Mechanisms for the Removal of Benzyl Protecting Groups in Synthetic Peptides by Trifluoromethanesulfonic Acid-Trifluoroacetic Acid-Dimethyl Sulfide

Article abstract of DOI:10.1021/ja00277a031

The need to improve petide synthesis has led to the development of less acidic and milder S_N2 deprotection conditions to remove benzyl protecting groups and to avoid reactive carbocations associated with the conventional S_N1 conditions.To further understand the relationships of both mechanisms and the acidity of the reaction, the S_N1 and S_N2 deprotection mechanisms for synthetic peptides with O-benzyl protecting groups were studied in a ternary mixture of trifluoromethanesulfonic acid (TFMSA)-trifluoroacetic acid (TFA)-dimethyl sulfide (DMS).Kinetic studies of the deprotection rate-acid profiles of O-benzylserine in sets of experiments containing predetermined amounts of DMS revealed sharp changeover points in the mechanism from S_N2 (A_AL2) to S_N1 (A_AL1) when the concentration of TFMSA in TFA was increased.Similar changeover points in mechanism were also found in the deprotection product-acid profiles of O-benzyltyrosine.The activities of DMS required for the S_N2 reaction were determined by (1)H NMR, and the acidities of the reaction media were calculated from the Yates-McClelland equation.The changeover points were found to be in the range where DMS activities were approaching zero.In general, the reaction mechanism depended on the activity of DMS and the acidity of the reaction mixture.The S_N1 deprotection mechanism predominated at high acidities and low DMS activities.S_N2 reaction mechanisms were observed at moderate acidities and high DMS activities.On the basis of the changeover points, a mechanism-reagent composition diagram could be constructed in the form of an equilateral triangle in which the S_N1 and S_N2 regions could be defined as a function of reagent composition.Furthermore, from the mechanistic considerations, a practical mixture for the S_N2 deprotection reaction was found to be TFMSA-TFA -DMS-m-cresol (10:50:30:10 (v/v)).For the deprotection of Trp(For)-containing peptides, the reagent was adjusted to TFMSA-TFA-DMS-m-cresol-ethanedithiol (10:50:30:8:2 v/v)) so that the Nⁱ-formyl could be removed concomitantly with other protecting groups.Both deprotection mixtures also converted Met(O) to Met efficiently.