A highly efficient synthesis of fibrinogen receptor antagonist L-734,217 via a novel chemoselective silyl-mediated conjugate addition of δ-lactams to 4-vinylpyridine

Journal of Organic Chemistry

Volumn 61, Issue 1, 1996, Pages 215-222

  Chung, John Y L ^a   Hughes, David L ^a   Zhao, Dalian ^a   Song, Zhiguo ^a   Mathre, David J ^a   Ho, Guo Jie ^a   McNamara, James M ^a   Douglas, Alan W ^a   Reamer, R A ^a   Tsay, Fuh Rong ^a   Varsolona, Richard ^a   McCauley, James ^a   Grabowski, Edward J J ^a   Reider, Paul J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FIBRINOGEN RECEPTOR ANTAGONIST; L 734217; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 13344270353     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo951214f     Document Type: Article

References (31)

1. (a) Nichols, A. J.; Ruffolo Jr., R. R.; Huffman, W. F.; Poste, G.; Samanen, J. Trends Pharmacol. Sci. 1992, 13, 413.
2. (b) Coller, B. S. N. Engl. J. Med. 1990, 322, 248.
3. (c) Ellis, S. G.; Bates, E. R.; Schaible, T.; Weisman, H. F.; Pitt, B.; Topol, E. J. J. Am. Coll. Cardiology 1991, 17, 89b.
4. (a) Kleinman, N. S., Ohman, E. M.; Keriakes, D. J.; Ellis, S. G.; Weisman, H. F.; Topol, E. J. Circulation 1991, 84 (Suppl. II), 522.
5. (b) Aiken, J. W.; Gorman, R. R.; Shebuski, R. J. Prostaglandins 1979, 17, 483.
6. Blackburn, B. K.; Gadek, T. R. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press, Inc.: San Diego, 1993; Vol. 28, Chapter 10, p 89.
7. Cheng, S.; Craig, W. S.; Mullen, D.; Tschopp, J. F.; Dixon, D.; Pierschbacher, M. D. J. Med. Chem. 1994, 37, 1 and references therein.
8. (a) Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J. J.; Anderson, P. S.; Chang, C. T.-C.; Cook, J. J.; Gould, R. J.; Ihle, N. C.; Hartman, G. D.; Lynch, J. J.; Lynch, R. J.; Manno, P. D.; Schaffer, L. W.; Smith, R. L. J. Med. Chem. 1995, in press.
9. (b) Duggan, M. E.; Egbertson, M. S.; Ihle, N.; Hartman, G. D.; Turchi, L. M.; Hoffman, W. F. U S. Patent 5,281,585, Jan 5, 1994.
10. 5 required 17 steps (14 linear steps and 3 steps to prepare the tert-butyl ester analog of 2), 11 chromatographies, and several raw materials and reagents that are not readily available in bulk.
11. Chiral benzyl β-aminobutyrate 2 is commericially available from Celgene Corp., 7 Powder Horn Drive, Warren, NJ 07059.
12. For a review on enantioselective synthesis of β-amino acids, see: Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3.
13. Siperko, L. G.; Smith, F. X. Synth. Commun. 1979, 9, 383, and references therein.
14. (a) Koelsch, C. F. J. Am. Chem. Soc. 1943, 65, 2458.
15. (b) Liebman, A. A ; Malarek, D. H.; Dorsky, A. M.; Kaegi, H. H. J. Heterocycl. Chem. 1974, 11, 1105.
16. For preparation of the dianion of 2-piperidone, see: Yamamoto, Y.; Morita, Y. Chem. Pharm. Bull. 1984, 32, 2555.
17. (a) Conjugate addition of N,N-dibutylpropionamide to 2-vinylpyridine in DMF at 110°C with catalytic potassium tert-butoxide in 51% yield has been reported: Hintermeier, K.; Brachel, H. Ger. Offen. 2025009, Dec 9, 1971.
18. (b) For various Michael reactions of amide and lactam enolates with enones, see: Heathcock, C. H.; Henderson, M. A.; Oare, D. A; Sanner, M. A. J. Org. Chem. 1985, 50, 3019.
19. 15 (Matrix Presented)
20. Irreversible 1,3-boryl shifts are known: Paetzold, P.; Biermann, H.-P. Chem. Ber. 1977, 110, 3678.
21. Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 499.
22. a values (Data from: Organic Chemistry; 3rd ed.; Streitwieser, A.; Heathcock, C H., Eds.; Macmillan Publishing Co.: New York, 1985): (Matrix Presented)
23. For formation of O-silyl imidate cations, see: (a) Frick, U.; Simchen, G. Liebigs Ann. Chem. 1987, 839 (b) Simchen, G.; Kober, W. Synthesis 1976, 259.
24. For formation of O-silyl imidate cations, see: (a) Frick, U.; Simchen, G. Liebigs Ann. Chem. 1987, 839 (b) Simchen, G.; Kober, W. Synthesis 1976, 259.
25. For iodotrimethylsilane-mediated 2-monohalogenation of 4-aza-5α-androstan-3-one steroids, see: King, A. O.; Anderson, R. K.; Shuman, R. F.; Karady, S.; Abramson, N. L.; Douglas, A. W. J. Org. Chem. 1993, 58, 3384.
26. For silylation of acetonitrile by TMS-X, see: (a) Emde, H.; Simchen, G. Synthesis 1977, 636. (b) Kira, M.; Hino, T.; Sakurai, H. J. Am. Chem. Soc. 1992, 114, 6697, footnote 6.
27. For silylation of acetonitrile by TMS-X, see: (a) Emde, H.; Simchen, G. Synthesis 1977, 636. (b) Kira, M.; Hino, T.; Sakurai, H. J. Am. Chem. Soc. 1992, 114, 6697, footnote 6.
28. For silylation of tertiary amines, see ref 21, pp 14-15.
29. For a review, see: Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Gotz, A.; Hergott, H. H.; Hofmann, K.; Kober, W.; Krageloh, K.; Oesterle, T.; Steppan, W.; West, W.; Simchen, G. Synthesis 1982, 1.
30. Enantiomers, Racemates, and Resolutions, Jacques, J.; Collet, A.; Wilen, S. H.; Eds.; John Wiley & Sons: New York, 1981.
31. Kaye, P. T.; Learmonth, R. A. Synth. Commun. 1989, 19, 2337.