A New Highly Versatile Handle for Chemistry on a Solid Support: The Pipecolic Linker

Abstract

The design, synthesis, and potential application of the pipecolic linker is presented. This new versatile handle can immobilize primary, secondary, and aromatic amines, as well as alcohols, phenols, and hydrazides, on a solid support. Compared with other linkers, the anchoring step is easy and efficient. The release of final products from the resin proceeds upon acidic treatment with high purities. The pipecolic linker offers the promise of being using in peptide chemistry to produce peptides modified at the N and C terminus, peptidomimetics, as well as small organic molecules.

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

“…10 This hydrolytic sensitivity of peptidyl pipecolic acid residues was exploited by Zajdel, Subra, and co-workers in the design of pipecolic resin linkers for solid-phase applications. 11,12 …”

A New Highly Versatile Handle for Chemistry on a Solid Support: The Pipecolic Linker

“…The structure of compound 11 was ascertained by 1 H NMR and ESI‐mass spectroscopy ( m/z =223.1). The ureidodipeptide was not stable enough to be observed, contrary to the behavior of the corresponding monoacyl gem ‐diamino derivative 8. This result can be explained by the well‐known weak stability of pseudo gem ‐diamino compounds,17 which lead to the N ‐ monosubstituted urea derivative 11 after loss of isobutylamine.…”

“…However, these handles suffer from low yields of anchoring7 and high sensitivity to acidic conditions, limiting the use of other orthogonal acid‐labile protecting groups. Recently, we proposed the pipecolic linker (Pip‐linker), a novel trifluoroacetic acid (TFA)‐labile linker based on the pipecolic acid scaffold, which can be readily activated to anchor effectively and simply alcohol and amine groups 8. Anchoring of hydrazine is also possible, which constitutes an efficient way for the preparation of C‐terminal hydrazide peptides by conventional Fmoc solid‐phase peptide synthesis (SPPS) 8.…”

“…Recently, we proposed the pipecolic linker (Pip‐linker), a novel trifluoroacetic acid (TFA)‐labile linker based on the pipecolic acid scaffold, which can be readily activated to anchor effectively and simply alcohol and amine groups 8. Anchoring of hydrazine is also possible, which constitutes an efficient way for the preparation of C‐terminal hydrazide peptides by conventional Fmoc solid‐phase peptide synthesis (SPPS) 8. After anchoring and synthesis of target compound, the acidic treatment by TFA or acetic acid can easily release the target molecule from the Pip‐linker (Scheme ).…”

“…Anchoring of an amino acid through its side chain could represent a method of choice for the synthesis of N‐ to C‐cyclic peptides, for the coupling of peptide fragments, or for generation of C‐terminus‐modified peptides. Anchoring of serine, threonine, or tyrosine by the side chains proved to be efficient with the Pip‐linker 8. We now explored the anchoring of the lysine side chain to access C‐terminus‐modified peptides and to synthesize cyclic peptides.…”