Dramatically enhanced N→O acyl migration during the trifluoroacetic acid-based deprotection step in solid phase peptide synthesis

Tetrahedron Letters

Volumn 46, Issue 8, 2005, Pages 1361-1364

  Carpino, Louis A ^a   Krause, Eberhard ^b   Sferdean, Calin Dan ^a   Bienert, Michael ^b   Beyermann, Michael ^b  

^a UNIVERSITY OF MASSACHUSETTS   (United States)

^b LEIBNIZ INSTITUT FÜR MOLEKULARE PHARMAKOLOGIE   (Germany)

Author keywords

d Amino acid containing peptides; Depsipeptides; N O Acyl migration; Trifluoroacetic acid deblocking

Indexed keywords

DEPSIPEPTIDE; NITROGEN; OXYGEN; PEPTIDE DERIVATIVE; PROTEIN; SERINE; THREONINE; TRIFLUOROACETIC ACID;

ACIDITY; AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ARTICLE; DEPROTECTION REACTION; MIGRATION; PEPTIDE SYNTHESIS; SOLID;

EID: 13244298384     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2004.12.089     Document Type: Article

References (28)

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18. An exception involves the doubly hydroxylated, hindered amino acid, α-(hydroxymethyl)serine, which upon incorporation into a short peptide gives up to 40% of the corresponding depsipeptide upon treatment with TFA for 4 h [ M. Stasiak, and M.T. Leplawy Lett. Pept. Sci. 5 1998 449 ]
19. A more unusual case involves N-trifluoroacetylation of N-terminal threonine-containing peptides upon long time treatment with 99% TFA, which apparently occurs via initial O-trifluoroacetylation of the threonine hydroxyl group, which than rearranges to the N-TFA derivative. If, on the other hand 99% TFA/6 M HCl is used the completely deprotected peptide is obtained. These striking results suggest that 99% TFA does not completely protonate the terminal amino function of a peptide [ W. Gerd-Hübner, W. Göhring, H.-J. Musiol, and L. Moroder Pept. Res. 5 1992 287 ]
20. For a remarkable example of the difference between TFA and a stronger acid (e.g., methanesulfonic acid, MSA) see: M. Fujino, M. Wakimasu, S. Shinagawa, C. Kitada, and H. Yajima Chem. Pharm. Bull. 26 1978 539 These workers prepared mammalian glucagon by a solution-based segment coupling process using Boc/Bn chemistry. Five of the six segments used in the process contained unprotected serine or threonine units. TFA was used to deblock the N-terminal Boc protectant from each segment in preparation for segment coupling. No contamination due to the formation of depsipetides occurred whereas when the same segments were treated with MSA impurities arising from N→O shifts were encountered. The final deblocking to give the unprotected 29-mer required MSA to remove benzyl-based side chain protection and in this case, it was only after treatment with 0.5 N aqueous ammonia (O→N reversal) that a pure peptide could be obtained
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25. Authentic samples of the three threonine-linked depsipeptides were synthesized by standard methods and HPLC-based co-injection experiments confirmed their probable identity with the three unknown peaks. While not an absolute proof of structure since the small peaks in question were not isolated and sequenced, the corresponding serine-linked depsipeptide was synthesized in the same way and shown definitively by a similar experiment to be absent from the mixture of peptides obtained by assembly of all-l peptide 1
26. The term 'depsipeptide' refers here to the homomeric species in which the peptide is O-linked at serine or threonine in place of the normal amide linkage. For a recent discussion of the nomenclature and structural representation of these materials see: S.V. Filip, and F. Cavelier J. Pept. Sci. 10 2004 115
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