A novel handle for chemistry on solid support: the Pipecolic linker

Paweł Zajdel 1Gael Nomezine 2Nicolas Masurier 2Muriel Amblard 2Maciej Pawłowski 1Jean Martinez 2Gilles Subra 2

1. Jagiellonian University, Medical College, Department of Medicinal Chemistry, Medyczna 9, Kraków 30-688, Poland
2. Institute Biomolecules Max Mousseron, Department of Amino Acids, Peptides and Proteins (IBMM), 15 Av. Charles Flahault, Montpellier 34-093, France

Abstract

Here we present the design, the synthesis and the use of a new linker for solid-phase chemistry. The pipecolic linker (Pip) was designed on the basis of a side reaction observed on BAL linker functionalized SynPhase Lanterns while synthesizing a focused library of long-chain arylpiperazines.1 Surprisingly, the TFA cleavage of the Lantern-bound pipecolic acid derivatives did not yield the desired N-acylpipecolyl amides. TFA treatment caused an unprecedented selective hydrolysis of the linker-bound amide bond, which yielded two unexpected products: the free primary amines, and the N-acylated pipecolic acid.

The pipecolic linker is a highly versatile handle as it can immobilize on solid support primary, secondary and aromatic amines as well as alcohols, phenols, and hydrazides.

The advantages of the Pipecolic linker over commercially available ones are very easy and efficient anchoring and high purity of the released products. In addition, solid supports functionalized with pipecolic linker are fully recyclables.2

Pipecolic linker can accommodate a wide range of compounds and could be useful in many fields of supported chemistry (i.e. peptide and pseudopeptide synthesis, heterocycle synthesis). The use of this TFA-labile linker is demonstrated for side chain and N-terminus anchoring of peptides and pseudopeptides as well as for the preparation of C-terminal peptide hydrazides.3

References

1. Zajdel, P.; Subra, G.; Bojarski, A.J.; Duszyńska, B.; Pawłowski, M.; Martinez, J. A new class of arylpiperazine derivatives: the library synthesis on SynPhaseTM lanterns and biological evaluation on serotonin 5-HT1A and 5-HT2A receptors. J. Comb. Chem. 2004, 6, 761-767.

2. Martinez, J.; Zajdel, P.; Pawłowski, M.; Subra, G. Pipecolic linker and its use for chemistry on solid support. PCT/EP2009/061171.

3. Zajdel, P.; Nomezine, G; Masurier, N.; Amblard, M.; Pawłowski, M.; Martinez, J.; Subra, G. A new, highly versatile handle for chemistry on a solid support: the Pipecolic linker (Pip). Chem. A Eur. J. Chem.201000313.

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Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Paweł Zajdel
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-13 13:29
Revised:   2010-03-14 16:35
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