Avoiding Racemization: Fmoc-Aaa-MPPAs as Alternatives for Wang Linker during SPPS

The growing interest in peptide-based drugs highlights the importance to emerge improved synthetic strategies in terms of efficiency, yield, and purity especially for longer peptides so that peptide drugs can reach their full potential.

One of the most prominent systems yielding peptides with a free carboxylic acid at the C-terminus after cleavage from the solid support is the so-called “Wang linker” based on a para-alkoxybenzyl ester anchoring linkage towards the resin. However, the coupling of Fmoc-amino acids to para-hydroxymethylphenoxymethyl resins using dicyclohexylcarbodiimide (DCC) in the presence of 4-dimethylaminopyridine (DMAP) typically suffers from two problems, namely, the formation of dimers and racemization.

Herein, based on the Wang-linker, we present a set of protected amino acid loaded oxymethylphenoxy propionic acid (MPPA) building blocks, which serve as precursors for the linkage to amino substituted solid supports (e.g. aminomethyl polystyrene, BHA or MBHA resins) by standard coupling procedures. As protecting group, the base-labile 9-fluorenylmethyloxycarbonyl (Fmoc) is used. After successful synthesis, the peptide is released from the resin by TFA-mediated cleavage yielding the free carboxylic acid on the C-terminus.

This method guarantees a low (max 0.5%) and reproducible epimerization level of the C-terminal amino acid in your peptide and allows the synthesis of pure peptides even in large scale.

➔ Scroll down and see all available preloaded MPPA building blocks in the section “related products”. Besides, we listed a selection of available polystyrene amino resins.

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References:

• Improved approach for anchoring Nalpha-9-fluorenylmethyloxycarbonylamino acids as p-alkoxybenzyl esters in solid-phase peptide synthesis; F. Albericio, G. Barany; Int. J. Peptide. Protein. Res. 1985; 26(1): 92-97. https://doi.org/10.1111/j.1399-3011.1985.tb03182.x.

• Application of N,N-dimethylformamide dineopentyl acetal for efficient anchoring of N alpha-9-fluorenylmethyloxycarbonylamino acids as p-alkoxybenzyl esters in solid-phase peptide synthesis. F. Albericio, G. Barany; Int. J. Pept. Protein Res. 1984; 23(4): 342-349. https://doi.org/10.1111/j.1399-3011.1984.tb02729.x.

• Amino acid derivatives used as agents bonding to a solid support; NeoMPS S.A. 2005; French Patent Application FR 0402973, International Patent Application WO2005/095332.

• Synthesis and Evaluation of Novel TLR2 Agonists as Potential Adjuvants for Cancer Vaccines; B. L. Lu, G. M. Williams, D. J. Verdon, P. R. Dunbar, M. A. Brimble; J. Med. Chem. 2020; 63(5): 2282-2291. https://doi.org/10.1021/acs.jmedchem.9b01044.

• Native Chemical Ligation via N-Acylurea Thioester Surrogates Obtained by Fmoc Solid-Phase Peptide Synthesis; J. Palà-Puljadas, J. B. Blanco-Canosa; Int. J. Pept. Res. Ther. 2012; 18: 63-70. https://doi.org/10.1007/978-1-0716-0434-2_7.

• Preparation of amino acid derivatives for use in solid-phase peptide synthesis; F. Andre, P. Maetz, C. C. Devin, S. Plaue, X. Zhang; WO2005095332; 2005.

• Convergent solid phase peptide synthesis. I. Synthesis of protected segments on a hydroxymethylphenyloxymethyl resin using the base labile FMOC alpha-amine protection. Model synthesis of LHRH. E. Redroso, A. Grandas, M. A. Saralegui, E. Giralt, C. Granier, J. van Rietschoten; Tetrahedron 1982; 38(9): 1183-1192. https://doi.org/10.1016/0040-4020(82)85102-8.