Incorporation of a phosphonic acid isostere of aspartic acid into peptides using Fmoc-solid phase synthesis

Tetrahedron Letters

Volumn 39, Issue 15, 1998, Pages 2067-2070

  Lohse, P A ^a,b   Felber, R ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b Phylos Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ASPARTIC ACID DERIVATIVE; PEPTIDE; PHOSPHONIC ACID DERIVATIVE;

ARTICLE; CATALYSIS; PEPTIDE SYNTHESIS; PURIFICATION;

EID: 0032499093     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)00189-0     Document Type: Article

References (30)

1. 19 we think that (L)-AP-3 is identical to (R)-AP-3.
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17. 9. The dialkylphosphite 4 was prepared in analogy to the protocol for the synthesis of Bisf[2,2,2-trifluoroethyl]phosphite by Gibbs, D. E.; Larsen, C. Synthesis 1984, 410-413. The crude product was distilled at 0.4 mbar and 43 °C to give pure 4 (for analytical data see: Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.; Kraszewski, A. Synthesis 1995, 427). Synthesis of diallyl(trimethylsilyl)phosphite 5 was carried out in analogy to the procedure described: Afarinkia, K.; Rees, C. W.; Cadogan, J. I. G. Tetrahedron 1990, 46, 7187. The crude product was distilled at 0.5 mbar and 70 °C to give pure 5.
18. 9. The dialkylphosphite 4 was prepared in analogy to the protocol for the synthesis of Bisf[2,2,2-trifluoroethyl]phosphite by Gibbs, D. E.; Larsen, C. Synthesis 1984, 410-413. The crude product was distilled at 0.4 mbar and 43 °C to give pure 4 (for analytical data see: Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.; Kraszewski, A. Synthesis 1995, 427). Synthesis of diallyl(trimethylsilyl)phosphite 5 was carried out in analogy to the procedure described: Afarinkia, K.; Rees, C. W.; Cadogan, J. I. G. Tetrahedron 1990, 46, 7187. The crude product was distilled at 0.5 mbar and 70 °C to give pure 5.
19. 9. The dialkylphosphite 4 was prepared in analogy to the protocol for the synthesis of Bisf[2,2,2-trifluoroethyl]phosphite by Gibbs, D. E.; Larsen, C. Synthesis 1984, 410-413. The crude product was distilled at 0.4 mbar and 43 °C to give pure 4 (for analytical data see: Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.; Kraszewski, A. Synthesis 1995, 427). Synthesis of diallyl(trimethylsilyl)phosphite 5 was carried out in analogy to the procedure described: Afarinkia, K.; Rees, C. W.; Cadogan, J. I. G. Tetrahedron 1990, 46, 7187. The crude product was distilled at 0.5 mbar and 70 °C to give pure 5.
20. 18
21. 11. Reaction conditions were not optimized.
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23. 13. Fmoc-L-Phe-O-Wang resin was purchased from Novabiochem (Wang-resin: p-alkoxybenzyl-polystyrene). Fmoc cleavage was carried out with 20 % piperidine in dimethylacetamide (DMA) and resin washes with DMA-isopropanol-DMA. Building block 2b, Fmoc-Gly-OH (Bachem) and Fmoc-L-Arg(PMC)-OH (Bachem) were used for peptide-couplings. Flash-purified 2b was coevaporated with toluene to remove residual acetic acid before coupling. Couplings were performed in standard fashion in N-methylpyrrolidone using 2 eq. of Fmoc-amino acid and 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluroniumfluoroborate (TPTU, Fluka)/ diisopropylamine/ Fmoc-amino acid in a 1:1:1 ratio. Coupling was complete after 2 h reaction time as indicated by the Kaiser test: Kaiser, E. T.; Colescott, R. L.; Bossinger, C. D.; Cock, P. I. Anal. Biochem. 1970, 54, 595.
24. 14. Kates, S. A.; Daniels, S. B.; Sole, N. A.; Barany, G.; Albericio, F. Peptides, Structure & Biology, Proc. 13th American Peptide Symposium, ESCOM, Leiden, 1994, p. 114. Cleavage of the allyl ester protecting groups using the rapid azide-mediated, palladium (0) catalyzed cleavage works as well and yielded phosphonopeptides of comparable purity: Shapiro, G., Buechler, D. Tetrahedron Lett. 1994, 35, 5421-5424.
25. 14. Kates, S. A.; Daniels, S. B.; Sole, N. A.; Barany, G.; Albericio, F. Peptides. Structure & Biology, Proc. 13 th American Peptide Symposium, ESCOM, Leiden, 1994, p. 114. Cleavage of the allyl ester protecting groups using the rapid azide-mediated, palladium (0) catalyzed cleavage works as well and yielded phosphonopeptides of comparable purity: Shapiro, G., Buechler, D. Tetrahedron Lett. 1994, 35, 5421-5424.
26. 15. After washing with dimethylacetamide and methylene chloride, the resin was treated with trifluoracetic acid/ water 95:5 for 3 h at room temperature. The resin was filtered off and the filtrate was added to a 20 fold excess of hexane/ tert. butyl methyl ether 1:9. After standing for 45 min. at 4 °C, the precipitate was collected by centrifugation and dried under high vacuum to yield 3a as a colorless powder.
27. 15 to yield 3b as a colorless powder.
28. 2O/ 0.1 % trifluoracetic acid (eluent A) and acetonitrile/ 0.1 % trifluoracetic acid (eluent B) from 2 % to 60 % B over 10 min; flow rate 0.7 ml/min, detection at 215 nm, retention time: 3.72 min.
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