2-Oxopiperazine scaffolds by [3+2] cycloaddition reactions with a polymer-supported cyclic nitrone

European Journal of Organic Chemistry

Volumn , Issue 11, 2004, Pages 2321-2324

  Wierschem, Frank ^a   Rück Braun, Karola ^a  

^a TECHNISCHE UNIVERSITÄT BERLIN   (Germany)

Author keywords

Cycloaddition; Isoxazoli(di)nes; N O bond cleavage; Piperazin 2 one scaffolds; Solid phase synthesis

Indexed keywords

AMINE; AMINOALCOHOL; NITRONE DERIVATIVE; PIPERAZINE DERIVATIVE; POLYMER;

ACYLATION; ARTICLE; CHEMICAL BOND; CHEMICAL REACTION; CYCLOADDITION; MITSUNOBU REACTION; REACTION ANALYSIS;

EID: 4544332561     PISSN: 1434193X     EISSN: None     Source Type: Journal    
DOI: 10.1002/ejoc.200400150     Document Type: Article

References (32)

1. J. J. Tufariello, 1,3-Dipolar Cycloaddition Chemistry (Ed.: A. Padwa), Wiley-Intersience, 1984, 83-168.
2. A. Padwa, W. H. Pearson, Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocydes and Natural Products, Vol. 1 (Ed.: A. Padwa), John Wiley & Sons Inc., New York, 2002.
3. For the application of polymer-bound alkenes in 1,3-dipolar cycloadditions with nitrones, see: [3a) W. J. Haap, D. Kaiser, T. B. Walk, G. Jung, Tetrahedron 1998, 54, 3705-3724.
4. [3b] D. S. Tan, M. A. Foley, B. R. Stockwell, M. D. Shair, S. L. Schreiber, J. Am. Chem. Soc. 1999, 121, 9073-9087.
5. [3c] F. Pisaneschi, C. D. Monica, F. M. Cordero, A. Brandi, Tetrahedron Lett. 2002, 43, 5711-5714.
6. [3d] G. Desimoni, G. Faita, A. Galbiati, D. Pasini, P. Quadrelli, F. Rancati, Tetrahedron: Asymmetry 2002, 13, 333-337.
7. [4a] G. J. Küster, H. W. Scheeren, Tetrahedron Lett. 1998, 39, 3613-3616.
8. [4b] G. J. T. Küster, H. W. Scheeren, High Pressure Chemistry (Eds.: R. van Eldik, F. G. Klaerner), Wiley-VCH, Weinheim, 2002, 284-304.
9. S. Kobayashi, R. Akiyama, Tetrahedron Lett. 1998, 39, 9211-9214.
10. S. I. Murahashi, H. Mitsui, T. Shiota, T. Tsuda, S. Watanabe, J. Org. Chem. 1990, 95, 1736-1744 and references cited therein.
11. W. W. Zajac Jr., T. R Walters, M. G. Darcy, J. Org. Chem. 1988, 53, 5856-5860 and references cited therein.
12. Piperazin-2-one-containing scaffolds are promising pharmaceutical lead structures. This is reflected in numerous fields of application, e.g. thrombotic diseases, amnesia.[8al A. Benjahad, R. Benhaddou, R. Granet, M. Kaouadji, P. Krausz, S. Piekarski, F. Thomasson, C. Bosgiraud, S. Delebassée, Tetrahedron Lett. 1994, 35, 9545-9548.
13. [8b] K. L. Yu, G. Rajakumar, L. K. Srivastava, R. K. Mishra, R. L. Johnson, J. Med. Chem. 1988, 31, 1430-1436.
14. [8c] S. Maignan, J. P. Guilloteau, Y. M. Choi-Sledeski, M. R. Becker, W. R. Ewing, H. W. Pauls, A. P. Spada, V. Mikol, J. Med Chem. 2003, 46, 685-690.
15. [8d] S. Kitamura, H. Fukushi, T. Miyawaki, M. Kawamura, Z. Terashita. H. Sugihara, T. Naka, Chem. Pharm. Bull. 2001, 49, 258-267.
16. [8e] S. Herrero, A. Salgado, M. T. García-López, R. Herranz, Tetrahedron Lett. 2002, 43, 4899-4902.
17. [9a] B. M. Trost, L. S. Chupak, T. Lübbers, J. Am. Chem. Soc. 1998, 120, 1732-1740.
18. [9b] S. Cicchi, A. Goti, A. Brandi, A. Guarna, F. De Sarlo, Tetrahedron Lett 1990, 31, 3351-3354 and references cited therein.
