A selectively cleavable protecting group for the epsilon-amino group of lysine plays an important role during peptide synthesis, e.g., for the modification of the lysine side chain on the synthesis resin.

Trityl-based, mildly acidic cleavable protecting groups, e.g., Mtt or Mmt, are incompatible with strongly acid-labile resin linkers such as trityl. Amino acid derivatives, which carry the hydrazinolysis-susceptible protecting group Dde [1] or ivDde [2] are frequently used for the synthesis of branched, cyclic, or side chain-modified peptides. These protecting groups are stable towards 20% piperidine and TFA. Compared to ivDde, Dde is easier to cleave, but is less robust. Thus, during Fmoc cleavage, Dde might migrate to free lysine epsilon‑amino groups or, in the case of diaminopropionic acid, to the free alpha‑amino group. Especially during the synthesis of longer peptide sequences, a certain extent of Dde is removed during Fmoc cleavage with piperidine [3]. The sterically more demanding protecting group ivDde is more stable towards piperidine and does not migrate to free lysine epsilon-amino groups, but still to free amino groups of diaminopropionic acid [4]. Besides, for some sequences, total removal of ivDde is hardly possible [5], especially at the C-terminus or in aggregating sequences.

A newer group for the orthogonal protection of amino groups is MeDmb (methyl dimethylbarbituric acid) [6,7]. In this project we present the possibilities and limitations of the new lysine Dmb derivatives (MeDmb, EtDmb, ivDmb) and compare their properties with the existing protecting groups Dde and ivDde.

References

[1]      J. Chem. Soc. Chem. Commun. 1993, 778-779.

[2]       Tetrahedron Lett. 1998, 39, 1603-1606.

[3]       J. Peptide Res. 1998, 51, 127-133.

[4]       Peptides for the New Millennium, Proc. 16th American Peptide Symposium, p. 58f.

[5]       Tetrahedron Lett. 2003, 44, 1911-1913.

[6]       Tetrahedron Lett. 2003, 44, 3621-3624.

[7]       J. Braz. Chem. Soc. 2004, 15, 433-436.