Molecular modeling, synthesis, and structures of N-methylated 3,5-linked pyrrolin-4-ones toward the creation of a privileged nonpeptide scaffold

Bioorganic and Medicinal Chemistry

Volumn 7, Issue 1, 1999, Pages 9-22

  Smith III, Amos B ^a   Favor, David A ^a   Sprengeler, Paul A ^a   Guzman, Mark C ^a   Carroll, Patrick J ^a   Furst, George T ^a   Hirschmann, Ralph ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Mimetics; Molecular modeling mechanics; Peptides and polypeptides; X ray crystal structures

Indexed keywords

PYRROLINE DERIVATIVE;

CRYSTAL STRUCTURE; DRUG SYNTHESIS; IN VITRO STUDY; INFRARED SPECTROMETRY; MASS SPECTROMETRY; MOLECULAR DYNAMICS; MOLECULAR MODEL; NUCLEAR MAGNETIC RESONANCE; PROTEIN STRUCTURE; SHORT SURVEY; X RAY ANALYSIS;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 0033011780     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0968-0896(98)00234-X     Document Type: Article

References (45)

1. Pauling, L. The Nature of the Chemical Bond; Cornell University Press: Ithaca, NY, 1960; p 498.
2. For an exception to this, see: Hamuro, Y.; Geib, S. T.; Hamilton, A. D. J. Am. Chem. Soc. 1996, 118, 7529.
3. (a) Smith, A. B., III; Keenan, T. P.; Holcomb, R. C.; Sprengeler, P. A.; Guzman, M. C.; Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am. Chem. Soc. 1992, 114, 10672.
4. (b) Smith, A. B., III; Holcomb, R. C.; Guzman, M. C.; Keenan, T. P.; Sprengeler, P. A.; Hirschmann, R. Tetrahedron Lett. 1993, 34, 63.
5. (c) Smith, A. B., III; Hirschmann, R.; Pasternak, A.; Akaishi, R.; Guzman, M. C.; Jones, D. R.; Keenan, T. P.; Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Holloway, M. K.; Schleif, W. A. J. Med. Chem. 1994, 37, 215.
6. (d) Smith, A. B., III; Guzman, M. C.; Sprengeler, P. A.; Keenan, T. P.; Holcomb, R. C.; Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am. Chem. Soc. 1994, 116, 9947.
7. (e) Smith, A. B., III; Akaishi, R.; Jones, D. R.; Keenan, T. P.; Guzman, M. C.; Holcomb, R. C.; Sprengeler, P. A.; Wood, J. L.; Hirschmann, R.; Holloway, M. K. Biopolymers (Peptide Science) 1995, 37, 29.
8. (f) Smith, A. B., III; Hirschmann, R.; Pasternak, A.; Guzman, M. C.; Yokoyama, A.; Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Schleif, W. A. J. Am. Chem. Soc. 1995, 117, 11113.
9. (g) Smith, A. B., III; Benowitz, A. B.; Favor, D. A.; Sprengeler, P. A.; Hirschmann, R. Tetrahedron Lett. 1997, 38, 3809.
10. (h) Smith, A. B., III; Hirschmann, R.; Pasternak, A.; Yao, W.; Sprengeler, P. A.; Holloway, M. K.; Chen, Z.; Darke, P. L.; Schleif, W. A. J. Med. Chem. 1997, 40, 2440.
11. Smith, A. B., III; Guzman, M. C.; Favor, D. A.; Berova, N.; Hirschmann, R. manuscript in preparation.
12. For these calculations, the 1987 version of the MM2 force field in conjunction with Macromodel program (version 3.1×) was employed; see respectively, (a) Bowen, J. P.; Pathiaserli, A.; Profeta, Jr. S.; Allinger, N. L. J. Org. Chem. 1987, 52, 5162.; See also: Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127.
13. For these calculations, the 1987 version of the MM2 force field in conjunction with Macromodel program (version 3.1×) was employed; see respectively, (a) Bowen, J. P.; Pathiaserli, A.; Profeta, Jr. S.; Allinger, N. L. J. Org. Chem. 1987, 52, 5162.; See also: Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127.
14. (b) Still, W. C.; Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Lipton, M.; Liskamp, R.; Chang, G.; Hendrickson, T.; DeGunst, F.; Hasel, W. Department of Chemistry, Columbia University, New York, NY 10027.