19. [10a] N. R. Natale, Tetrahedron Lett. 1982, 23, 5009-5012.
20. [10b] B. Westermann. A. Walter, U. Flörke, H.-J. Altenbach, Org. Lett. 2001, 3, 1375-1378.
21. Sk. A. Ali, M. I. M. Wazeer, Tetrahedron 1993, 49, 4339-4354.
22. R. C. Bernotas, G. Adams, Tetrahedron Lett. 1996, 37, 7339-7342.
23. J. M. Kane, A. A. Carr, Tetrahedron Lett. 1980, 21, 3019-3020.
24. -1 All resins prepared were characterized after attachment of the Fmoc-protected nitrone precursor by elemental analysis (nitrogen analysis: > 95 % conversion).
25. Solid phase studies: the 1,3-dipolar cycloadditions and N-O-bond cleavages on solid support were carried out manually on a 0.1 mmol scale up to a 1.3 mmol scale. For all reactions, overall yields were calculated including the synthesis of the piperazin-2-one precursor 2, which is commercially available since July 2003.
26. F. A. Davis, S. Chattopadhyay, J. C. Towson, S. Lal, T. Reddy, J. Org. Chem. 1988, 53, 2087-2089.
27. Solution phase studies: the synthesis and application of nitrone 4 (five-step sequence: 43 % overall yield) will be described else-where. All overall yields for solution-phase studies were calculated by including the synthesis of nitrone 4. For the application of a 3-benzyl-2-oxopiperazine- derived nitrone, see reference.
28. The 1,3-dipolar cycloaddition reactions of alkenes were studied in detail in solution (ten examples) and on a solid support (twelve examples) with monosubstituted alkenes (allylpheny-lether, allylcyclohexylamine, 2-vinylpyridine, 4-vinylpyridine, N-methyl-N-vinyl-acetamide, acrylic acid methyl ester, N,N-dimethyl acrylic acid amide), 1,1-disubstituted alkenes (methyl-encyclohexane, methacrylic acid methyl ester) and 1,2-disubstituted alkenes (N-methyl maleic imide, N-phenyl maleic imide, 5H-furan-2-one). Reactions carried out with allylcyclohexylamine, N-methyl-Ar-vinyl acetamide, N,N-dimethyl acrylamide and 5H-furan-one on solid support gave inconsistent and unsatisfactory results in our hands or failed. The regioselectivities observed were in accordance with solution phase chemistry, yielding 5-substituted isoxazolidines starting from monosubstituted and 1,1-disubstituted alkenes and 4-substituted isoxazolidines in cycloaddition reactions to 1,2-disubstituted alkenes.
29. The structures of all non-polymeric compounds prepared by manual synthesis on solid support have been characterized by NMR-, IR- and elemental analysis or HRMS after purification of the crude products isolated by preparative RP-HPLC. The endolexo selectivities of 6e (ratio endo:exo = 57:43) and 6f (ratio endo:exo = 100:0) were confirmed by NOE experiments.
30. J. J. Tufariello, J. P. Tette, J. Org. Chem. 1975, 40, 3866-3869.
31. 2: 90% purity, 44 % yield.
32. All crude products obtained by automated syntheses were characterized with RP-HPLC/LC-MS after cleavage from the resin. Percent conversions and purities were determined by analytical RP-HPLC at 210 nm based on the sum of the peak areas of the starting materials and all isomeric products observed for the desired esters and the parent acids.