Combinatorial modification of 2-ketopiperazine with solid phase C- alkylation and N-acylations

Tetrahedron Letters

Volumn 39, Issue 41, 1998, Pages 7479-7482

  Zhu, Zhaoning ^a   McKittrick, Brian ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Acylation; Benzylation; Solid Phase Synthesis

Indexed keywords

2 KETOPIPERAZINE; PIPERAZINE DERIVATIVE; RESIN; UNCLASSIFIED DRUG;

ACYLATION; ALKYLATION; ARTICLE; DRUG SYNTHESIS; SOLID STATE; STRUCTURE ANALYSIS;

EID: 0032497667     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)01675-X     Document Type: Article

References (22)

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8. 2 Gante, J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1699-1720; Kolter, T.; Dahl, C. and Giannis, A. Liebigs Ann. 1995, 625-629; Toniolo, C. Int. J. Peptide Protein Res. 1990, 35, 287-300; Liskamp, R. M. J. Recl. Trav. Chim. Pays-Bas 1994, 113, 1-19; Pohlmann, A.; Schanen, V.; Guillaume, D.; Quirion, J-C. and Husson, H-P. J. Org. Chem. 1997, 62, 1016-1022.
9. 2 Gante, J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1699-1720; Kolter, T.; Dahl, C. and Giannis, A. Liebigs Ann. 1995, 625-629; Toniolo, C. Int. J. Peptide Protein Res. 1990, 35, 287-300; Liskamp, R. M. J. Recl. Trav. Chim. Pays-Bas 1994, 113, 1-19; Pohlmann, A.; Schanen, V.; Guillaume, D.; Quirion, J-C. and Husson, H-P. J. Org. Chem. 1997, 62, 1016-1022.
10. 3 For other solid phase C-alkylation reactions, see Moon, H-S.; Schore, N. E. and Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915; Backes, B. J. and Ellman, J. A. J. Amer. Chem. Soc. 1994, 11171, Patchornik A. and Kraus, M. A. J. Amer. Chem. Soc. 1970, 92, 7587; Worster, P. M.; McArthur, C. R. and Leznoff, C. C. Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Chang, Y. H.; Ford, W. T. J. Org. Chem. 1981, 46, 5364; O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
11. 3 For other solid phase C-alkylation reactions, see Moon, H-S.; Schore, N. E. and Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915; Backes, B. J. and Ellman, J. A. J. Amer. Chem. Soc. 1994, 11171, Patchornik A. and Kraus, M. A. J. Amer. Chem. Soc. 1970, 92, 7587; Worster, P. M.; McArthur, C. R. and Leznoff, C. C. Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Chang, Y. H.; Ford, W. T. J. Org. Chem. 1981, 46, 5364; O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
12. 3 For other solid phase C-alkylation reactions, see Moon, H-S.; Schore, N. E. and Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915; Backes, B. J. and Ellman, J. A. J. Amer. Chem. Soc. 1994, 11171, Patchornik A. and Kraus, M. A. J. Amer. Chem. Soc. 1970, 92, 7587; Worster, P. M.; McArthur, C. R. and Leznoff, C. C. Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Chang, Y. H.; Ford, W. T. J. Org. Chem. 1981, 46, 5364; O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
13. 3 For other solid phase C-alkylation reactions, see Moon, H-S.; Schore, N. E. and Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915; Backes, B. J. and Ellman, J. A. J. Amer. Chem. Soc. 1994, 11171, Patchornik A. and Kraus, M. A. J. Amer. Chem. Soc. 1970, 92, 7587; Worster, P. M.; McArthur, C. R. and Leznoff, C. C. Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Chang, Y. H.; Ford, W. T. J. Org. Chem. 1981, 46, 5364; O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
14. 3 For other solid phase C-alkylation reactions, see Moon, H-S.; Schore, N. E. and Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915; Backes, B. J. and Ellman, J. A. J. Amer. Chem. Soc. 1994, 11171, Patchornik A. and Kraus, M. A. J. Amer. Chem. Soc. 1970, 92, 7587; Worster, P. M.; McArthur, C. R. and Leznoff, C. C. Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Chang, Y. H.; Ford, W. T. J. Org. Chem. 1981, 46, 5364; O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
15. 3 For other solid phase C-alkylation reactions, see Moon, H-S.; Schore, N. E. and Kurth, M. J. Tetrahedron Lett. 1994, 35, 8915; Backes, B. J. and Ellman, J. A. J. Amer. Chem. Soc. 1994, 11171, Patchornik A. and Kraus, M. A. J. Amer. Chem. Soc. 1970, 92, 7587; Worster, P. M.; McArthur, C. R. and Leznoff, C. C. Angew. Chem. Int. Ed. Engl. 1979, 18, 221; Chang, Y. H.; Ford, W. T. J. Org. Chem. 1981, 46, 5364; O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070.
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18. 5 Detailed procedure for dibenzylation of 4: To a slurry of 2-chlorotrityl Resin 4 (200 mg, 1.3 mmol/g loading) swelled for 5 min in 3 ml anh. THF in a 10 ml cartridge capped with a rubber septa was added 0.22 ml (1.87 mmol) benzyl bromide. After shaking for 5 min, 2.0 ml of a 1M THF solution of lithium hexamethyldisilazide was added and the mixture was shaken overnight. The beads were then washed with THF × 2, DCM × 2, MeOH × 2 and DCM × 2 and cleaved with 2 ml of 7:1:2 DCM:MeOH:TFA to generate 80 mg of crystalline solid 5b as the only product.
19. 6 We also examined the use of Schwesenger's bases without success. See O'Donnell, M. J.; Zhou, C. and Scott, W. L. J. Am. Chem. Soc. 1996, 118, 6070 for related studies.
20. 7 Unpulished result from Mckittrick, B.
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22. b. IRORI, P.O. Box 502778, San Diego, CA 92150-2778.