Efficient acylation of the N-terminus of highly hindered Cα,α-disubstituted amino acids via amino acid symmetrical anhydrides

Organic Letters

Volumn 4, Issue 2, 2002, Pages 237-240

  Fu, Yanwen ^a   Hammer, Robert P ^a  

^a LOUISIANA STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACID ANHYDRIDE; AMINO ACID; OLIGOPEPTIDE; SOLVENT;

ACYLATION; ARTICLE; CHEMISTRY; HYDROGEN BOND; PROTEIN SECONDARY STRUCTURE; SYNTHESIS;

ACYLATION; AMINO ACIDS; ANHYDRIDES; HYDROGEN BONDING; OLIGOPEPTIDES; PROTEIN STRUCTURE, SECONDARY; SOLVENTS;

EID: 0037165373     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol016965k     Document Type: Article

References (29)

1. For recent examples of αβAAs in highly structured peptides, see: (a) Formaggio, F.; Crisma, M.; Rossi, P.; Scrimin, P.; Kaptein, B.; Broxterman, Q. B.; Kamphuis, J.; Toniolo, C. Chem.-Eur. J. 2000, 6, 4498-4504. (b) Vijayalakshmi, S.; Rao, R. B.; Karle, I. L.; Balaram, P. Biopolymers 2000, 53, 84. (c) Yokum, T. S.; Gauthier, T. J.; Hammer, R. P.; McLaughlin, M. L. J. Am. Chem. Soc. 1997, 119, 1167-1168.
2. For recent examples of αβAAs in highly structured peptides, see: (a) Formaggio, F.; Crisma, M.; Rossi, P.; Scrimin, P.; Kaptein, B.; Broxterman, Q. B.; Kamphuis, J.; Toniolo, C. Chem.-Eur. J. 2000, 6, 4498-4504. (b) Vijayalakshmi, S.; Rao, R. B.; Karle, I. L.; Balaram, P. Biopolymers 2000, 53, 84. (c) Yokum, T. S.; Gauthier, T. J.; Hammer, R. P.; McLaughlin, M. L. J. Am. Chem. Soc. 1997, 119, 1167-1168.
3. For recent examples of αβAAs in highly structured peptides, see: (a) Formaggio, F.; Crisma, M.; Rossi, P.; Scrimin, P.; Kaptein, B.; Broxterman, Q. B.; Kamphuis, J.; Toniolo, C. Chem.-Eur. J. 2000, 6, 4498-4504. (b) Vijayalakshmi, S.; Rao, R. B.; Karle, I. L.; Balaram, P. Biopolymers 2000, 53, 84. (c) Yokum, T. S.; Gauthier, T. J.; Hammer, R. P.; McLaughlin, M. L. J. Am. Chem. Soc. 1997, 119, 1167-1168.
4. For examples of antimicrobial active peptides containing ααAAs, see: (a) Epand, R. F.; Epand, R. M.; Formaggio, F.; Crisma, M.; Wu, H.; Lehrer, R. I.; Toniolo, C. Eur. J. Biochem. 2001, 268, 703-712. (b) Yokum, T. S.; Elzer, P. H.; McLaughlin, M. L. J. Med. Chem. 1996, 39, 3603-3604.
5. For examples of antimicrobial active peptides containing ααAAs, see: (a) Epand, R. F.; Epand, R. M.; Formaggio, F.; Crisma, M.; Wu, H.; Lehrer, R. I.; Toniolo, C. Eur. J. Biochem. 2001, 268, 703-712. (b) Yokum, T. S.; Elzer, P. H.; McLaughlin, M. L. J. Med. Chem. 1996, 39, 3603-3604.
6. αα-dipropylglycine; Fmoc, 9-fluorenylmethoxycarbonyl; HATU, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HBTU, O-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOAt, hydroxy-7-azabenzotriazole; MALDI-MS, matrix assisted laser desorption ionization mass spectrometry; PAL, 5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid; PEG-PS, poly(ethylene glycol)polystyrene graft; PyAOP, 7-azabenzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate; TFA, trifluoroacetic acid; TOAC, 2,2,6,6-tetramethylpiperidine-1-oxyl-4-carboxylic acid; TPS, triisopropylsilane.
7. For a review of coupling methods for sterically hindered amino acids, see: Humphrey, J. M.; Chamberlain, A. R. Chem. Rev. 1997, 2243-2266.
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21. 2 (xxx = Lys and/or Glu) were performed on Perseptive Biosystem Peptide Synthesizer 9050 with Fmoc-PAL-PEG-PS resin as solid support. Solvent, DMF; PyAOP, 4 equiv; DIEA, 8 equiv; Fmoc amino acids, 4 equiv. Acylation of the W-terminal Dpg was performed at 50°C, while all other couplings were carried out without heating. Deblock, piperdine:DBU:DMF (5:2:93).
22. 2, see: Fu, Y.; Hammarström, L. G. J.; Miller, T. J.; Fronczek, F. R.; McLaughlin, M. L.; Hammer, R. P. J. Org. Chem. 2001, 66, 7118-7124.
23. PyAOP and HATU are not soluble in DCE or DCE-DMF (9:1); couplings in these solvents were not attempted.
24. Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J. Am. Chem. Soc. 1990, 112, 9651-9652.
25. (a) Rich, D. H.; Bhatnagar, P.; Mathiaparanam, P.; Grant, J. A.; Tam, J. P. J. Org. Chem. 1978, 43, 296-302.
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27. Colucci, W. J.; Tung, R. D.; Petri, J. A.; Rich, D. H. J. Org. Chem. 1990, 55, 2895-2903.
28. Acylation using PyAOP/HOAt, via amino acid fluorides or symmetrical anhydrides, were performed under the same conditions as described in Table 1, note c.
29. The first six Lys residues were coupled to PAL-PEG-PS resin under PyAOP/DIEA/DMF coupling conditions on Perseptive Biosystem Peptide Synthesizer 9050. The rest of amino acid residues were incorporated manually into the sequence. Dpg, Phe, and Dbzg were incorporated into sequence using PyAOP/DIEA in DCE-DMF (1:1); Val residue was coupled to N-terminus of Dbzg via amino acid symmetrical anhydride method; Dibg was coupled to Val using HATU (4 equiv), HOAt (4 equiv), DIEA (8 equiv), and Fmoc-Dibg-OH (4 equiv, 0.3 M) in DCE/DMF (1:1) at 50°C; Lys residue was coupled to Dibg via symmetrical anhydride at 50°C.