Alkylation studies of N-protected-5-substituted morpholin-3-ones. A stereoselective approach to novel methylene ether dipeptide isosteres

Journal of Organic Chemistry

Volumn 61, Issue 15, 1996, Pages 4990-4998

  Norman, Bryan H ^a   Kroin, Julian S ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MORPHOLINE DERIVATIVE; PSEUDOPEPTIDE;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS; STEREOCHEMISTRY; TECHNIQUE;

EID: 0030037030     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo960496w     Document Type: Article

References (24)

1. The Annual Reports in Medicinal Chemistry has published several recent reviews on disease targets which have been addressed by peptidomimetics. Greenlee, W. J.; Siegl, P. K. S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1992; Vol. 27, p 59 (ACE and Renin Inhibitors). Blackburn, B. K.; Gadek, T. R. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1993; Vol. 28, p 79 (Glycoprotein IIb/IIIa Antagonists). Thaisrivongs, S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 133 (HIV Protease Inhibitors). Bolton, G. L.; Sebolt-Leopold, J. S.; Hodges, J. C. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 165 (Ras Farnesyltransferase Inhibitors) and references cited therein.
2. The Annual Reports in Medicinal Chemistry has published several recent reviews on disease targets which have been addressed by peptidomimetics. Greenlee, W. J.; Siegl, P. K. S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1992; Vol. 27, p 59 (ACE and Renin Inhibitors). Blackburn, B. K.; Gadek, T. R. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1993; Vol. 28, p 79 (Glycoprotein IIb/IIIa Antagonists). Thaisrivongs, S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 133 (HIV Protease Inhibitors). Bolton, G. L.; Sebolt-Leopold, J. S.; Hodges, J. C. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 165 (Ras Farnesyltransferase Inhibitors) and references cited therein.
3. The Annual Reports in Medicinal Chemistry has published several recent reviews on disease targets which have been addressed by peptidomimetics. Greenlee, W. J.; Siegl, P. K. S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1992; Vol. 27, p 59 (ACE and Renin Inhibitors). Blackburn, B. K.; Gadek, T. R. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1993; Vol. 28, p 79 (Glycoprotein IIb/IIIa Antagonists). Thaisrivongs, S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 133 (HIV Protease Inhibitors). Bolton, G. L.; Sebolt-Leopold, J. S.; Hodges, J. C. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 165 (Ras Farnesyltransferase Inhibitors) and references cited therein.
4. The Annual Reports in Medicinal Chemistry has published several recent reviews on disease targets which have been addressed by peptidomimetics. Greenlee, W. J.; Siegl, P. K. S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1992; Vol. 27, p 59 (ACE and Renin Inhibitors). Blackburn, B. K.; Gadek, T. R. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1993; Vol. 28, p 79 (Glycoprotein IIb/IIIa Antagonists). Thaisrivongs, S. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 133 (HIV Protease Inhibitors). Bolton, G. L.; Sebolt-Leopold, J. S.; Hodges, J. C. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Acedemic Press: San Diego, 1994; Vol. 29, p 165 (Ras Farnesyltransferase Inhibitors) and references cited therein.
