggio, M. Crisma, O. B. Broxterman, J. Kamphuis, C. Toniolo, T. A. Keiderling, J. Am. Chem. Soc. 1997, 119, 10278-10285.
39. -3; GOF = 2.28 for 633 variables. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC-101810. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (+44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
40. Residues at the ends of peptide helices are often irregular in conformation. This effect is more pronounced at the C-terminus. See: C. Chothia, Annu. Rev. Biochem. 1984, 53, 537-572.
41. C. Toniolo, E. Benedetti, Trends Biochem. Sci. 1991, 16, 350-353.
42. The 4 → 11 N ⋯ O=C angles for these four hydrogen bonds range from 118 to 131°.
43. The analogous hydrogen-bonding pattern in α-helices is 5→1, spanning three residues. See reference [30].
44. 1H NMR analyses of peptides 3, 4, 7, and 8 will be reported in a separate publication.
45. All peptide helix axes are parallel in the unit cell of 8. Head-to-tail hydrogen bonding is commonly observed in crystalline hydrophobic peptide helices. See reference [16].
46. 2O for 2) may contribute to the disparity in their crystal structures.
47. a) C. Toniolo, M. Crisma, F. Formaggio, C. Peggion, V. Monaco, C. Goulard, S. Rebuffat, B. Bodo, J. Am. Chem. Soc. 1996, 118, 4952-4958;
48. b) C. Toniolo, C. Peggion, M. Crisma, F. Formaggio, X. Q. Shui, D. S. Eggleston, Nature Struct. Biol. 1994, 12, 908-914;
49. c) E. Benedetti, A. Bavoso, B. Di Blasio, V. Pavone, C. Pedone, C. Toniolo, G. M. Bonora, Proc. Natl. Acad. Sci. USA 1982, 79, 7951-7954.
50. D. M. Lynn, B. Mohr, R. H. Grubbs, J. Am. Chem. Soc. 1998, 120, 1627-1628, and references therein.