"Safety-catch" anchoring linkages and protecting groups in solid-phase peptide synthesis

The C-terminal amide functionality which is found in many natural peptides often serves as a focal point for the development of synthetic methodology. The recent advances in peptide synthesis have opened vast new ideas for the intelligently designed use of anchoring linkages and protecting groups in synthesis of complex peptides [I]. In particular, there is growing interest in the use of linkages and protecting groups, the cleavage of which is based on the "safety-catch" principle [2,3,4]. Depending on the structure and cleavage conditions, these "protected protecting systems" may be applicable to Boc-lFmoc-/Allyl-chemistries since such anchoring and protection offer the benefit of enhanced dimension of orthogonality during the synthesis. Moreover, the advantage that side-chain deprotection may be accomplished prior to cleavage from the support makes this methodology even more attractive. In OUf preliminary communication we have reported on the "safety-catch" anchoring linkage (SCAL) for synthesis of peptide amides [5]. The present report summarizes the results obtained with the SeAL anchoring and introduces a new "safety-catch" 2-methoxy-4,4'-bis(methylsulfinyl)benzhydryl (Msbh) (Figure I) and 4,4'-bis(methylsulfinyl)trityl (Strt) protecting gronps which have been evaluated as potential side-chain amide and SH protecting groups, respectively (Figure 2).