PotM: Safety Catch - Orthogonally Protected Amino Acids

PotM: Safety Catch - Orthogonally Protected Amino Acids

Published on 10.07.2023

Add a new dimension of orthogonality to your peptide synthesis by using Safety-Catch arylalkyl sulfoxide protecting groups! This newsletter tells you about benefits and usage – Read on!

PotM: Safety Catch - Orthogonally Protected Amino Acids

Safety-Catch protecting groups are useful when another dimension of orthogonality to the „conventional“ protection schemes (Fmoc, Boc, Trt, tBu, Mmt, Dmt) is needed, e.g. during the controlled synthesis of cyclic peptides with multiple disulfide bridges, with complex and difficult peptides, or as remedy against aggregation during synthesis.

Among these Safety-Catch protecting groups, the arylalkyl-sulfoxides Msz [4-(methylsulfinyl)benzyl-], MsbH [bis(4-(methylsulfinyl)benzhydryl)-], Mmsb [2-methoxy-4-(methylsulfinyl)benzyl-] and Msib [4-(methylsulfinyl)benzyl-] have proven to be especially useful for masking functional groups which contain terminal atoms with free electron pairs (-OH, -SH, -NH2). Thus, they are suitable to protect, e.g., the side chains of the natural amino acids Lys, Tyr, Asp, Glu, Cys, Ser, and Thr, and of other building blocks which are used for peptide synthesis. To our portfolio, we have added additional sidechain protected amino acids available as ready to use Fmoc-protected building blocks.

Structures of the Msz, MsbH, Mmsb, and Msib protecting groups: The arylalkyl sulfoxide moieties are highlighted in blue, bonds that will be broken during deprotection are highlighted in red.

Removal: upon reduction of the sulfoxide(s) to thioethers, Msz and related groups will become acid labile. This may be achieved by treatment with e.g., Me3SiCl/Ph3P in THF, followed by acidification with TFA, or with NH4I/Me2S/TFA in one step.

Reductive acidolytic removal of an arylalkyl sulfoxide protecting group, exemplified with an Msz protected amine. The bonds which will be broken are highlighted in red. As a specialty of Msz, carbon dioxide is formed during the process, this is further driving the removal reaction to completion.

From a chemical point of view, a massive change of the electron density distribution in the protecting group is happening after its reduction, and the bond between the protected functional group and the protective moiety becomes acid labile, as then a stabilized carbenium ion is formed.

In practice, the acidolysis with TFA warrants a quick and smooth deprotection, which conveniently may be included in the final resin cleavage step of an Fmoc based SPPS process.

→ You are looking for a safety catch derivative not listed in the section related products at the end of this page? Inquire for a custom synthesis! 
→ Interested in the synthesis of cyclic peptides with multiple disulfide bridges? Download our brochure Cyclic Peptides

References:

A new safety-catch protecting group and linker for solid-phase synthesis; S. Thennarasu, C. Liu; Tetrahedron Lett. 2010; 51: 3218-3220. https://doi.org/10.1016/j.tetlet.2010.04.047

Semipermanent C-terminal carboxylic acid protecting group: Application to solubilizing peptides and fragment condensation; M. Paradís-Bas, J. Tulla-Puche, F. Albericio; Org. Lett. 2015; 17: 294-297. https://doi.org/10.1021/ol5033943

2-Methoxy-4-methylsulfinylbenzyl alcohol as a Safety-Catch linker for the Fmoc/tBu solid-phase peptide synthesis strategy; K. P. Nandhini, F. Albericio, B. G. de la Torre; J. Org. Chem. 2022; 87: 9433-9442. https://doi.org/10.1021/acs.joc.2c01057

Solid-phase peptide synthesis using a four-dimensional (Safety-Catch) protecting group scheme; S. Noki, E. Brasil, H. Zhang, T. Bruckdorfer, B. G. de la Torre, F. Albericio; J. Org. Chem. 2022; 87: 9443-9453. https://doi.org/10.1021/acs.joc.2c01056

A safety-catch type of amide protecting group; M. Pátek, M. Lebl; Tetrahedron Lett. 1990; 31: 5209-5212. http://doi.org/10.1016/S0040-4039(00)97844-4

Verwandte Produkte
    1. Fmoc-L-Cys(Msbh)-OH
      Fmoc-L-Cys(Msbh)-OH

      Art-Nr.: FAA4155

      Ab 90,00 €

    2. Fmoc-NH-MsbH-COOH
      Fmoc-NH-MsbH-COOH

      Art-Nr.: RL-2260

      Ab 150,00 €

    3. Structure image for Fmoc-D-Cys(Msbh)-OH
      Fmoc-D-Cys(Msbh)-OH

      Art-Nr.: FAA8150

      Ab 1.000,00 €

    4. Fmoc-L-Ser(Msbh)-OH
      Fmoc-L-Ser(Msbh)-OH

      Art-Nr.: FAA8835

      Ab 375,00 €

    5. Fmoc-D-Ser(Msbh)-OH
      Fmoc-D-Ser(Msbh)-OH

      Art-Nr.: FAA8837

      Ab auf Anfrage

    6. Fmoc-L-Lys(Msz)-OH
      Fmoc-L-Lys(Msz)-OH

      Art-Nr.: FAA9100

      Ab 900,00 €

    7. Fmoc-L-Thr(MsbH)-OH
      Fmoc-L-Thr(MsbH)-OH

      Art-Nr.: FAA7865

      Ab 600,00 €

    8. Fmoc-L-Tyr(Msib)-OH
      Fmoc-L-Tyr(Msib)-OH

      Art-Nr.: FAA7885

      Ab 900,00 €

    9. Fmoc-L-Asp(Msib)-OH
      Fmoc-L-Asp(Msib)-OH

      Art-Nr.: FAA7895

      Ab 600,00 €

    10. Fmoc-L-Glu(Msib)-OH
      Fmoc-L-Glu(Msib)-OH

      Art-Nr.: FAA7905

      Ab 600,00 €

    11. Fmoc-N(Mmsb)-Gly-OH
      Fmoc-N(Mmsb)-Gly-OH

      Art-Nr.: FAA7340

      Ab 175,00 €

    12. Mmsb-OH Linker
      Mmsb-OH Linker

      Art-Nr.: RL-3895

      Ab 375,00 €