Alkylation of Peptide Bonds to Decrease Aggregation Oxazolidines and Thiazolidines Pseudo-Prolines

6 ALKYLATION OF PEPTIDE BONDS TO DECREASE AGGREGATION OXAZOLIDINES AND THIAZOLIDINES (PSEUDO-PROLINES) 

FIGURE 8.8 A peptide sequence containing an oxazolidine ring that gives rise to a serine residue on acidolysis and a thiazolidine ring that gives rise to a cysteine residue on acidolysis. Substituents at C-2 can be H2, H,Me, or Me2. A structure with a methyl group at C produces a threonine residue on acidolysis. 

FIGURE 8.9 Synthesis of 2,2-dimethyl-l,3-oxazolidines by reaction of the Fmoc-dipeptide with 2,2-dimethoxypropane (A) giving Fmoc-Xaa-Ser((4 MeMepro)-OH and (B) giving Fmoc-Xaa-Thr(4 MeMepro)-OH. Synthesis of a 2-methyl-1,3-thiazolidine by acylation of the cyclic parent (C) giving Fmoc-Xaa-Cys(YHMepro)-OH. NCA = /V-carboxyanhydridc. 

M Mutter, A Nefzi, T Sato, X Sun, F Wahl, T Wohr. Pseudo-prolines (Tpro) for accessing inaccessible peptides. Pept Res 8, 145, 1995. 

T Wohr, F Wahl, A Nefzi, B Rodwedder, T Sato, X Sun, M Mutter. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. JAm Chem Soc 118, 9218, 1996. 

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