A convenient synthesis of 3-substituted pipecolic acid methyl esters

Tetrahedron Letters

Volumn 37, Issue 4, 1996, Pages 459-462

  Subramanyam, Chakrapani ^a,b   Chattarjee, Sankar ^a   Mallamo, John P ^a  

^a CEPHALON INC   (United States)

^b AFFYMAX RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PIPECOLIC ACID DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 0030052780     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(95)02198-1     Document Type: Article

References (15)

1. The incorporation of conformationally-constrained amino acids into peptide based inhibitors of proteases have been shown to improve their stability towards proteolytic enzymes and hence improve their biological half life. e.g.: see Thaisrivongs, S.; Pals, D.T.; Turner, S.R.; Kroll, L.T. J. Med. Chem. 1988, 31, 1369.
2. For a review on the use of conformationally constrained amino acids in peptidomimetic inhibitors design and synthesis, see Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993, 32, 1244.
3. Shuman, R.T.; Ornstein, P.L.; Paschal, J.W.; Gesellchen, P.D. J. Org. Chem. 1990, 55, 738 and references therein.
4. Angle, S.R.; Arnaiz, D.O. Tetrahedron Lett. 1989, 30, 515.
5. The synthesis and use of optically pure 3-substituted (and 3,3-disubstituted) pipecolic acids as conformationally constrained glutamate antagonists have been reported. For e.g.: see, (a) Whitten, J.P.; Muench, D.; Cube, R.V.; Nyce, P.L.; Baron, B.M.; McDonald, I. BioMed. Chem. Lett. 1991, 1, 441.
6. (b) Whitten, J.P.; Cube, R.W.; Baron, B.M.; McDonald, I. ibid, 1993, 3, 19.
7. (c) Claesson, et al. ibid, 1992, 2, 1247.
8. Esterification of acid 4 using diazomethane to give 5 has been reported. However, the authors report that they obtained only very low yields of 5 under other esterification conditions, cf. Drummond, J. et al. J. Med. Chem. 1989, 32, 2116.
9. Echavaren, A.M.; Stille, J.K. J. Am. Chem. Soc. 1987, 109, 5478
10. Heck, R.F. Org. React. 1982, 27, 345
11. Pendrak, I.; Chambers, P.A. J. Org. Chem. 1995, 60, 3249
12. Suzuki, A.; Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh. J. Am. Chem. Soc. 1989, 111, 314.
13. Shieh, W.C.; Carlson, J.A. J. Org. Chem. 1992, 57, 379.
14. 1H NMR, IR and electrospray mass spectra.
15. Hydrolysis of the Cbz-protected derivatives of esters 3a, c could be cleanly achieved using 2N NaOH in MeOH at 70 °C. The resulting pipecolic acids were a 1:1 mixture of the cis and trans isomers. This result is not surprising, because it has been reported by Shuman et al (ref. 4), that when the hydrogenation of the pyridine ring was carried out in the presence of 1M KOH, a 60:40 mixture of the corresponding DL cis and DL trans substituted pipecolic acids were obtained.