15. Acetal (-)-2 was prepared from (-)-4 in 80% overall yield via amine protection (Cbz) followed by ozonolysis, acetalization, and Cbz removal.
16. 3, Z=2. Oxygens and nitrogens are depicted in red and blue respectively. See supplementary material for complete X-ray data.
17. For novel of examples, see: (a) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. Rev. 1995, 95, 2229, and references cited therein.
18. (b) Keort, U.; Harding, M. M.; Lehn, J.-M. Nature 1990, 346, 339.
19. (c) Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913.
20. (d) Seebach, D.; Ciceri, P. E.; Overhand, M.; Jaun, B.; Rigo, D.; Oberer, L.; Hommel, U.; Amstutz, R.; Widmer, H. Helv. Chim. Acta 1996, 79, 2043.
21. (e) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997, 2015.
22. (f) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Amer. Chem. Soc. 1996, 118, 13071.
23. (g) Appella, D. H.; Christianson, L. A., Klein, D. A.; Powell, D. R.; Huang, X.; Barchi, Jr. J. K.; Gellman, S. H. Nature 1997, 387, 381.
24. Miller, R. B. Synth. Commun. 1972, 2, 267.
25. 2), hydroxyl protection (SEMCl, DIPEA), and ozonolysis.
26. Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
27. (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1571.
28. (b) Okabe, M.; Sun, R.-C.; Scalone, M.; Jibilian, C. H.; Hutchings, S. D. J. Org. Chem. 1995, 60, 767.
29. Brown, H. C.; Midland, M. M. Angew. Chem., Int. Ed. Engl. 1972, 11, 692.
30. Dangles, O.; Guibé, F.; Balavoine, G.; Lavielle, S.; Marquet, A. J. Org. Chem. 1987, 52, 4984.
31. 3, Z=9. Oxygens and nitrogens are depicted in red and blue, respectively. See supplementary material for complete X-ray data.
32. 3, Z=1. Oxygens and nitrogens are depicted in red and blue, respectively. See supplementary material for complete X-ray data.
33. Gellman, S. H.; Dado, G. P.; Liang, G. J. Am. Chem. Soc. 1991, 113, 1164.
34. The concentration range over which the intermolecular interactions would be minimal was determined by plotting log [(-)-1] versus the chemical shift of the NH in ring d for each solvent systems. The resultant plot indicated that no intermolecular hydrogen bonding occurs below 0.001 M.
35. (a) Gellman, S. H.; Dado, G. P.; Liang, G. J. Am. Chem. Soc. 1991, 113, 1164.
36. (b) Kristen, C. N.; Schrader, T. H. J. Am. Chem. Soc. 1997, 119, 12061.
37. (c) Nowick, J. S.; Smith, E. M.; Noronha, G. J. Org. Chem. 1995, 60, 7386.
38. (a) Ribeiro, A. A.; Goodman, M.; Naider, F. Int. J. Peptide Protein Res. 1979, 14, 414.
39. (b) Stevens, E. S.; Sugawara, N.; Bonora, G. M.; Toniolo, C. J. Am. Chem. Soc. 1980, 102, 7048.
40. (c) Gellman, S. H.; Adams, B. R. Tetrahedron Lett. 1989, 30, 3381.
41. We would like to thank Dr. Clemens Anklin of Bruker Instruments Inc., Billerica, MA for obtaining the NOESY spectra of compound (-)-6.
42. 1/6; R is the atomic distance and I is intensity.
43. Smith, A. B., III; Knight, S. D.; Sprengeler, P. A.; Hirschmann, R. Bioorg. Med. Chem. 1996, 4, 1021.
44. Pedersen-Morris, M., The University of Pennsylvania, unpublished report.
45. 3 shims adjusted. Variable concentration experiments were done on the same instrument. The most concentrated sample was prepared first; subsequent concentrations were reached via serial dilution. All shims were adjusted at each concentration. IR measurements were performed on a Perkin-Elmer 1600 Series FT-IR. Spectra were taken using NaCl plates with a path length of 1.0 mm. Microanalyses were performed by Dr. Rakesh K. Kohli at the University of Pennsylvania.