Soluble polymer-supported synthesis of imines and β-lactams

Tetrahedron Letters

Volumn 39, Issue 10, 1998, Pages 1257-1260

  Molteni, Valentina ^a   Annunziata, Rita ^a   Cinquini, Mauro ^a   Cozzi, Franco ^a   Benaglia, Maurizio ^a  

^a CNR   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BETA LACTAM DERIVATIVE; IMINE; POLYMER;

ARTICLE; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; REACTION ANALYSIS; STEREOISOMERISM;

EID: 0032485222     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)10770-5     Document Type: Article

References (31)

1. 1. a) Balkenhohl, F.; von dem Busschl-Hünnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem. Int. Ed. Engl. 1996, 35, 2288.
2. b) Lowe, G. Chem. Soc. Rev. 1995, 309.
3. 2. a) Früchtel, J.S.; Jung, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 17;
4. b) Thompson, L.A.; Ellman, J.A. Chem. Rev. 1996, 96, 555.
5. c) Hermkens, P.H.H.; Ottenheijm, H.C.J.; Rees, D. Tetrahedron 1996, 52, 4527.
6. 3. For a review on soluble polymer-supported synthesis, see: Graven, D.J.; Janda, K.D. Chem. Rev. 1997, 97, 489.
7. 4. By comparing the prices of different polymers functionalized with primary OH groups, and considering the number of functional groups per gram of polymer ("loading", expressed in meq/g) MeOPEG 5000 ("loading" = 0.2) costs 10 to 500 times less than other commercially available polymeric matrixes.
8. 5. a) Han, H.; Wolfe, M.M.; Brenner, S.; Janda, K.D. Proc. Nat'l Acad. USA 1995, 92, 6419;
9. b) Jung, K.W.; Zhao, X.; Janda, K.D. Tetrahedron Lett. 1996, 37, 6491 and 1997, 38, 977.
10. b) Jung, K.W.; Zhao, X.; Janda, K.D. Tetrahedron Lett. 1996, 37, 6491 and 1997, 38, 977.
11. c) Han, H.; Janda, K.D. J. Am. Chem. Soc. 1996, 118, 2539.
12. 6. MeoPEG has been previously used as support for the iterative synthesis of polypeptides, oligonucleotides, and oligosaccharides. For a list of leading references, see Ref. 3.
13. 7. a) Han, H.; Janda, K.D. J. Am. Chem. Soc. 1996, 118, 7632, and Tetrahedron Lett. 1997, 38, 1527.
14. 7. a) Han, H.; Janda, K.D. J. Am. Chem. Soc. 1996, 118, 7632, and Tetrahedron Lett. 1997, 38, 1527.
15. 8. Bolm, C.; Gerlach, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 741.
16. 9. For the immobilization of different catalysts on soluble polymers, see: Bergbreiter, D.E.; Zhang, L.; Mariagnanam, V.M. J. Am. Chem. Soc. 1993, 115, 9295, and references therein.
17. 10. The synthesis of imines on insoluble polymers has been described in Ref. 2c.
18. 11. Only one synthesis of polymer immobilized β-lactams has been described: Ruhland, B.; Bhandari, A.; Gordon, E.M.; Gallop, M.A. J. Am. Chem. Soc. 1996, 118, 253. The polymer was insoluble (Sasrin), and the azetidinones were formed by a ketene/imine cycloaddition using a 1000 fold excess of ketene precursor. The attachment of two commercially available β-lactams to MeOPEG and their modification to afford a β-lactam library has been claimed: Janda, K.D.; Hyunsoo, H. Pat. Appl. WO 96/03418. Very recently, the solid-phase synthesis of β-sultams has been reported: Gordeev, M. F.; Gordon, E.M.; Patel, D. V. J. Org. Chem. 1997, 62, 8177.
