Orthogonal Protection and Implications to Peptide Elongation

Concerning the first approach, methyl or alkyl protection of the phosphinic group requires suitable masking of the carboxylic terminus of the main pseudodi-peptidic unit which could be selectively removed prior to C-elongation. Selective deprotection of carboxylic esters in the presence of alkyl phosphinates include enzymatic hydrolysis of methyl carboxylates [18, 58], controlled alkaline hydrolysis of ethyl carboxylates [59, 60], acidic cleavage of 3,4-dimethoxybenzyl 

Several reports have dealt with the use of phosphinic pseudodipeptide building blocks in peptide couplings where both phosphinic and carboxylic acids are unprotected. Among the coupling reagents used successfully for such transformations are W,W -carbonyldiimidazole (CDl) [66-68], (benzotriazol-l-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (BOP) [69, 70], 

Campagne et al. have studied both C- and N-terminus peptide elongation with BOP (or pyBOP) and verified that this process is epimerization-free and applicable to peptide synthesis in the solid phase [69]. In some case, EDC has also been used in the solid phase peptide synthesis using the Fmoc protocol [54, 

However, none of these protocols have ever been used in synthesis of phosphinic peptide libraries by automated synthetic methods. 

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