Solid-Phase Synthesis of Selectively Protected Peptides: Use of Thallous Alkoxide as Catalyst in the Transesterification Step

Transesterification with 2-dimethylaminoethanol, in the presence of thallous alkoxide, was found to provide a useful method for the cleavage of protected peptides from the Merrifield resin after solid-phase synthesis. The extent of racemization, at the C-terminal residue, was low (< 1%) in the case of peptides containing C-terminal alanine or valine residues. The method was also found to provide good yields of the protected peptide derivative even in the case of the severely sterically hindered C-terminal valine peptides. A study of the α → β aspartyl transpeptidation, showed that the extent of this side reaction was low (< 1% β-isomer) in the case of the labile α-aspartylglycine sequence, when a short transesterification time was employed. The t-butyl ester group was shown to be stable under the conditions of transesterification and this group is recommended for the protection of carboxylic acid side chains. Hydrolysis of the 2-dimethylaminoethyl esters was accomplished by treatment with water or dilute base, to yield the selectively protected peptide acids, suitable for use as building units in the synthesis of large molecules by solid-phase or solution techniques.