Combinatorial libraries based on a novel and readily accessible 'centroid' scaffold

Tetrahedron Letters

Volumn 39, Issue 30, 1998, Pages 5317-5320

  Neustadt, Bernard R ^a   Smith, Elizabeth M ^a   Nechuta, Terry ^a   Zhang, Yongzheng ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACID; FUNCTIONAL GROUP;

ACYLATION; ARTICLE; HYDROGENATION; LIBRARY;

EID: 0032560832     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)01076-4     Document Type: Article

References (22)

1. 1. Recent reviews on combinatorial chemistry and applications in drug discovery: (a) Bristol, J.A., Ed. Tetrahedron, 1997, 53, 6573.
2. (b) Szostak, J., Ed. Chemical Reviews, 1997, 97, 347.
3. (c) Beutel, B.A. Ann. Reports Med. Chem. 1997, 32, 261.
4. (d) Plunkett, M.J.; Ellman, J.A. Scientific American 1997, 276(4), 68.
5. (e) Hogan, J.C. Nature Biotech., 1997, 15, 328.
6. A centro-symmetric library based on Kemp's triacid: Kocis, P.; Issakova, O.; Sepetov, N.; Lebl, M. Tetrahedron Lett. 1995, 36, 6623. A centro-symmetric library based on 3-amino-5-hydroxybenzoic acid: Dankwardt, S. M.; Phan, T. M.; Krstenansky, J. L. Mol. Diversity 1996, 1, 113. A centro-symmetric library based on triaminotriazine: Stankova, M.; Lebl, M. Mol. Diversity 1996, 2, 75.
7. A centro-symmetric library based on Kemp's triacid: Kocis, P.; Issakova, O.; Sepetov, N.; Lebl, M. Tetrahedron Lett. 1995, 36, 6623. A centro-symmetric library based on 3-amino-5-hydroxybenzoic acid: Dankwardt, S. M.; Phan, T. M.; Krstenansky, J. L. Mol. Diversity 1996, 1, 113. A centro-symmetric library based on triaminotriazine: Stankova, M.; Lebl, M. Mol. Diversity 1996, 2, 75.
8. A centro-symmetric library based on Kemp's triacid: Kocis, P.; Issakova, O.; Sepetov, N.; Lebl, M. Tetrahedron Lett. 1995, 36, 6623. A centro-symmetric library based on 3-amino-5-hydroxybenzoic acid: Dankwardt, S. M.; Phan, T. M.; Krstenansky, J. L. Mol. Diversity 1996, 1, 113. A centro-symmetric library based on triaminotriazine: Stankova, M.; Lebl, M. Mol. Diversity 1996, 2, 75.
9. 3. Lancaster Synthesis, catalog no. 6046. Also available from other suppliers.
10. 4. (a) Terpko, M.O.; Heck, R.F. J. Org. Chem. 1980, 45, 4992.
11. (b) Georg, G.I.; Boge, T.C.; Park, H.; Himes, R. H. Bioorg. Med. Chem. Lett. 1995, 57, 615.
12. 5. Preparation of 1: To an N2-degassed solution of Na2CO3 (14.6 g, 138mmol) in water (160 mL) was added nitro-acid 2 (10.0 g, 55mmol) in dioxane (130 mL). The mixture was cooled to 5°C, and Fmoc-chloride (14.2 g, 55mmol) in dioxane (90 mL) was added dropwise over 15min. The mixture was stirred in the bath 30min., then 24h. without the bath. The solid was filtered and washed with water (40 mL). The filtrate was concentrated to 160 g, allowed to cool, filtered and washed with water. The two solids were combined, stirred with water (75 mL) for 30min., filtered and washed. The procedure was repeated with ether (100 mL), then the solid partitioned between 250 mL each EtOAc and 1N HCl. The EtOAc was washed with brine, dried over MgSO4 and concentrated. Drying at 0.1mm left 18.9 g of 3 as a yellow solid, m.p. 249-52°C, single component HPLC. In a one-liter Parr bottle were placed 5% Pd/C (1.5 g), CH2Cl2 (225 mL), MeOH (175 mL), Fmoc-acid 3 (15.5 g, 38mmol), and MeSO3H (3.6 g, 38mmol). The mixture was hydrogenated at 50 psi for 40 min, then filtered. The filtrate was concentrated and the residue treated with EtOAc (100 mL) and MeOH (4 mL). Filtration and drying left 8.7 g powder. The initial catalyst-containing solid was treated withMeOH (300 mL) and CH2Cl2(50 mL). Concentration left a solid which was treated with EtOAc-MeOH as above to provide 9.4 g solid. The two solids 1 were combined. The product shows clean PMR, with 0.7 equiv. MeOH, and HPLC gives a single peak.
13. 6. A dialkoxybenzyl alcohol resin obtained from BACHEM: Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P. Tetrahedron Lett. 1988, 29, 4005.
14. 7. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927.
15. 8. Vydac column, 25-95% MeCN-H2O gradient (0.1%TFA), 1ml/min., UV detection at 254nM.
16. 9. PyBroP=bromo-tris-pyrrolidinophosphonium hexafluorophosphate: Coste, J.; Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991, 32, 1967.
17. 10. Obtained from AnaSpec Inc., San Jose, CA.
18. 11. Utilization of 1 in library synthesis: Aminoacyl resin (0.30g, 0.15mmol)) was treated with salt 1 (3 equiv.), 0.5M HBTU/HOBt in DMF (3 equiv.) and DIPEA (12 equiv.) for 1.5 h., followed by DMF and CH2Cl2 washes, 5×20ml each.. All agitation was achieved by nitrogen sparge through a fritted plate. Resin (0.10g) was then treated with aroyl chloride (10 equiv.) and DIPEA (20 equiv.) in CH2Cl2 for 1.5 h, followed by DMF and CH2Cl2 washes, 3×10ml each. The Fmoc group was removed by two 15 min. treatments with 20% piperidine/DMF. The second acylation with acyl chloride was conducted under the same conditions as the first. If this reaction was not complete (HPLC), the procedure was repeated. For cleavage, the resin was treated with CH2Cl2-TFA-H2O 99:1:0.05 (three 15min. cycles) and the combined filtrates concentrated in vacuo.
19. 12. PyBroP (10 equiv.), RCOOH (10 equiv.), DIPEA (20 equiv.), CH2Cl2, 18h. shaking.
20. 13. Yang, L.; Guo, L. Tetrahedron Lett. 1996, 37, 5041.
21. 14. Ester formation by cleavage from the resin with alkoxide or with rnethanol+amine have been utilized: (a) Fagnola, M.C.; Candiani, I.; Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307
22. (b) Cheng, Y.; Chapman, K.T. Tetrahedron Lett. 1997, 38, 1497. As an alternative, we have conducted successful cleavage with HCl/MeOH to yield methyl esters.