An efficient, versatile linker is developed for the synthesis of C-terminal primary/secondary amides and hydrazides as well as peptide alcohols, which is compatible with solid-phase peptide synthesis (SPPS) and suppresses side reactions.  It is termed as Ramage Linker.

The basis for the Ramage linker is a dibenzocyclohepta-1,3-dienyl system with an additional oxygen substituent which serves on one hand for further stabilization. The Ramage linker represents an alternative to the commonly used Rinklinker for the synthesis of C-terminal peptide amides. The three-circular structure of the Ramage linker prevents its fragmentation cleavage from the resin followed by back alkylation. This is a drawback commonly observed during peptide synthesis with the Rinklinker. Consequently, the Ramage linker delivers peptides in higher purity with less impurities compared to peptides produced with the Rinklinker.

Besides C-terminal amides, the Ramage linker can also be used for the synthesis of C-terminal peptide alcohols.

Their diverse biological activities and clinical importance are described in various publications. One prominent example is Octreotide, a metabolically stable analog of somatostatin which contains threoninol at the C-terminus. Starting from the Ramage linker or resin, the deprotected primary amine can be converted to a hydroxy moiety and further to the corresponding chloride, which can then be loaded with Fmoc-amino alcohols.  Analogous to the preparation of peptide amides, the synthesized sequence can be detached from the linker and fully deprotected by conventional reagents.

References:

  • Design of a versatile linker for solid phase peptide synthesis: Synthesis of C-terminal primary / secondary amides and hydrazides; R. Ramage, S. L. Irving and C. McInnes; Tetrahedron Lett 1993; 34: 6599-6602
  • Functionalized Resins for the Synthesis of Peptide Alcohols; F. J. Ferrer Gago, L. Q. Koh, D. P. Lane; Chem. Eur. J. 2020; 26(2): 379-383
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