5. Grahm, S. L.; deSolms, S. J.; Giuliani, E. A.; Kohl, N. E.; Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J.; Deana, A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs, J. B.; Smith, R. L. J. Med. Chem. 1994, 37, 725.
6. Breton, P.; Monsigny, M.; Mayer, R. Int. J. Pep. Protein Res. 1990, 35, 346.
7. Ho, M.; Chung, J. K. K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513. Ho, M.; Uhrin, A.; Huang, M. Bioorg. Med. Chem. Lett. 1994, 4, 553.
8. Ho, M.; Chung, J. K. K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513. Ho, M.; Uhrin, A.; Huang, M. Bioorg. Med. Chem. Lett. 1994, 4, 553.
9. Ondetti, M.; Pluscec, J.; Weaver, E.; Williams, N.; Sabo, E.; Kocy, O. In Proceedings of the Third American Peptide Symposium; Meienhofer, J., Ed.; Ann Arbor, 1972; p 525.
10. Nicolaides, E. D.; Tinney, F. J.; Kaltenbronn, J. S.; Repine, J. T.; DeJohn, D. A.; Lunney, E. A.; Roark, W. H.; Marriott, J. G.; Davis, R. E.; Voigtman, R. E. J. Med. Chem. 1986, 29, 959.
11. TenBrink, R. E. J. Org. Chem. 1987, 52, 418.
12. Norman, B. H.; Kroin, J. S. Tetrahedron Lett. 1995, 36, 4151.
13. Anthony, N. J.; Gomez, R. P.; Holtz, W. J.; Murphy, J. S.; Ball, R. G.; Lee, T. Tetrahedron Lett. 1895, 36, 3821.
14. Clarke, F. H. J. Org. Chem. 1962, 27, 3251.
15. Williams, R. M.; Im, M. N. Tetrahedron Lett. 1988, 29, 6075. Williams, R. M.; Im, M. N. J. Am. Chem Soc. 1991, 113, 9276.
16. Williams, R. M.; Im, M. N. Tetrahedron Lett. 1988, 29, 6075. Williams, R. M.; Im, M. N. J. Am. Chem Soc. 1991, 113, 9276.
17. Dellaria, J. F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29, 6079. Dellaria, J. F. J. Org.Chem. 1989, 54, 3916. Ornstein, P. L. J. Org. Chem. 1989, 54, 2251. Baker, W. R.; Condon, S. L.; Spanton, S. Tetrahedron Lett. 1992, 33, 1573. Baker, W. R.; Condon, S. L. Tetrahedron Lett. 1992, 33, 1577.
18. Dellaria, J. F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29, 6079. Dellaria, J. F. J. Org.Chem. 1989, 54, 3916. Ornstein, P. L. J. Org. Chem. 1989, 54, 2251. Baker, W. R.; Condon, S. L.; Spanton, S. Tetrahedron Lett. 1992, 33, 1573. Baker, W. R.; Condon, S. L. Tetrahedron Lett. 1992, 33, 1577.
19. Dellaria, J. F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29, 6079. Dellaria, J. F. J. Org.Chem. 1989, 54, 3916. Ornstein, P. L. J. Org. Chem. 1989, 54, 2251. Baker, W. R.; Condon, S. L.; Spanton, S. Tetrahedron Lett. 1992, 33, 1573. Baker, W. R.; Condon, S. L. Tetrahedron Lett. 1992, 33, 1577.
20. Dellaria, J. F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29, 6079. Dellaria, J. F. J. Org.Chem. 1989, 54, 3916. Ornstein, P. L. J. Org. Chem. 1989, 54, 2251. Baker, W. R.; Condon, S. L.; Spanton, S. Tetrahedron Lett. 1992, 33, 1573. Baker, W. R.; Condon, S. L. Tetrahedron Lett. 1992, 33, 1577.
21. Dellaria, J. F.; Santarsiero, B. D. Tetrahedron Lett. 1988, 29, 6079. Dellaria, J. F. J. Org.Chem. 1989, 54, 3916. Ornstein, P. L. J. Org. Chem. 1989, 54, 2251. Baker, W. R.; Condon, S. L.; Spanton, S. Tetrahedron Lett. 1992, 33, 1573. Baker, W. R.; Condon, S. L. Tetrahedron Lett. 1992, 33, 1577.
22. CH = ∼3 Hz, indicating a Z orientation between the C-3 carbonyl and the olefinic proton. Therefore, we have assigned the olefin as Z.
23. The stereochemistries of 15 and 20 have been established by NOE studies.
24. The selectivities in these reactions are not base dependent. 29 was formed with 10:1 selectivity using LDA or n-BuLi.