19. 11. Only one synthesis of polymer immobilized β-lactams has been described: Ruhland, B.; Bhandari, A.; Gordon, E.M.; Gallop, M.A. J. Am. Chem. Soc. 1996, 118, 253. The polymer was insoluble (Sasrin), and the azetidinones were formed by a ketene/imine cycloaddition using a 1000 fold excess of ketene precursor. The attachment of two commercially available β-lactams to MeOPEG and their modification to afford a β-lactam library has been claimed: Janda, K.D.; Hyunsoo, H. Pat. Appl. WO 96/03418. Very recently, the solid-phase synthesis of β-sultams has been reported: Gordeev, M. F.; Gordon, E.M.; Patel, D. V. J. Org. Chem. 1997, 62, 8177.
20. 11. Only one synthesis of polymer immobilized β-lactams has been described: Ruhland, B.; Bhandari, A.; Gordon, E.M.; Gallop, M.A. J. Am. Chem. Soc. 1996, 118, 253. The polymer was insoluble (Sasrin), and the azetidinones were formed by a ketene/imine cycloaddition using a 1000 fold excess of ketene precursor. The attachment of two commercially available β-lactams to MeOPEG and their modification to afford a β-lactam library has been claimed: Janda, K.D.; Hyunsoo, H. Pat. Appl. WO 96/03418. Very recently, the solid-phase synthesis of β-sultams has been reported: Gordeev, M. F.; Gordon, E.M.; Patel, D. V. J. Org. Chem. 1997, 62, 8177.
21. 2-COOR signal at 4.20 ppm as internal standard. The estimated integration error is ± 7%.
22. 13. Caldwell, J.B.; Ledger, R.; Milligan, B. Aust. J. Chem. 1966, 19, 1297.
23. 2 or CH=N, ppm) of compound 3-8 were at: 3: 6.60, 6.80, 2.60; 4: 6.70, 6.87, 8.43; 5: 7.17, 7.06, 8.50; 6: 7.20, 7.10, 8.27; 7: 7.00, 7.00, 8.07; 8: 7.13, 7.33, 7.93. Imines 4-6 were single isomers, likely of E configuration. In the case of compounds 7 and 8 two isomers were detected in a ca. 66:34 ratio. The minor isomers of 7 and 8 showed the CH=N signal at 7.80 and 7.60 ppm, respectively.
24. 2 atmosphere (23°C, 15h). After filtration and evaporation of the solvent, imines 7 and 8 were obtained in 40 and 30% yield, respectively, along with unreacted amine 3 and, surprisingly, monoester 1 (see Ref. 12 and 14). Imines 4-6 can also be obtained by this procedure, but in slightly lower yields with respect to those reported in the text.
25. 16. a) Hart, D.J.; Ha, D.C. Chem. Rev. 1989, 89, 1447;
26. b) Georg, G.I.; Ravikumar, V.T. in The Organic Chemistry of β-Lactams, Georg, G.I., Ed.; VCH Publisher Inc., New York, 1993, pp 295-368.
27. 17. Annunziata, R.; Benaglia, M.; Chiovato, A.; Cinquini, M.; Cozzi, F. Tetrahedron 1995, 51, 10025, and references therein.
28. cis 5.0-6.0 Hz. In the case of compound 12 a single β-lactam was detected (see Ref. 20 for configurational assignment). It seems unlikely that isolation of the products by precipitation in diethylether can alter the original diastereoisomeric ratio.
29. 19. Separate experiments showed that the unbound β-lactams were stable in the conditions employed for removal. The difference in the trans:cis ratios observed for the β-lactams attached to and removed from the polymer can be due to partial removal. All new compounds gave analytical and spectral data in agreement with the proposed structures.
30. 2SiCl, imidazole, DMF, 23°C, 15h) of the secondary alcohol of 19 to give the known azetidinone 23: Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P.G. J. Org. Chem. 1992, 57, 4155.
31. 6 (CAN) in acetonitrile/water to attempt the one-step removal of the polymer and of the linker, the reaction proceeded only to the ester hydrolysis stage, affording β-lactams 18 in 45% yield. N-deprotection required further reaction with CAN (67% yield), as described by: Georg, G.I.; Kant, J.; Gill, H.S. J. Am. Chem. Soc. 1987, 109, 1129.