Selective side chain introduction onto small peptides mediated by samariumdiiodide: A potential route to peptide libraries

A mild and simple method for the selective introduction of carbinol side ch ains onto glycine residues in peptides is presented as a potential route fo r the preparation of peptide libraries. A series of di- and tripeptides, as well as one tetrapeptide, each possessing one glycine residue, were first selectively functionalized at this amino acid unit by a two-step sequence i nvolving bromination with N-bromosuccinimide and then sulfide formation by treatment of the unstable glycyl bromide with 2-mercaptopyridine. These mod ified peptides were then reduced with samarium diiodide at room temperature in the presence of alkyl aldehydes and ketones, affording a series of pept ides in yields of 40-65% containing serine/threonine derivatives as new fun ctionalities. These reactions are quite efficient, considering the presence of as many as four amide protons in the enolate intermediate. The diastere oselectivities of these reactions are low or nonexistent, which is ascribed to either (a) the formation of single enolate, where the neighboring chira l centers impart no influence in the alkylation step or (b) the generation of an enolate mixture, where each stereoisomer leads to opposite enantiomer s with respect to the newly formed amino acid upon alkylation. The successf ul nonselective double alkylation of the tripeptide, Bz-Gly-Val-Gly-OMe, su ggests the possibility that the reductive samariation approach to the C-alk ylation of peptides may be a viable route for the preparation of peptide li braries based on multiple serine/threonine derivatives. Finally, a prelimin ary investigation on one peptide has shown that the addition of Ilo of nick el(II) iodide to these condensation reactions has a significant effect on t he coupling yields.