2-Methoxy-4-methylsulfinylbenzyl Alcohol as a Safety-Catch Linker for the Fmoc/tBu Solid-Phase Peptide Synthesis Strategy

Fmoc and Boc group are the two main groups used to protect the alpha-amino function in Solid-Phase Peptide Synthesis (SPPS). In this regard, the use of the Mmsb linker allows the combination of these two groups. Peptide-O-Mmsb-Resin is stable to the piperidine and trifluoroacetic acid (TFA) treatment used to remove Fmoc and Boc, respectively. The peptide is detached in a two-step protocol, namely reduction of the sulfoxide to the sulfide with Me3SiCl and Ph3P, and then treatment with TFA. The advantage of this strategy has been demonstrated by the following: preparation of peptide with no diketopiperazine formation in sequences prone to this side reaction; on-resin cyclization without the concourse of common organic reagents such as Pd(0) but of difficult use in a biological laboratory; and on-resin disulfide formation in a total side-chain unprotected peptide. The use of Mmsb linker together with Msib (4-(methylsulfinyl)benzyl) and Msbh (4,4 & PRIME;-bis(methylsulfinyl)benzhydryl) described in the accompanying manuscript add a fourth dimension to the SPPS protecting group scheme.

Automated summary

Fmoc and Boc groups are commonly used protective groups in solid-phase peptide synthesis, and the Mmsb linker allows for their simultaneous use. Peptide-O-Mmsb-Resin remains stable during the removal of Fmoc and Boc using piperidine and trifluoroacetic acid (TFA) treatment. This strategy has advantages such as preventing diketopiperazine formation in sequences prone to this side reaction, enabling on-resin cyclization without the use of common organic reagents, and facilitating on-resin disulfide formation in unprotected peptides.